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Erschienen in: Calcified Tissue International 2/2018

27.10.2017 | Review

Bone-Targeted Therapies in Cancer-Induced Bone Disease

verfasst von: Sofia Sousa, Philippe Clézardin

Erschienen in: Calcified Tissue International | Ausgabe 2/2018

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Abstract

Cancer-induced bone disease is a major source of morbidity and mortality in cancer patients. Thus, effective bone-targeted therapies are essential to improve disease-free, overall survival and quality of life of cancer patients with bone metastases. Depending of the cancer-type, bone metastases mainly involve the modulation of osteoclast and/or osteoblast activity by tumour cells. To inhibit metastatic bone disease effectively, it is imperative to understand its underlying mechanisms and identify the target cells for therapy. If the aim is to prevent bone metastasis, it is essential to target not only bone metastatic features in the tumour cells, but also tumour-nurturing bone microenvironment properties. The currently available bone-targeted agents mainly affect osteoclasts, inhibiting bone resorption (e.g. bisphosphonates, denosumab). Some agents targeting osteoblasts begin to emerge which target osteoblasts (e.g. romosozumab), activating bone formation. Moreover, certain drugs initially thought to target only osteoclasts are now known to have a dual action (activating osteoblasts and inhibiting osteoclasts, e.g. proteasome inhibitors). This review will focus on the evolution of bone-targeted therapies for the treatment of cancer-induced bone disease, summarizing preclinical and clinical findings obtained with anti-resorptive and bone anabolic therapies.
Literatur
1.
Zurück zum Zitat Gerratana L, Fanotto V, Bonotto M, Bolzonello S, Minisini AM, Fasola G, Puglisi F (2015) Pattern of metastasis and outcome in patients with breast cancer. Clin Exp Metastasis 32:125–133PubMedCrossRef Gerratana L, Fanotto V, Bonotto M, Bolzonello S, Minisini AM, Fasola G, Puglisi F (2015) Pattern of metastasis and outcome in patients with breast cancer. Clin Exp Metastasis 32:125–133PubMedCrossRef
2.
Zurück zum Zitat Sternberg C, Baskin-Bey E, Watson M, Worsfold A, Rider A, Tombal B (2013) Treatment patterns and characteristics of European patients with castration-resistant prostate cancer. BMC Urol 13:58PubMedPubMedCentralCrossRef Sternberg C, Baskin-Bey E, Watson M, Worsfold A, Rider A, Tombal B (2013) Treatment patterns and characteristics of European patients with castration-resistant prostate cancer. BMC Urol 13:58PubMedPubMedCentralCrossRef
3.
Zurück zum Zitat Hoffmann NE, Gillett MD, Cheville JC, Lohse CM, Leibovich BC, Blute ML (2008) Differences in organ system of distant metastasis by renal cell carcinoma subtype. J Urol 179:474–477PubMedCrossRef Hoffmann NE, Gillett MD, Cheville JC, Lohse CM, Leibovich BC, Blute ML (2008) Differences in organ system of distant metastasis by renal cell carcinoma subtype. J Urol 179:474–477PubMedCrossRef
4.
Zurück zum Zitat Coleman RE (2001) Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27:165–176PubMedCrossRef Coleman RE (2001) Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27:165–176PubMedCrossRef
5.
Zurück zum Zitat Mirabello L, Troisi RJ, Savage SA (2009) International osteosarcoma incidence patterns in children and adolescents, middle ages, and elderly persons. Int J Cancer 125:229–234PubMedPubMedCentralCrossRef Mirabello L, Troisi RJ, Savage SA (2009) International osteosarcoma incidence patterns in children and adolescents, middle ages, and elderly persons. Int J Cancer 125:229–234PubMedPubMedCentralCrossRef
6.
Zurück zum Zitat Gnant M, Baselga J, Rugo HS, Noguchi S, Burris HA, Piccart M, Hortobagyi GN, Eakle J, Mukai H, Iwata H, Geberth M, Hart LL, Hadji P, El-Hashimy M, Rao S, Taran T, Sahmoud T, Lebwohl D, Campone M, Pritchard KI (2013) Effect of everolimus on bone marker levels and progressive disease in bone in BOLERO-2. J Natl Cancer Inst 105:654–663PubMedCrossRef Gnant M, Baselga J, Rugo HS, Noguchi S, Burris HA, Piccart M, Hortobagyi GN, Eakle J, Mukai H, Iwata H, Geberth M, Hart LL, Hadji P, El-Hashimy M, Rao S, Taran T, Sahmoud T, Lebwohl D, Campone M, Pritchard KI (2013) Effect of everolimus on bone marker levels and progressive disease in bone in BOLERO-2. J Natl Cancer Inst 105:654–663PubMedCrossRef
7.
Zurück zum Zitat Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827PubMedPubMedCentralCrossRef Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827PubMedPubMedCentralCrossRef
8.
Zurück zum Zitat Peinado H, Lavotshkin S, Lyden D (2011) The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 21:139–146PubMedCrossRef Peinado H, Lavotshkin S, Lyden D (2011) The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 21:139–146PubMedCrossRef
9.
Zurück zum Zitat Cox TR, Rumney RMH, Schoof EM, Perryman L, Høye AM, Agrawal A, Bird D, Latif NA, Forrest H, Evans HR, Huggins ID, Lang G, Linding R, Gartland A, Erler JT (2015) The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 522:106–110PubMedPubMedCentralCrossRef Cox TR, Rumney RMH, Schoof EM, Perryman L, Høye AM, Agrawal A, Bird D, Latif NA, Forrest H, Evans HR, Huggins ID, Lang G, Linding R, Gartland A, Erler JT (2015) The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 522:106–110PubMedPubMedCentralCrossRef
10.
Zurück zum Zitat González Á, García de Durango C, Alonso V, Bravo B, Rodríguez de Gortázar A, Wells A, Forteza J, Vidal-Vanaclocha F (2017) Distinct osteomimetic response of androgen-dependent and independent human prostate cancer cells to mechanical action of fluid flow: prometastatic implications. Prostate 77:321–333PubMedCrossRef González Á, García de Durango C, Alonso V, Bravo B, Rodríguez de Gortázar A, Wells A, Forteza J, Vidal-Vanaclocha F (2017) Distinct osteomimetic response of androgen-dependent and independent human prostate cancer cells to mechanical action of fluid flow: prometastatic implications. Prostate 77:321–333PubMedCrossRef
11.
Zurück zum Zitat Tan C, Li G, Tan L, Du X, Li X, He R, Wang Q, Feng Y (2016) Breast cancer cells obtain an osteomimetic feature via epithelial-mesenchymal transition that have undergone BMP2/RUNX2 signaling pathway induction. Oncotarget 7:79688–79705PubMedPubMedCentral Tan C, Li G, Tan L, Du X, Li X, He R, Wang Q, Feng Y (2016) Breast cancer cells obtain an osteomimetic feature via epithelial-mesenchymal transition that have undergone BMP2/RUNX2 signaling pathway induction. Oncotarget 7:79688–79705PubMedPubMedCentral
12.
Zurück zum Zitat Guise TA (2002) The vicious cycle of bone metastases. J Musculoskelet Neuronal Interact 2:570–572PubMed Guise TA (2002) The vicious cycle of bone metastases. J Musculoskelet Neuronal Interact 2:570–572PubMed
13.
Zurück zum Zitat Plotkin LI, Bivi N, Bellido T (2011) A bisphosphonate that does not affect osteoclasts prevents osteoblast and osteocyte apoptosis and the loss of bone strength induced by glucocorticoids in mice. Bone 49:122–127PubMedCrossRef Plotkin LI, Bivi N, Bellido T (2011) A bisphosphonate that does not affect osteoclasts prevents osteoblast and osteocyte apoptosis and the loss of bone strength induced by glucocorticoids in mice. Bone 49:122–127PubMedCrossRef
14.
Zurück zum Zitat Plotkin LI, Manolagas SC, Bellido T (2006) Dissociation of the pro-apoptotic effects of bisphosphonates on osteoclasts from their anti-apoptotic effects on osteoblasts/osteocytes with novel analogs. Bone 39:443–452PubMedCrossRef Plotkin LI, Manolagas SC, Bellido T (2006) Dissociation of the pro-apoptotic effects of bisphosphonates on osteoclasts from their anti-apoptotic effects on osteoblasts/osteocytes with novel analogs. Bone 39:443–452PubMedCrossRef
15.
Zurück zum Zitat Rogers MJ, Crockett JC, Coxon FP, Mönkkönen J (2011) Biochemical and molecular mechanisms of action of bisphosphonates. Bone 49:34–41PubMedCrossRef Rogers MJ, Crockett JC, Coxon FP, Mönkkönen J (2011) Biochemical and molecular mechanisms of action of bisphosphonates. Bone 49:34–41PubMedCrossRef
16.
Zurück zum Zitat Mönkkönen H, Auriola S, Lehenkari P, Kellinsalmi M, Hassinen IE, Vepsäläinen J, Mönkkönen J (2006) A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates. Br J Pharmacol 147:437–445PubMedPubMedCentralCrossRef Mönkkönen H, Auriola S, Lehenkari P, Kellinsalmi M, Hassinen IE, Vepsäläinen J, Mönkkönen J (2006) A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates. Br J Pharmacol 147:437–445PubMedPubMedCentralCrossRef
17.
Zurück zum Zitat Daubiné F, Le Gall C, Gasser J, Green J, Clézardin P (2007) Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst 99:322–330PubMedCrossRef Daubiné F, Le Gall C, Gasser J, Green J, Clézardin P (2007) Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst 99:322–330PubMedCrossRef
18.
Zurück zum Zitat Van Der Pluijm G, Vloedgraven H, van Beek E, van der Wee-Pals L, Löwik C, Papapoulos S (1996) Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. J Clin Invest 98:698–705PubMedPubMedCentralCrossRef Van Der Pluijm G, Vloedgraven H, van Beek E, van der Wee-Pals L, Löwik C, Papapoulos S (1996) Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. J Clin Invest 98:698–705PubMedPubMedCentralCrossRef
19.
Zurück zum Zitat Hiraga T, Williams PJ, Mundy GR, Yoneda T (2001) The bisphosphonate ibandronate promotes apoptosis in MDA-MB-231 human breast cancer cells in bone metastases. Cancer Res 61:4418–4424PubMed Hiraga T, Williams PJ, Mundy GR, Yoneda T (2001) The bisphosphonate ibandronate promotes apoptosis in MDA-MB-231 human breast cancer cells in bone metastases. Cancer Res 61:4418–4424PubMed
20.
Zurück zum Zitat Yuen T, Stachnik A, Iqbal J, Sgobba M, Gupta Y, Lu P, Colaianni G, Ji Y, Zhu L-, Kim S-, Li J, Liu P, Izadmehr S, Sangodkar J, Bailey J, Latif Y, Mujtaba S, Epstein S, Davies TF, Bian Z, Zallone A, Aggarwal AK, Haider S, New MI, Sun L, Narla G, Zaidi M (2014) Bisphosphonates inactivate human EGFRs to exert antitumor actions. Proc Natl Acad Sci USA 111:17989–17994PubMedPubMedCentralCrossRef Yuen T, Stachnik A, Iqbal J, Sgobba M, Gupta Y, Lu P, Colaianni G, Ji Y, Zhu L-, Kim S-, Li J, Liu P, Izadmehr S, Sangodkar J, Bailey J, Latif Y, Mujtaba S, Epstein S, Davies TF, Bian Z, Zallone A, Aggarwal AK, Haider S, New MI, Sun L, Narla G, Zaidi M (2014) Bisphosphonates inactivate human EGFRs to exert antitumor actions. Proc Natl Acad Sci USA 111:17989–17994PubMedPubMedCentralCrossRef
21.
Zurück zum Zitat Räikkönen J, Mönkkönen H, Auriola S, Mönkkönen J (2010) Mevalonate pathway intermediates downregulate zoledronic acid-induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells. Biochem Pharmacol 79:777–783PubMedCrossRef Räikkönen J, Mönkkönen H, Auriola S, Mönkkönen J (2010) Mevalonate pathway intermediates downregulate zoledronic acid-induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells. Biochem Pharmacol 79:777–783PubMedCrossRef
22.
Zurück zum Zitat Ory B, Blanchard F, Battaglia S, Gouin F, Redini F, Heymann D (2007) Zoledronic acid activates the DNA S-phase checkpoint and induces osteosarcoma cell death characterized by apoptosis-inducing factor and endonuclease-G translocation independently of p53 and retinoblastoma status. Mol Pharmacol 71:333–343PubMedCrossRef Ory B, Blanchard F, Battaglia S, Gouin F, Redini F, Heymann D (2007) Zoledronic acid activates the DNA S-phase checkpoint and induces osteosarcoma cell death characterized by apoptosis-inducing factor and endonuclease-G translocation independently of p53 and retinoblastoma status. Mol Pharmacol 71:333–343PubMedCrossRef
23.
Zurück zum Zitat Brown HK, Ottewell PD, Evans CA, Coleman RE, Holen I (2012) A single administration of combination therapy inhibits breast tumour progression in bone and modifies both osteoblasts and osteoclasts. J Bone Oncol 1:47–56PubMedPubMedCentralCrossRef Brown HK, Ottewell PD, Evans CA, Coleman RE, Holen I (2012) A single administration of combination therapy inhibits breast tumour progression in bone and modifies both osteoblasts and osteoclasts. J Bone Oncol 1:47–56PubMedPubMedCentralCrossRef
24.
Zurück zum Zitat Coscia M, Quaglino E, Iezzi M, Curcio C, Pantaleoni F, Riganti C, Holen I, Mönkkönen H, Boccadoro M, Forni G, Musiani P, Bosia A, Cavallo F, Massaia M (2010) Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway. J Cell Mol Med 14:2803–2815PubMedCrossRef Coscia M, Quaglino E, Iezzi M, Curcio C, Pantaleoni F, Riganti C, Holen I, Mönkkönen H, Boccadoro M, Forni G, Musiani P, Bosia A, Cavallo F, Massaia M (2010) Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway. J Cell Mol Med 14:2803–2815PubMedCrossRef
25.
Zurück zum Zitat Melani C, Sangaletti S, Barazzetta FM, Werb Z, Colombo MP (2007) Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma. Cancer Res 67:11438–11446PubMedPubMedCentralCrossRef Melani C, Sangaletti S, Barazzetta FM, Werb Z, Colombo MP (2007) Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma. Cancer Res 67:11438–11446PubMedPubMedCentralCrossRef
26.
Zurück zum Zitat Junankar S, Shay G, Jurczyluk J, Ali N, Down J, Pocock N, Parker A, Nguyen A, Sun S, Kashemirov B, McKenna CE, Croucher PI, Swarbrick A, Weilbaecher K, Phan TG, Rogers MJ (2015) Real-time intravital imaging establishes tumor-associated Macrophages as the extraskeletal target of bisphosphonate action in cancer. Cancer Discov 5:35–42PubMedCrossRef Junankar S, Shay G, Jurczyluk J, Ali N, Down J, Pocock N, Parker A, Nguyen A, Sun S, Kashemirov B, McKenna CE, Croucher PI, Swarbrick A, Weilbaecher K, Phan TG, Rogers MJ (2015) Real-time intravital imaging establishes tumor-associated Macrophages as the extraskeletal target of bisphosphonate action in cancer. Cancer Discov 5:35–42PubMedCrossRef
27.
Zurück zum Zitat Kalyan S, Chandrasekaran V, Quabius ES, Lindhorst TK, Kabelitz D (2014) Neutrophil uptake of nitrogen-bisphosphonates leads to the suppression of human peripheral blood γδ T cells. Cell Mol Life Sci 71:2335–2346PubMedCrossRef Kalyan S, Chandrasekaran V, Quabius ES, Lindhorst TK, Kabelitz D (2014) Neutrophil uptake of nitrogen-bisphosphonates leads to the suppression of human peripheral blood γδ T cells. Cell Mol Life Sci 71:2335–2346PubMedCrossRef
28.
Zurück zum Zitat Hewitt RE, Lissina A, Green AE, Slay ES, Price DA, Sewell AK (2005) The bisphosphonate acute phase response: rapid and copious production of proinflammatory cytokines by peripheral blood γδ T cells in response to aminobisphosphonates is inhibited by statins. Clin Exp Immunol 139:101–111PubMedPubMedCentralCrossRef Hewitt RE, Lissina A, Green AE, Slay ES, Price DA, Sewell AK (2005) The bisphosphonate acute phase response: rapid and copious production of proinflammatory cytokines by peripheral blood γδ T cells in response to aminobisphosphonates is inhibited by statins. Clin Exp Immunol 139:101–111PubMedPubMedCentralCrossRef
29.
Zurück zum Zitat Cabillic F, Toutirais O, Lavoué V, De La Pintière CT, Daniel P, Rioux-Leclerc N, Turlin B, Mönkkönen H, Mönkkönen J, Boudjema K, Catros V, Bouet-Toussaint F (2010) Aminobisphosphonate-pretreated dendritic cells trigger successful Vγ9Vδ2 T cell amplification for immunotherapy in advanced cancer patients. Cancer Immunol Immunother 59:1611–1619PubMedCrossRef Cabillic F, Toutirais O, Lavoué V, De La Pintière CT, Daniel P, Rioux-Leclerc N, Turlin B, Mönkkönen H, Mönkkönen J, Boudjema K, Catros V, Bouet-Toussaint F (2010) Aminobisphosphonate-pretreated dendritic cells trigger successful Vγ9Vδ2 T cell amplification for immunotherapy in advanced cancer patients. Cancer Immunol Immunother 59:1611–1619PubMedCrossRef
30.
Zurück zum Zitat Gutman D, Epstein-Barash H, Tsuriel M, Golomb G (2011) Alendronate liposomes for antitumor therapy: activation of γδ T cells and inhibition of tumor growth. Adv Exp Med Biol 733:165–179CrossRef Gutman D, Epstein-Barash H, Tsuriel M, Golomb G (2011) Alendronate liposomes for antitumor therapy: activation of γδ T cells and inhibition of tumor growth. Adv Exp Med Biol 733:165–179CrossRef
31.
Zurück zum Zitat Benzaïd I, Mönkkönen H, Stresing V, Bonnelye E, Green J, Mönkkönen J, Touraine JL, Clézardin P (2011) High phosphoantigen levels in bisphosphonate-treated human breast tumors promote Vγ9Vδ2 T-cell chemotaxis and cytotoxicity in vivo. Cancer Res 71:4562–4572PubMedCrossRef Benzaïd I, Mönkkönen H, Stresing V, Bonnelye E, Green J, Mönkkönen J, Touraine JL, Clézardin P (2011) High phosphoantigen levels in bisphosphonate-treated human breast tumors promote Vγ9Vδ2 T-cell chemotaxis and cytotoxicity in vivo. Cancer Res 71:4562–4572PubMedCrossRef
32.
Zurück zum Zitat Haider MT, Hunter KD, Robinson SP, Graham TJ, Corey E, Dear TN, Hughes R, Brown NJ, Holen I (2015) Rapid modification of the bone microenvironment following short-term treatment with Cabozantinib in vivo. Bone 81:581–592PubMedPubMedCentralCrossRef Haider MT, Hunter KD, Robinson SP, Graham TJ, Corey E, Dear TN, Hughes R, Brown NJ, Holen I (2015) Rapid modification of the bone microenvironment following short-term treatment with Cabozantinib in vivo. Bone 81:581–592PubMedPubMedCentralCrossRef
34.
Zurück zum Zitat Ottewell PD, Wang N, Brown HK, Reeves KJ, Fowles CA, Croucher PI, Eaton CL, Holen I (2014) Zoledronic acid has differential antitumor activity in the pre- and postmenopausal bone microenvironment in vivo. Clin Cancer Res 20:2922–2932PubMedPubMedCentralCrossRef Ottewell PD, Wang N, Brown HK, Reeves KJ, Fowles CA, Croucher PI, Eaton CL, Holen I (2014) Zoledronic acid has differential antitumor activity in the pre- and postmenopausal bone microenvironment in vivo. Clin Cancer Res 20:2922–2932PubMedPubMedCentralCrossRef
35.
Zurück zum Zitat Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2015) Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 386:1353–1361CrossRef Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2015) Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 386:1353–1361CrossRef
36.
Zurück zum Zitat Winter MC, Wilson C, Syddall SP, Cross SS, Evans A, Ingram CE, Jolley IJ, Hatton MQ, Freeman JV, Mori S, Holen I, Coleman RE (2013) Neoadjuvant chemotherapy with or without zoledronic acid in early breast cancer-a randomized biomarker pilot study. Clin Cancer Res 19:2755–2765PubMedCrossRef Winter MC, Wilson C, Syddall SP, Cross SS, Evans A, Ingram CE, Jolley IJ, Hatton MQ, Freeman JV, Mori S, Holen I, Coleman RE (2013) Neoadjuvant chemotherapy with or without zoledronic acid in early breast cancer-a randomized biomarker pilot study. Clin Cancer Res 19:2755–2765PubMedCrossRef
37.
Zurück zum Zitat Foroni C, Milan M, Strina C, Cappelletti M, Fumarola C, Bonelli M, Bertoni R, Ferrero G, Maldotti M, Takano E, Andreis D, Venturini S, Brugnoli G, Petronini PG, Zanoni V, Pritzker L, Pritzker K, Parissenti A, Santini D, Fox SB, Bottini A, Generali D (2014) Pure anti-tumor effect of zoledronic acid in naïve bone-only metastatic and locally advanced breast cancer: proof from the “biological window therapy”. Breast Cancer Res Treat 144:113–121PubMedCrossRef Foroni C, Milan M, Strina C, Cappelletti M, Fumarola C, Bonelli M, Bertoni R, Ferrero G, Maldotti M, Takano E, Andreis D, Venturini S, Brugnoli G, Petronini PG, Zanoni V, Pritzker L, Pritzker K, Parissenti A, Santini D, Fox SB, Bottini A, Generali D (2014) Pure anti-tumor effect of zoledronic acid in naïve bone-only metastatic and locally advanced breast cancer: proof from the “biological window therapy”. Breast Cancer Res Treat 144:113–121PubMedCrossRef
38.
Zurück zum Zitat Santini D, Zoccoli A, Gregorj C, Di Cerbo M, Iuliani M, Pantano F, Zamarchi R, Sergi F, Flammia G, Buscarini M, Rizzo S, Cicero G, Russo A, Vincenzi B, Avvisati G, Tonini G (2013) Zoledronic acid induces a significant decrease of circulating endothelial cells and circulating endothelial precursor cells in the early prostate cancer neoadjuvant setting. Oncology 85:342–347PubMedCrossRef Santini D, Zoccoli A, Gregorj C, Di Cerbo M, Iuliani M, Pantano F, Zamarchi R, Sergi F, Flammia G, Buscarini M, Rizzo S, Cicero G, Russo A, Vincenzi B, Avvisati G, Tonini G (2013) Zoledronic acid induces a significant decrease of circulating endothelial cells and circulating endothelial precursor cells in the early prostate cancer neoadjuvant setting. Oncology 85:342–347PubMedCrossRef
39.
Zurück zum Zitat Kroep JR, Charehbili A, Coleman RE, Aft RL, Hasegawa Y, Winter MC, Weilbaecher K, Akazawa K, Hinsley S, Putter H, Liefers GJ, Nortier JWR, Kohno N (2016) Effects of neoadjuvant chemotherapy with or without zoledronic acid on pathological response: a meta-analysis of randomised trials. Eur J Cancer 54:57–63PubMedCrossRef Kroep JR, Charehbili A, Coleman RE, Aft RL, Hasegawa Y, Winter MC, Weilbaecher K, Akazawa K, Hinsley S, Putter H, Liefers GJ, Nortier JWR, Kohno N (2016) Effects of neoadjuvant chemotherapy with or without zoledronic acid on pathological response: a meta-analysis of randomised trials. Eur J Cancer 54:57–63PubMedCrossRef
40.
Zurück zum Zitat Paterson AHG, Anderson SJ, Lembersky BC, Fehrenbacher L, Falkson CI, King KM, Weir LM, Brufsky AM, Dakhil S, Lad T, Baez-Diaz L, Gralow JR, Robidoux A, Perez EA, Zheng P, Geyer CE, Swain SM, Costantino JP, Mamounas EP, Wolmark N (2012) Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial. Lancet Oncol 13:734–742PubMedPubMedCentralCrossRef Paterson AHG, Anderson SJ, Lembersky BC, Fehrenbacher L, Falkson CI, King KM, Weir LM, Brufsky AM, Dakhil S, Lad T, Baez-Diaz L, Gralow JR, Robidoux A, Perez EA, Zheng P, Geyer CE, Swain SM, Costantino JP, Mamounas EP, Wolmark N (2012) Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial. Lancet Oncol 13:734–742PubMedPubMedCentralCrossRef
41.
Zurück zum Zitat Brufsky AM, Harker WG, Beck JT, Bosserman L, Vogel C, Seidler C, Jin L, Warsi G, Argonza-Aviles E, Hohneker J, Ericson SG, Perez EA (2012) Final 5-year results of Z-FAST trial: adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole. Cancer 118:1192–1201PubMedCrossRef Brufsky AM, Harker WG, Beck JT, Bosserman L, Vogel C, Seidler C, Jin L, Warsi G, Argonza-Aviles E, Hohneker J, Ericson SG, Perez EA (2012) Final 5-year results of Z-FAST trial: adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole. Cancer 118:1192–1201PubMedCrossRef
42.
Zurück zum Zitat Coleman R, De Boer R, Eidtmann H, Llombart A, Davidson N, Neven P, Von Minckwitz G, Sleeboom HP, Forbes J, Barrios C, Frassoldati A, Campbell I, Paija O, Martin N, Modi A, Bundred N (2013) Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol 24:398–405PubMedCrossRef Coleman R, De Boer R, Eidtmann H, Llombart A, Davidson N, Neven P, Von Minckwitz G, Sleeboom HP, Forbes J, Barrios C, Frassoldati A, Campbell I, Paija O, Martin N, Modi A, Bundred N (2013) Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol 24:398–405PubMedCrossRef
43.
Zurück zum Zitat Coleman R, Cameron D, Dodwell D, Bell R, Wilson C, Rathbone E, Keane M, Gil M, Burkinshaw R, Grieve R, Barrett-Lee P, Ritchie D, Liversedge V, Hinsley S, Marshall H (2014) Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. Lancet Oncol 15:997–1006PubMedCrossRef Coleman R, Cameron D, Dodwell D, Bell R, Wilson C, Rathbone E, Keane M, Gil M, Burkinshaw R, Grieve R, Barrett-Lee P, Ritchie D, Liversedge V, Hinsley S, Marshall H (2014) Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. Lancet Oncol 15:997–1006PubMedCrossRef
44.
Zurück zum Zitat Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Knauer M, Moik M, Jakesz R, Seifert M, Taucher S, Bjelic-Radisic V, Balic M, Eidtmann H, Eiermann W, Steger G, Kwasny W, Dubsky P, Selim U, Fitzal F, Hochreiner G, Wette V, Sevelda P, Ploner F, Bartsch R, Fesl C, Greil R (2015) Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol 26:313–320PubMedCrossRef Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Knauer M, Moik M, Jakesz R, Seifert M, Taucher S, Bjelic-Radisic V, Balic M, Eidtmann H, Eiermann W, Steger G, Kwasny W, Dubsky P, Selim U, Fitzal F, Hochreiner G, Wette V, Sevelda P, Ploner F, Bartsch R, Fesl C, Greil R (2015) Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol 26:313–320PubMedCrossRef
45.
Zurück zum Zitat Rodrigues P, Hering FO, Meller A (2011) Adjuvant effect of IV clodronate on the delay of bone metastasis in high-risk prostate cancer patients: a prospective study. Cancer Res Treat 43:231–235PubMedPubMedCentralCrossRef Rodrigues P, Hering FO, Meller A (2011) Adjuvant effect of IV clodronate on the delay of bone metastasis in high-risk prostate cancer patients: a prospective study. Cancer Res Treat 43:231–235PubMedPubMedCentralCrossRef
46.
Zurück zum Zitat Dearnaley DP, Mason MD, Parmar MK, Sanders K, Sydes MR (2009) Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol 10:872–876PubMedPubMedCentralCrossRef Dearnaley DP, Mason MD, Parmar MK, Sanders K, Sydes MR (2009) Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol 10:872–876PubMedPubMedCentralCrossRef
47.
Zurück zum Zitat Denham JW, Nowitz M, Joseph D, Duchesne G, Spry NA, Lamb DS, Matthews J, Turner S, Atkinson C, Tai KH, Gogna NK, Kenny L, Diamond T, Smart R, Rowan D, Moscato P, Vimieiro R, Woodfield R, Lynch K, Delahunt B, Murray J, D’Este C, McElduff P, Steigler A, Kautto A, Ball J (2014) Impact of androgen suppression and zoledronic acid on bone mineral density and fractures in the Trans-Tasman Radiation Oncology Group (TROG) 03.04 Randomised Androgen Deprivation and Radiotherapy (RADAR) randomized controlled trial for locally advanced prostate cancer. BJU Int 114:344–353PubMed Denham JW, Nowitz M, Joseph D, Duchesne G, Spry NA, Lamb DS, Matthews J, Turner S, Atkinson C, Tai KH, Gogna NK, Kenny L, Diamond T, Smart R, Rowan D, Moscato P, Vimieiro R, Woodfield R, Lynch K, Delahunt B, Murray J, D’Este C, McElduff P, Steigler A, Kautto A, Ball J (2014) Impact of androgen suppression and zoledronic acid on bone mineral density and fractures in the Trans-Tasman Radiation Oncology Group (TROG) 03.04 Randomised Androgen Deprivation and Radiotherapy (RADAR) randomized controlled trial for locally advanced prostate cancer. BJU Int 114:344–353PubMed
48.
Zurück zum Zitat Wirth M, Tammela T, Cicalese V, Gomez Veiga F, Delaere K, Miller K, Tubaro A, Schulze M, Debruyne F, Huland H, Patel A, Lecouvet F, Caris C, Witjes W (2015) Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and Safety Results of the Zometa European Study (ZEUS). Eur Urol 67:482–491PubMedCrossRef Wirth M, Tammela T, Cicalese V, Gomez Veiga F, Delaere K, Miller K, Tubaro A, Schulze M, Debruyne F, Huland H, Patel A, Lecouvet F, Caris C, Witjes W (2015) Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and Safety Results of the Zometa European Study (ZEUS). Eur Urol 67:482–491PubMedCrossRef
49.
Zurück zum Zitat James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, Ritchie AWS, Parker CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, Chowdhury S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hetherington J, Hughes R, Laing R, McKinna F, McLaren DB, O’Sullivan JM, Parikh O, Peedell C, Protheroe A, Robinson AJ, Srihari N, Srinivasan R, Staffurth J, Sundar S, Tolan S, Tsang D, Wagstaff J, Parmar MKB (2016) Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 387:1163–1177PubMedPubMedCentralCrossRef James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, Ritchie AWS, Parker CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, Chowdhury S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hetherington J, Hughes R, Laing R, McKinna F, McLaren DB, O’Sullivan JM, Parikh O, Peedell C, Protheroe A, Robinson AJ, Srihari N, Srinivasan R, Staffurth J, Sundar S, Tolan S, Tsang D, Wagstaff J, Parmar MKB (2016) Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 387:1163–1177PubMedPubMedCentralCrossRef
50.
Zurück zum Zitat Reyes C, Hitz M, Prieto-Alhambra D, Abrahamsen B (2015) Risks and benefits of bisphosphonate therapies. J Cell Biochem 117:20–28CrossRef Reyes C, Hitz M, Prieto-Alhambra D, Abrahamsen B (2015) Risks and benefits of bisphosphonate therapies. J Cell Biochem 117:20–28CrossRef
51.
Zurück zum Zitat Cole LE, Vargo-Gogola T, Roeder RK (2016) Targeted delivery to bone and mineral deposits using bisphosphonate ligands. Adv Drug Deliv Rev 99:12–27PubMedCrossRef Cole LE, Vargo-Gogola T, Roeder RK (2016) Targeted delivery to bone and mineral deposits using bisphosphonate ligands. Adv Drug Deliv Rev 99:12–27PubMedCrossRef
52.
Zurück zum Zitat Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, Morony S, Rubin E, Sarao R, Hojilla CV, Komnenovic V, Kong YY, Schreiber M, Dixon SJ, Sims SM, Khokha R, Wada T, Penninger JM (2006) Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440:692–696PubMedCrossRef Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, Morony S, Rubin E, Sarao R, Hojilla CV, Komnenovic V, Kong YY, Schreiber M, Dixon SJ, Sims SM, Khokha R, Wada T, Penninger JM (2006) Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440:692–696PubMedCrossRef
53.
Zurück zum Zitat Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer M, Erwert R, Pinkas J, Branstetter D, Dougall WC (2010) RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468:103–107PubMedCrossRef Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer M, Erwert R, Pinkas J, Branstetter D, Dougall WC (2010) RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468:103–107PubMedCrossRef
54.
Zurück zum Zitat Leibbrandt A, Penninger JM (2008) RANK/RANKL: regulators of immune responses and bone physiology. Ann N Y Acad Sci 1143:123–150PubMedCrossRef Leibbrandt A, Penninger JM (2008) RANK/RANKL: regulators of immune responses and bone physiology. Ann N Y Acad Sci 1143:123–150PubMedCrossRef
55.
Zurück zum Zitat Pfitzner BM, Branstetter D, Loibl S, Denkert C, Lederer B, Schmitt WD, Dombrowski F, Werner M, Rüdiger T, Dougall WC, Von Minckwitz G (2014) RANK expression as a prognostic and predictive marker in breast cancer. Breast Cancer Res Treat 145:307–315PubMedCrossRef Pfitzner BM, Branstetter D, Loibl S, Denkert C, Lederer B, Schmitt WD, Dombrowski F, Werner M, Rüdiger T, Dougall WC, Von Minckwitz G (2014) RANK expression as a prognostic and predictive marker in breast cancer. Breast Cancer Res Treat 145:307–315PubMedCrossRef
56.
Zurück zum Zitat Kostenuik PJ, Smith SY, Jolette J, Schroeder J, Pyrah I, Ominsky MS (2011) Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody. Bone 49:151–161PubMedCrossRef Kostenuik PJ, Smith SY, Jolette J, Schroeder J, Pyrah I, Ominsky MS (2011) Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody. Bone 49:151–161PubMedCrossRef
57.
Zurück zum Zitat Ominsky MS, Stouch B, Schroeder J, Pyrah I, Stolina M, Smith SY, Kostenuik PJ (2011) Denosumab, a fully human RANKL antibody, reduced bone turnover markers and increased trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys. Bone 49:162–173PubMedCrossRef Ominsky MS, Stouch B, Schroeder J, Pyrah I, Stolina M, Smith SY, Kostenuik PJ (2011) Denosumab, a fully human RANKL antibody, reduced bone turnover markers and increased trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys. Bone 49:162–173PubMedCrossRef
58.
Zurück zum Zitat Kostenuik PJ, Nguyen HQ, McCabe J, Warmington KS, Kurahara C, Sun N, Chen C, Li L, Cattley RC, Van G, Scully S, Elliott R, Grisanti M, Morony S, Tan HL, Asuncion F, Li X, Ominsky MS, Stolina M, Dwyer D, Dougall WC, Hawkins N, Boyle WJ, Simonet WS, Sullivan JK (2009) Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J Bone Miner Res 24:182–195PubMedCrossRef Kostenuik PJ, Nguyen HQ, McCabe J, Warmington KS, Kurahara C, Sun N, Chen C, Li L, Cattley RC, Van G, Scully S, Elliott R, Grisanti M, Morony S, Tan HL, Asuncion F, Li X, Ominsky MS, Stolina M, Dwyer D, Dougall WC, Hawkins N, Boyle WJ, Simonet WS, Sullivan JK (2009) Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J Bone Miner Res 24:182–195PubMedCrossRef
59.
Zurück zum Zitat Rinotas V, Niti A, Dacquin R, Bonnet N, Stolina M, Han CY, Kostenuik P, Jurdic P, Ferrari S, Douni E (2014) Novel genetic models of osteoporosis by overexpression of human RANKL in transgenic mice. J Bone Miner Res 29:1158–1169PubMedCrossRef Rinotas V, Niti A, Dacquin R, Bonnet N, Stolina M, Han CY, Kostenuik P, Jurdic P, Ferrari S, Douni E (2014) Novel genetic models of osteoporosis by overexpression of human RANKL in transgenic mice. J Bone Miner Res 29:1158–1169PubMedCrossRef
60.
Zurück zum Zitat Canon J, Bryant R, Roudier M, Branstetter DG, Dougall WC (2012) RANKL inhibition combined with tamoxifen treatment increases anti-tumor efficacy and prevents tumor-induced bone destruction in an estrogen receptor-positive breast cancer bone metastasis model. Breast Cancer Res Treat 135:771–780PubMedCrossRef Canon J, Bryant R, Roudier M, Branstetter DG, Dougall WC (2012) RANKL inhibition combined with tamoxifen treatment increases anti-tumor efficacy and prevents tumor-induced bone destruction in an estrogen receptor-positive breast cancer bone metastasis model. Breast Cancer Res Treat 135:771–780PubMedCrossRef
61.
Zurück zum Zitat Ottewell PD, Wang N, Brown HK, Fowles CA, Croucher PI, Eaton CL, Holen I (2015) OPG-Fc inhibits ovariectomy-induced growth of disseminated breast cancer cells in bone. Int J Cancer 137:968–977PubMedCrossRef Ottewell PD, Wang N, Brown HK, Fowles CA, Croucher PI, Eaton CL, Holen I (2015) OPG-Fc inhibits ovariectomy-induced growth of disseminated breast cancer cells in bone. Int J Cancer 137:968–977PubMedCrossRef
62.
Zurück zum Zitat Canon JR, Bryant R, Roudier M, Dougall WC (2013) Abstract 3947: AMG 161, a fully human monoclonal antibody to human RANKL, inhibits tumor-induced osteoclastogenesis and reduces skeletal tumor burden in mice that express chimeric (murine/human) RANKL. Cancer Res 73:3947CrossRef Canon JR, Bryant R, Roudier M, Dougall WC (2013) Abstract 3947: AMG 161, a fully human monoclonal antibody to human RANKL, inhibits tumor-induced osteoclastogenesis and reduces skeletal tumor burden in mice that express chimeric (murine/human) RANKL. Cancer Res 73:3947CrossRef
63.
Zurück zum Zitat Body JJ, Facon T, Coleman RE, Lipton A, Geurs F, Fan M, Holloway D, Peterson MC, Bekker PJ (2006) A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res 12:1221–1228PubMedCrossRef Body JJ, Facon T, Coleman RE, Lipton A, Geurs F, Fan M, Holloway D, Peterson MC, Bekker PJ (2006) A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res 12:1221–1228PubMedCrossRef
64.
Zurück zum Zitat Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti GV, Sleeboom H, Spencer A, Vadhan-Raj S, Von Moos R, Willenbacher W, Woll PJ, Wang J, Jiang Q, Jun S, Dansey R, Yeh H (2011) Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 29:1125–1132PubMedCrossRef Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti GV, Sleeboom H, Spencer A, Vadhan-Raj S, Von Moos R, Willenbacher W, Woll PJ, Wang J, Jiang Q, Jun S, Dansey R, Yeh H (2011) Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 29:1125–1132PubMedCrossRef
65.
Zurück zum Zitat Raje N, Vadhan-Raj S, Willenbacher W, Terpos E, Hungria V, Spencer A, Alexeeva Y, Facon T, Stewart AK, Feng A, Braun A, Balakumaran A, Roodman GD (2016) Evaluating results from the multiple myeloma patient subset treated with denosumab or zoledronic acid in a randomized phase 3 trial. Blood Cancer J 6:e378PubMedPubMedCentralCrossRef Raje N, Vadhan-Raj S, Willenbacher W, Terpos E, Hungria V, Spencer A, Alexeeva Y, Facon T, Stewart AK, Feng A, Braun A, Balakumaran A, Roodman GD (2016) Evaluating results from the multiple myeloma patient subset treated with denosumab or zoledronic acid in a randomized phase 3 trial. Blood Cancer J 6:e378PubMedPubMedCentralCrossRef
66.
Zurück zum Zitat Lipton A, Steger GG, Figueroa J, Alvarado C, Solal-Celigny P, Body JJ, de Boer R, Berardi R, Gascon P, Tonkin KS, Coleman RE, Paterson AHG, Gao GM, Kinsey AC, Peterson MC, Jun S (2008) Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy. Clin Cancer Res 14:6690–6696PubMedCrossRef Lipton A, Steger GG, Figueroa J, Alvarado C, Solal-Celigny P, Body JJ, de Boer R, Berardi R, Gascon P, Tonkin KS, Coleman RE, Paterson AHG, Gao GM, Kinsey AC, Peterson MC, Jun S (2008) Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy. Clin Cancer Res 14:6690–6696PubMedCrossRef
67.
Zurück zum Zitat Stopeck AT, Lipton A, Body J-, Steger GG, Tonkin K, De Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A (2010) Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 28:5132–5139PubMedCrossRef Stopeck AT, Lipton A, Body J-, Steger GG, Tonkin K, De Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A (2010) Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 28:5132–5139PubMedCrossRef
68.
Zurück zum Zitat Stopeck AT, Fizazi K, Body J-, Brown JE, Carducci M, Diel I, Fujiwara Y, Martín M, Paterson A, Tonkin K, Shore N, Sieber P, Kueppers F, Karsh L, Yardley D, Wang H, Maniar T, Arellano J, Braun A (2016) Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer. Support Care Cancer 24:447–455PubMedCrossRef Stopeck AT, Fizazi K, Body J-, Brown JE, Carducci M, Diel I, Fujiwara Y, Martín M, Paterson A, Tonkin K, Shore N, Sieber P, Kueppers F, Karsh L, Yardley D, Wang H, Maniar T, Arellano J, Braun A (2016) Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer. Support Care Cancer 24:447–455PubMedCrossRef
69.
Zurück zum Zitat Lipton A, Fizazi K, Stopeck AT, Henry DH, Smith MR, Shore N, Martin M, Vadhan-Raj S, Brown JE, Richardson GE, Saad F, Yardley DA, Zhou K, Balakumaran A, Braun A (2016) Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics. Eur J Cancer 53:75–83PubMedCrossRef Lipton A, Fizazi K, Stopeck AT, Henry DH, Smith MR, Shore N, Martin M, Vadhan-Raj S, Brown JE, Richardson GE, Saad F, Yardley DA, Zhou K, Balakumaran A, Braun A (2016) Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics. Eur J Cancer 53:75–83PubMedCrossRef
70.
Zurück zum Zitat Fizazi K, Lipton A, Mariette X, Body J, Rahim Y, Gralow JR, Gao G, Wu L, Sohn W, Jun S (2009) Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 27:1564–1571PubMedCrossRef Fizazi K, Lipton A, Mariette X, Body J, Rahim Y, Gralow JR, Gao G, Wu L, Sohn W, Jun S (2009) Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 27:1564–1571PubMedCrossRef
71.
Zurück zum Zitat Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C (2011) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377:813–822PubMedPubMedCentralCrossRef Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C (2011) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377:813–822PubMedPubMedCentralCrossRef
72.
Zurück zum Zitat Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, Miller K, Sieber P, Karsh L, Damião R, Tammela TL, Egerdie B, Van Poppel H, Chin J, Morote J, Gómez-Veiga F, Borkowski T, Ye Z, Kupic A, Dansey R, Goessl C (2012) Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 379:39–46PubMedCrossRef Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, Miller K, Sieber P, Karsh L, Damião R, Tammela TL, Egerdie B, Van Poppel H, Chin J, Morote J, Gómez-Veiga F, Borkowski T, Ye Z, Kupic A, Dansey R, Goessl C (2012) Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 379:39–46PubMedCrossRef
73.
Zurück zum Zitat Smith MR, Halabi S, Ryan CJ, Hussain A, Vogelzang N, Stadler W, Hauke RJ, Monk JP, Saylor P, Bhoopalam N, Saad F, Sanford B, Kelly WK, Morris M, Small EJ (2014) Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (Alliance). J Clin Oncol 32:1143–1150PubMedPubMedCentralCrossRef Smith MR, Halabi S, Ryan CJ, Hussain A, Vogelzang N, Stadler W, Hauke RJ, Monk JP, Saylor P, Bhoopalam N, Saad F, Sanford B, Kelly WK, Morris M, Small EJ (2014) Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (Alliance). J Clin Oncol 32:1143–1150PubMedPubMedCentralCrossRef
74.
Zurück zum Zitat Diel IJ, Body J-, Stopeck AT, Vadhan-Raj S, Spencer A, Steger G, von Moos R, Goldwasser F, Feng A, Braun A (2015) The role of denosumab in the prevention of hypercalcaemia of malignancy in cancer patients with metastatic bone disease. Eur J Cancer 51:1467–1475PubMedCrossRef Diel IJ, Body J-, Stopeck AT, Vadhan-Raj S, Spencer A, Steger G, von Moos R, Goldwasser F, Feng A, Braun A (2015) The role of denosumab in the prevention of hypercalcaemia of malignancy in cancer patients with metastatic bone disease. Eur J Cancer 51:1467–1475PubMedCrossRef
75.
Zurück zum Zitat Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Smith J, Fan M, Jun S (2008) Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol 26:4875–4882PubMedCrossRef Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Smith J, Fan M, Jun S (2008) Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol 26:4875–4882PubMedCrossRef
76.
Zurück zum Zitat Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Fan M, Kim D (2009) Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study. Breast Cancer Res Treat 118:81–87PubMedCrossRef Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, Fan M, Kim D (2009) Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study. Breast Cancer Res Treat 118:81–87PubMedCrossRef
77.
Zurück zum Zitat Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger GG, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Talbot S, Warner D, Fesl C, Singer CF (2015) Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 386:433–443PubMedCrossRef Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger GG, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Talbot S, Warner D, Fesl C, Singer CF (2015) Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 386:433–443PubMedCrossRef
78.
Zurück zum Zitat Smith MR, Egerdie B, Toriz NH, Feldman R, Tammela TLJ, Saad F, Heracek J, Szwedowski M, Ke C, Kupic A, Leder BZ, Goessl C (2009) Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 361:745–755PubMedPubMedCentralCrossRef Smith MR, Egerdie B, Toriz NH, Feldman R, Tammela TLJ, Saad F, Heracek J, Szwedowski M, Ke C, Kupic A, Leder BZ, Goessl C (2009) Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 361:745–755PubMedPubMedCentralCrossRef
79.
Zurück zum Zitat Palafox M, Ferrer I, Pellegrini P, Vila S, Hernandez-Ortega S, Urruticoechea A, Climent F, Soler MT, Munoz P, Vinals F, Tometsko M, Branstetter D, Dougall WC, Gonzalez-Suarez E (2012) RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Cancer Res 72:2879–2888PubMedCrossRef Palafox M, Ferrer I, Pellegrini P, Vila S, Hernandez-Ortega S, Urruticoechea A, Climent F, Soler MT, Munoz P, Vinals F, Tometsko M, Branstetter D, Dougall WC, Gonzalez-Suarez E (2012) RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Cancer Res 72:2879–2888PubMedCrossRef
80.
Zurück zum Zitat Sigl V, Owusu-Boaitey K, Joshi PA, Kavirayani A, Wirnsberger G, Novatchkova M, Kozieradzki I, Schramek D, Edokobi N, Hersl J, Sampson A, Odai-Afotey A, Lazaro C, Gonzalez-Suarez E, Pujana MA, Cimba F, Heyn H, Vidal E, Cruickshank J, Berman H, Sarao R, Ticevic M, Uribesalgo I, Tortola L, Rao S, Tan Y, Pfeiler G, Lee EYHP, Bago-Horvath Z, Kenner L, Popper H, Singer C, Khokha R, Jones LP, Penninger JM (2016) RANKL/RANK control Brca1 mutation-driven mammary tumors. Cell Res 26:761–774PubMedPubMedCentralCrossRef Sigl V, Owusu-Boaitey K, Joshi PA, Kavirayani A, Wirnsberger G, Novatchkova M, Kozieradzki I, Schramek D, Edokobi N, Hersl J, Sampson A, Odai-Afotey A, Lazaro C, Gonzalez-Suarez E, Pujana MA, Cimba F, Heyn H, Vidal E, Cruickshank J, Berman H, Sarao R, Ticevic M, Uribesalgo I, Tortola L, Rao S, Tan Y, Pfeiler G, Lee EYHP, Bago-Horvath Z, Kenner L, Popper H, Singer C, Khokha R, Jones LP, Penninger JM (2016) RANKL/RANK control Brca1 mutation-driven mammary tumors. Cell Res 26:761–774PubMedPubMedCentralCrossRef
81.
Zurück zum Zitat Ford JA, Jones R, Elders A, Mulatero C, Royle P, Sharma P, Stewart F, Todd R, Mowatt G (2013) Denosumab for treatment of bone metastases secondary to solid tumours: systematic review and network meta-analysis. Eur J Cancer 49:416–430PubMedCrossRef Ford JA, Jones R, Elders A, Mulatero C, Royle P, Sharma P, Stewart F, Todd R, Mowatt G (2013) Denosumab for treatment of bone metastases secondary to solid tumours: systematic review and network meta-analysis. Eur J Cancer 49:416–430PubMedCrossRef
83.
Zurück zum Zitat Bertoldo F, Silvestris F, Ibrahim T, Cognetti F, Generali D, Ripamonti CI, Amadori D, Colleoni MA, Conte P, Del Mastro L, De Placido S, Ortega C, Santini D (2014) Targeting bone metastatic cancer: role of the mTOR pathway. Biochim Biophys Acta 1845:248–254PubMed Bertoldo F, Silvestris F, Ibrahim T, Cognetti F, Generali D, Ripamonti CI, Amadori D, Colleoni MA, Conte P, Del Mastro L, De Placido S, Ortega C, Santini D (2014) Targeting bone metastatic cancer: role of the mTOR pathway. Biochim Biophys Acta 1845:248–254PubMed
84.
Zurück zum Zitat Glantschnig H, Fisher JE, Wesolowski G, Rodan GA, Reszka AA (2003) M-CSF, TNF alpha and RANK ligand promote osteoclast survival by signaling through mTOR//S6 kinase. Cell Death Differ 10:1165–1177PubMedCrossRef Glantschnig H, Fisher JE, Wesolowski G, Rodan GA, Reszka AA (2003) M-CSF, TNF alpha and RANK ligand promote osteoclast survival by signaling through mTOR//S6 kinase. Cell Death Differ 10:1165–1177PubMedCrossRef
85.
Zurück zum Zitat Kneissel M, Luong-Nguyen N, Baptist M, Cortesi R, Zumstein-Mecker S, Kossida S, O’Reilly T, Lane H, Susa M (2004) Everolimus suppresses cancellous bone loss, bone resorption, and cathepsin K expression by osteoclasts. Bone 35:1144–1156PubMedCrossRef Kneissel M, Luong-Nguyen N, Baptist M, Cortesi R, Zumstein-Mecker S, Kossida S, O’Reilly T, Lane H, Susa M (2004) Everolimus suppresses cancellous bone loss, bone resorption, and cathepsin K expression by osteoclasts. Bone 35:1144–1156PubMedCrossRef
86.
Zurück zum Zitat Mogi M, Kondo A (2009) Down-regulation of mTOR leads to up-regulation of osteoprotegerin in bone marrow cells. Biochem Biophys Res Commun 384:82–86PubMedCrossRef Mogi M, Kondo A (2009) Down-regulation of mTOR leads to up-regulation of osteoprotegerin in bone marrow cells. Biochem Biophys Res Commun 384:82–86PubMedCrossRef
87.
Zurück zum Zitat Lee KW, Yook JY, Son MY, Kim MJ, Koo DB, Han YM, Cho YS (2010) Rapamycin promotes the osteoblastic differentiation of human embryonic stem cells by blocking the mTOR pathway and stimulating the BMP/Smad pathway. Stem Cells Dev 19:557–568PubMedCrossRef Lee KW, Yook JY, Son MY, Kim MJ, Koo DB, Han YM, Cho YS (2010) Rapamycin promotes the osteoblastic differentiation of human embryonic stem cells by blocking the mTOR pathway and stimulating the BMP/Smad pathway. Stem Cells Dev 19:557–568PubMedCrossRef
88.
Zurück zum Zitat Hussein O, Tiedemann K, Murshed M, Komarova SV (2012) Rapamycin inhibits osteolysis and improves survival in a model of experimental bone metastases. Cancer Lett 314:176–184PubMedCrossRef Hussein O, Tiedemann K, Murshed M, Komarova SV (2012) Rapamycin inhibits osteolysis and improves survival in a model of experimental bone metastases. Cancer Lett 314:176–184PubMedCrossRef
89.
Zurück zum Zitat Moriceau G, Ory B, Mitrofan L, Riganti C, Blanchard F, Brion R, Charrier C, Battaglia S, Pilet P, Denis MG, Shultz LD, Mönkkönen J, Rédini F, Heymann D (2010) Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (everolimus): pivotal role of the prenylation process. Cancer Res 70:10329–10339PubMedPubMedCentralCrossRef Moriceau G, Ory B, Mitrofan L, Riganti C, Blanchard F, Brion R, Charrier C, Battaglia S, Pilet P, Denis MG, Shultz LD, Mönkkönen J, Rédini F, Heymann D (2010) Zoledronic acid potentiates mTOR inhibition and abolishes the resistance of osteosarcoma cells to RAD001 (everolimus): pivotal role of the prenylation process. Cancer Res 70:10329–10339PubMedPubMedCentralCrossRef
90.
Zurück zum Zitat Morgan TM, Pitts TE, Gross TS, Poliachik SL, Vessella RL, Corey E (2008) RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid. Prostate 68:861–871PubMedPubMedCentralCrossRef Morgan TM, Pitts TE, Gross TS, Poliachik SL, Vessella RL, Corey E (2008) RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid. Prostate 68:861–871PubMedPubMedCentralCrossRef
91.
Zurück zum Zitat Okui T, Shimo T, Fukazawa T, Kurio N, Hassan NM, Honami T, Takaoka M, Naomoto Y, Sasaki A (2010) Antitumor effect of temsirolimus against oral squamous cell carcinoma associated with bone destruction. Mol Cancer Ther 9:2960–2969PubMedCrossRef Okui T, Shimo T, Fukazawa T, Kurio N, Hassan NM, Honami T, Takaoka M, Naomoto Y, Sasaki A (2010) Antitumor effect of temsirolimus against oral squamous cell carcinoma associated with bone destruction. Mol Cancer Ther 9:2960–2969PubMedCrossRef
92.
Zurück zum Zitat Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP, Tseng L, Zhang Q, Shen K, Liu D, Dreosti LM, Burris HA, Toi M, Buyse ME, Cabaribere D, Lindsay M, Rao S, Pacaud LB, Taran T, Slamon D (2015) Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol 16:816–829PubMedCrossRef Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP, Tseng L, Zhang Q, Shen K, Liu D, Dreosti LM, Burris HA, Toi M, Buyse ME, Cabaribere D, Lindsay M, Rao S, Pacaud LB, Taran T, Slamon D (2015) Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol 16:816–829PubMedCrossRef
93.
Zurück zum Zitat Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520–529PubMedCrossRef Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520–529PubMedCrossRef
94.
Zurück zum Zitat Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, Hortobagyi GN, Campone M, Pistilli B, Piccart M, Melichar B, Petrakova K, Arena FP, Erdkamp F, Harb WA, Feng W, Cahana A, Taran T, Lebwohl D, Rugo HS (2013) Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther 30:870–884PubMedPubMedCentralCrossRef Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, Hortobagyi GN, Campone M, Pistilli B, Piccart M, Melichar B, Petrakova K, Arena FP, Erdkamp F, Harb WA, Feng W, Cahana A, Taran T, Lebwohl D, Rugo HS (2013) Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther 30:870–884PubMedPubMedCentralCrossRef
95.
Zurück zum Zitat Hortobagyi GN (2015) Everolimus plus exemestane for the treatment of advanced breast cancer: a review of subanalyses from BOLERO-2. Neoplasia 17:279–288PubMedPubMedCentralCrossRef Hortobagyi GN (2015) Everolimus plus exemestane for the treatment of advanced breast cancer: a review of subanalyses from BOLERO-2. Neoplasia 17:279–288PubMedPubMedCentralCrossRef
96.
Zurück zum Zitat Maass N, Harbeck N, Mundhenke C, Lerchenmüller C, Barinoff J, Lück H, Ettl J, Aktas B, Kümmel S, Rösel S, Wagner S, Müller L, Bischoff J, Lübbe K, Schwedler K, Schmidt M, Bauerschlag D, Nekljudova V, von Minckwitz G, Loibl S (2013) Everolimus as treatment for breast cancer patients with bone metastases only: results of the phase II RADAR study. J Cancer Res Clin Oncol 139:2047–2056PubMedCrossRef Maass N, Harbeck N, Mundhenke C, Lerchenmüller C, Barinoff J, Lück H, Ettl J, Aktas B, Kümmel S, Rösel S, Wagner S, Müller L, Bischoff J, Lübbe K, Schwedler K, Schmidt M, Bauerschlag D, Nekljudova V, von Minckwitz G, Loibl S (2013) Everolimus as treatment for breast cancer patients with bone metastases only: results of the phase II RADAR study. J Cancer Res Clin Oncol 139:2047–2056PubMedCrossRef
97.
Zurück zum Zitat Amato RJ, Flaherty A, Zhang Y, Ouyang F, Mohlere V (2014) Clinical prognostic factors associated with outcome in patients with renal cell cancer with prior tyrosine kinase inhibitors or immunotherapy treated with everolimus. Urol Oncol 32:345–354PubMedCrossRef Amato RJ, Flaherty A, Zhang Y, Ouyang F, Mohlere V (2014) Clinical prognostic factors associated with outcome in patients with renal cell cancer with prior tyrosine kinase inhibitors or immunotherapy treated with everolimus. Urol Oncol 32:345–354PubMedCrossRef
98.
Zurück zum Zitat Broom RJ, Hinder V, Sharples K, Proctor J, Duffey S, Pollard S, Fong PCC, Forgeson G, Harris DL, Jameson MB, O’Donnell A, North RT, Deva S, Hanning FJ, Grey A, Findlay MPN (2015) Everolimus and zoledronic acid in patients with renal cell carcinoma With bone metastases: a randomized first-line phase II trial. Clin Genitourin Cancer 13:50–58PubMedCrossRef Broom RJ, Hinder V, Sharples K, Proctor J, Duffey S, Pollard S, Fong PCC, Forgeson G, Harris DL, Jameson MB, O’Donnell A, North RT, Deva S, Hanning FJ, Grey A, Findlay MPN (2015) Everolimus and zoledronic acid in patients with renal cell carcinoma With bone metastases: a randomized first-line phase II trial. Clin Genitourin Cancer 13:50–58PubMedCrossRef
99.
Zurück zum Zitat Yu Y, Song Z, Yang S, Yang X, Zhang J, Lu S (2014) Everolimus and zoledronic acid—a potential synergistic treatment for lung adenocarcinoma bone metastasis. Acta Biochim Biophys Sin (Shanghai) 46:792–801CrossRef Yu Y, Song Z, Yang S, Yang X, Zhang J, Lu S (2014) Everolimus and zoledronic acid—a potential synergistic treatment for lung adenocarcinoma bone metastasis. Acta Biochim Biophys Sin (Shanghai) 46:792–801CrossRef
100.
Zurück zum Zitat Vaishampayan U, Shevrin D, Stein M, Heilbrun L, Land S, Stark K, Li J, Dickow B, Heath E, Smith D, Fontana J (2015) Phase II trial of carboplatin, everolimus, and prednisone in metastatic castration-resistant prostate cancer pretreated with docetaxel chemotherapy: a prostate cancer clinical trial consortium study. Urology 86:1206–1211PubMedCrossRef Vaishampayan U, Shevrin D, Stein M, Heilbrun L, Land S, Stark K, Li J, Dickow B, Heath E, Smith D, Fontana J (2015) Phase II trial of carboplatin, everolimus, and prednisone in metastatic castration-resistant prostate cancer pretreated with docetaxel chemotherapy: a prostate cancer clinical trial consortium study. Urology 86:1206–1211PubMedCrossRef
101.
Zurück zum Zitat Günther A, Baumann P, Burger R, Kellner C, Klapper W, Schmidmaier R, Gramatzki M (2015) Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: a phase I study. Haematologica 100:541–547PubMedPubMedCentralCrossRef Günther A, Baumann P, Burger R, Kellner C, Klapper W, Schmidmaier R, Gramatzki M (2015) Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: a phase I study. Haematologica 100:541–547PubMedPubMedCentralCrossRef
102.
Zurück zum Zitat Yee AJ, Hari P, Marcheselli R, Mahindra AK, Mahindra AK, Cirstea DD, Scullen TA, Burke JN, Rodig SJ, Hideshima T, Laubach JP, Ghobrial IM, Schlossman RL, Munshi NC, Anderson KC, Weller EA, Richardson PG, Raje NS (2014) Outcomes in patients with relapsed or refractory multiple myeloma in a phase I study of everolimus in combination with lenalidomide. Br J Haematol 166:401–409PubMedCrossRef Yee AJ, Hari P, Marcheselli R, Mahindra AK, Mahindra AK, Cirstea DD, Scullen TA, Burke JN, Rodig SJ, Hideshima T, Laubach JP, Ghobrial IM, Schlossman RL, Munshi NC, Anderson KC, Weller EA, Richardson PG, Raje NS (2014) Outcomes in patients with relapsed or refractory multiple myeloma in a phase I study of everolimus in combination with lenalidomide. Br J Haematol 166:401–409PubMedCrossRef
103.
Zurück zum Zitat Rugo HS, Pritchard KI, Gnant M, Noguchi S, Piccart M, Hortobagyi G, Baselga J, Perez A, Geberth M, Csoszi T, Chouinard E, Srimuninnimit V, Puttawibul P, Eakle J, Feng W, Bauly H, El-Hashimy M, Taran T, Burris HA III (2014) Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2. Ann Oncol 25:808–815PubMedPubMedCentralCrossRef Rugo HS, Pritchard KI, Gnant M, Noguchi S, Piccart M, Hortobagyi G, Baselga J, Perez A, Geberth M, Csoszi T, Chouinard E, Srimuninnimit V, Puttawibul P, Eakle J, Feng W, Bauly H, El-Hashimy M, Taran T, Burris HA III (2014) Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2. Ann Oncol 25:808–815PubMedPubMedCentralCrossRef
104.
Zurück zum Zitat Turner PG, O’Sullivan JM (2015) (223)Ra and other bone-targeting radiopharmaceuticals-the translation of radiation biology into clinical practice. Br J Radiol 88:20140752PubMedPubMedCentralCrossRef Turner PG, O’Sullivan JM (2015) (223)Ra and other bone-targeting radiopharmaceuticals-the translation of radiation biology into clinical practice. Br J Radiol 88:20140752PubMedPubMedCentralCrossRef
105.
Zurück zum Zitat Coleman R (2016) Treatment of metastatic bone disease and the emerging role of radium-223. Semin Nucl Med 46:99–104PubMedCrossRef Coleman R (2016) Treatment of metastatic bone disease and the emerging role of radium-223. Semin Nucl Med 46:99–104PubMedCrossRef
106.
Zurück zum Zitat Henriksen G, Fisher DR, Roeske JC, Bruland OS, Larsen RH (2003) Targeting of osseous sites with alpha-emitting 223Ra: comparison with the beta-emitter 89Sr in mice. J Nucl Med 44:252–259PubMed Henriksen G, Fisher DR, Roeske JC, Bruland OS, Larsen RH (2003) Targeting of osseous sites with alpha-emitting 223Ra: comparison with the beta-emitter 89Sr in mice. J Nucl Med 44:252–259PubMed
107.
Zurück zum Zitat Abou DS, Ulmert D, Doucet M, Hobbs RF, Riddle RC, Thorek DLJ (2015) Whole-body and microenvironmental localization of radium-223 in naive and mouse models of prostate cancer metastasis. J Natl Cancer Inst. doi:10.1093/jnci/djv380 PubMedPubMedCentral Abou DS, Ulmert D, Doucet M, Hobbs RF, Riddle RC, Thorek DLJ (2015) Whole-body and microenvironmental localization of radium-223 in naive and mouse models of prostate cancer metastasis. J Natl Cancer Inst. doi:10.​1093/​jnci/​djv380 PubMedPubMedCentral
108.
Zurück zum Zitat Henriksen G, Breistol K, Bruland OS, Fodstad O, Larsen RH (2002) Significant antitumor effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental skeletal metastases model. Cancer Res 62:3120–3125PubMed Henriksen G, Breistol K, Bruland OS, Fodstad O, Larsen RH (2002) Significant antitumor effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental skeletal metastases model. Cancer Res 62:3120–3125PubMed
109.
Zurück zum Zitat Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, Yachnin J, Garkavij M, Strang P, Harmenberg J, Bolstad B, Bruland ØS (2007) Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol 8:587–594PubMedCrossRef Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, Yachnin J, Garkavij M, Strang P, Harmenberg J, Bolstad B, Bruland ØS (2007) Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol 8:587–594PubMedCrossRef
110.
Zurück zum Zitat Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Widmark A, Johannessen DC, Hoskin P, James ND, Solberg A, Syndikus I, Vogelzang NJ, O’Bryan-Tear CG, Shan M, Bruland ØS, Parker C (2014) Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol 15:738–746PubMedCrossRef Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Widmark A, Johannessen DC, Hoskin P, James ND, Solberg A, Syndikus I, Vogelzang NJ, O’Bryan-Tear CG, Shan M, Bruland ØS, Parker C (2014) Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol 15:738–746PubMedCrossRef
111.
Zurück zum Zitat Suominen MI, Rissanen JP, Kakonen R, Fagerlund KM, Alhoniemi E, Mumberg D, Ziegelbauer K, Halleen JM, Kakonen SM, Scholz A (2013) Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis. J Natl Cancer Inst 105:908–916PubMedCrossRef Suominen MI, Rissanen JP, Kakonen R, Fagerlund KM, Alhoniemi E, Mumberg D, Ziegelbauer K, Halleen JM, Kakonen SM, Scholz A (2013) Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis. J Natl Cancer Inst 105:908–916PubMedCrossRef
113.
Zurück zum Zitat Coleman R, Aksnes A, Naume B, Garcia C, Jerusalem G, Piccart M, Vobecky N, Thuresson M, Flamen P (2014) A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease. Breast Cancer Res Treat 145:411–418PubMedPubMedCentralCrossRef Coleman R, Aksnes A, Naume B, Garcia C, Jerusalem G, Piccart M, Vobecky N, Thuresson M, Flamen P (2014) A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease. Breast Cancer Res Treat 145:411–418PubMedPubMedCentralCrossRef
114.
Zurück zum Zitat Accardi F, Toscani D, Bolzoni M, Dalla Palma B, Aversa F, Giuliani N (2015) Mechanism of action of bortezomib and the new proteasome inhibitors on myeloma cells and the bone microenvironment: impact on myeloma-induced alterations of bone remodeling. Biomed Res Int 2015:172458PubMedPubMedCentralCrossRef Accardi F, Toscani D, Bolzoni M, Dalla Palma B, Aversa F, Giuliani N (2015) Mechanism of action of bortezomib and the new proteasome inhibitors on myeloma cells and the bone microenvironment: impact on myeloma-induced alterations of bone remodeling. Biomed Res Int 2015:172458PubMedPubMedCentralCrossRef
115.
Zurück zum Zitat Niewerth D, Jansen G, Assaraf YG, Zweegman S, Kaspers GJ, Cloos J (2015) Molecular basis of resistance to proteasome inhibitors in hematological malignancies. Drug Resist Updat 18:18–35PubMedCrossRef Niewerth D, Jansen G, Assaraf YG, Zweegman S, Kaspers GJ, Cloos J (2015) Molecular basis of resistance to proteasome inhibitors in hematological malignancies. Drug Resist Updat 18:18–35PubMedCrossRef
116.
Zurück zum Zitat Scott K, Hayden PJ, Will A, Wheatley K, Coyne I (2016) Bortezomib for the treatment of multiple myeloma. Cochrane Database Syst Rev 4:CD010816PubMed Scott K, Hayden PJ, Will A, Wheatley K, Coyne I (2016) Bortezomib for the treatment of multiple myeloma. Cochrane Database Syst Rev 4:CD010816PubMed
117.
Zurück zum Zitat Vanderschueren D, Laurent MR, Claessens F, Gielen E, Lagerquist MK, Vandenput L, Borjesson AE, Ohlsson C (2014) Sex steroid actions in male bone. Endocr Rev 35:906–960PubMedPubMedCentralCrossRef Vanderschueren D, Laurent MR, Claessens F, Gielen E, Lagerquist MK, Vandenput L, Borjesson AE, Ohlsson C (2014) Sex steroid actions in male bone. Endocr Rev 35:906–960PubMedPubMedCentralCrossRef
118.
Zurück zum Zitat Haidar S, Ehmer PB, Barassin S, Batzl-Hartmann C, Hartmann RW (2003) Effects of novel 17alpha-hydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. J Steroid Biochem Mol Biol 84:555–562PubMedCrossRef Haidar S, Ehmer PB, Barassin S, Batzl-Hartmann C, Hartmann RW (2003) Effects of novel 17alpha-hydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. J Steroid Biochem Mol Biol 84:555–562PubMedCrossRef
119.
Zurück zum Zitat Wu J, Moverare-Skrtic S, Borjesson AE, Lagerquist MK, Sjogren K, Windahl SH, Koskela A, Grahnemo L, Islander U, Wilhelmson AS, Tivesten A, Tuukkanen J, Ohlsson C (2016) Enzalutamide reduces the bone mass in the axial but not the appendicular skeleton in male mice. Endocrinology 157:969–977PubMedCrossRef Wu J, Moverare-Skrtic S, Borjesson AE, Lagerquist MK, Sjogren K, Windahl SH, Koskela A, Grahnemo L, Islander U, Wilhelmson AS, Tivesten A, Tuukkanen J, Ohlsson C (2016) Enzalutamide reduces the bone mass in the axial but not the appendicular skeleton in male mice. Endocrinology 157:969–977PubMedCrossRef
120.
Zurück zum Zitat Iuliani M, Pantano F, Buttigliero C, Fioramonti M, Bertaglia V, Vincenzi B, Zoccoli A, Ribelli G, Tucci M, Vignani F, Berruti A, Scagliotti GV, Tonini G, Santini D (2015) Biological and clinical effects of abiraterone on anti-resorptive and anabolic activity in bone microenvironment. Oncotarget 6:12520–12528PubMedPubMedCentralCrossRef Iuliani M, Pantano F, Buttigliero C, Fioramonti M, Bertaglia V, Vincenzi B, Zoccoli A, Ribelli G, Tucci M, Vignani F, Berruti A, Scagliotti GV, Tonini G, Santini D (2015) Biological and clinical effects of abiraterone on anti-resorptive and anabolic activity in bone microenvironment. Oncotarget 6:12520–12528PubMedPubMedCentralCrossRef
121.
Zurück zum Zitat Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, Mainwaring P, Harland S, Goodman OB Jr, Sternberg CN, Li JH, Kheoh T, Haqq CM, de Bono JS, COU-AA-301 Investigators (2012) Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 13:983–992PubMedCrossRef Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, Staffurth JN, North S, Vogelzang NJ, Saad F, Mainwaring P, Harland S, Goodman OB Jr, Sternberg CN, Li JH, Kheoh T, Haqq CM, de Bono JS, COU-AA-301 Investigators (2012) Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 13:983–992PubMedCrossRef
122.
Zurück zum Zitat McCrea E, Sissung TM, Price DK, Chau CH, Figg WD (2016) Androgen receptor variation affects prostate cancer progression and drug resistance. Pharmacol Res 114:152–162PubMedPubMedCentralCrossRef McCrea E, Sissung TM, Price DK, Chau CH, Figg WD (2016) Androgen receptor variation affects prostate cancer progression and drug resistance. Pharmacol Res 114:152–162PubMedPubMedCentralCrossRef
123.
Zurück zum Zitat Littlewood-Evans AJ, Bilbe G, Bowler WB, Farley D, Wlodarski B, Kokubo T, Inaoka T, Sloane J, Evans DB, Gallagher JA (1997) The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res 57:5386–5390PubMed Littlewood-Evans AJ, Bilbe G, Bowler WB, Farley D, Wlodarski B, Kokubo T, Inaoka T, Sloane J, Evans DB, Gallagher JA (1997) The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res 57:5386–5390PubMed
124.
Zurück zum Zitat Le Gall C, Bellahcène A, Bonnelye E, Gasser JA, Castronovo V, Green J, Zimmermann J, Clézardin P (2007) A cathepsin K inhibitor reduces breast cancer-induced osteolysis and skeletal tumor burden. Cancer Res 67:9894–9902PubMedCrossRef Le Gall C, Bellahcène A, Bonnelye E, Gasser JA, Castronovo V, Green J, Zimmermann J, Clézardin P (2007) A cathepsin K inhibitor reduces breast cancer-induced osteolysis and skeletal tumor burden. Cancer Res 67:9894–9902PubMedCrossRef
125.
Zurück zum Zitat Brubaker KD, Vessella RL, True LD, Thomas R, Corey E (2003) Cathepsin K mRNA and protein expression in prostate cancer progression. J Bone Miner Res 18:222–230PubMedCrossRef Brubaker KD, Vessella RL, True LD, Thomas R, Corey E (2003) Cathepsin K mRNA and protein expression in prostate cancer progression. J Bone Miner Res 18:222–230PubMedCrossRef
126.
Zurück zum Zitat Husmann K, Muff R, Bolander ME, Sarkar G, Born W, Fuchs B (2008) Cathepsins and osteosarcoma: expression analysis identifies cathepsin K as an indicator of metastasis. Mol Carcinog 47:66–73PubMedCrossRef Husmann K, Muff R, Bolander ME, Sarkar G, Born W, Fuchs B (2008) Cathepsins and osteosarcoma: expression analysis identifies cathepsin K as an indicator of metastasis. Mol Carcinog 47:66–73PubMedCrossRef
128.
Zurück zum Zitat Jensen AB, Wynne C, Ramirez G, He W, Song Y, Berd Y, Wang H, Mehta A, Lombardi A (2010) The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: results of a 4-week, double-blind, randomized, controlled trial. Clin Breast Cancer 10:452–458PubMedCrossRef Jensen AB, Wynne C, Ramirez G, He W, Song Y, Berd Y, Wang H, Mehta A, Lombardi A (2010) The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: results of a 4-week, double-blind, randomized, controlled trial. Clin Breast Cancer 10:452–458PubMedCrossRef
129.
Zurück zum Zitat Duong LT, Wesolowski GA, Leung P, Oballa R, Pickarski M (2014) Efficacy of a cathepsin K inhibitor in a preclinical model for prevention and treatment of breast cancer bone metastasis. Mol Cancer Ther 13:2898–2909PubMedCrossRef Duong LT, Wesolowski GA, Leung P, Oballa R, Pickarski M (2014) Efficacy of a cathepsin K inhibitor in a preclinical model for prevention and treatment of breast cancer bone metastasis. Mol Cancer Ther 13:2898–2909PubMedCrossRef
130.
Zurück zum Zitat Langdahl B, Binkley N, Bone H, Gilchrist N, Resch H, Rodriguez Portales J, Denker A, Lombardi A, Le Bailly DeTilleghem C, DaSilva C, Rosenberg E, Leung A (2012) Odanacatib in the treatment of postmenopausal women with low bone mineral density: five years of continued therapy in a phase 2 study. J Bone Miner Res 27:2251–2258PubMedCrossRef Langdahl B, Binkley N, Bone H, Gilchrist N, Resch H, Rodriguez Portales J, Denker A, Lombardi A, Le Bailly DeTilleghem C, DaSilva C, Rosenberg E, Leung A (2012) Odanacatib in the treatment of postmenopausal women with low bone mineral density: five years of continued therapy in a phase 2 study. J Bone Miner Res 27:2251–2258PubMedCrossRef
131.
Zurück zum Zitat Bone HG, Dempster DW, Eisman JA, Greenspan SL, McClung MR, Nakamura T, Papapoulos S, Shih WJ, Rybak-Feiglin A, Santora AC, Verbruggen N, Leung AT, Lombardi A (2015) Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial. Osteoporos Int 26:699–712PubMedCrossRef Bone HG, Dempster DW, Eisman JA, Greenspan SL, McClung MR, Nakamura T, Papapoulos S, Shih WJ, Rybak-Feiglin A, Santora AC, Verbruggen N, Leung AT, Lombardi A (2015) Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial. Osteoporos Int 26:699–712PubMedCrossRef
132.
Zurück zum Zitat Soriano P, Montgomery C, Geske R, Bradley A (1991) Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64:693–702PubMedCrossRef Soriano P, Montgomery C, Geske R, Bradley A (1991) Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64:693–702PubMedCrossRef
133.
Zurück zum Zitat Horne WC, Sanjay A, Bruzzaniti A, Baron R (2005) The role(s) of Src kinase and Cbl proteins in the regulation of osteoclast differentiation and function. Immunol Rev 208:106–125PubMedCrossRef Horne WC, Sanjay A, Bruzzaniti A, Baron R (2005) The role(s) of Src kinase and Cbl proteins in the regulation of osteoclast differentiation and function. Immunol Rev 208:106–125PubMedCrossRef
134.
Zurück zum Zitat Lee YC, Huang CF, Murshed M, Chu K, Araujo JC, Ye X, deCrombrugghe B, Yu-Lee LY, Gallick GE, Lin SH (2010) Src family kinase/abl inhibitor dasatinib suppresses proliferation and enhances differentiation of osteoblasts. Oncogene 29:3196–3207PubMedPubMedCentralCrossRef Lee YC, Huang CF, Murshed M, Chu K, Araujo JC, Ye X, deCrombrugghe B, Yu-Lee LY, Gallick GE, Lin SH (2010) Src family kinase/abl inhibitor dasatinib suppresses proliferation and enhances differentiation of osteoblasts. Oncogene 29:3196–3207PubMedPubMedCentralCrossRef
135.
Zurück zum Zitat Roskoski R Jr (2015) Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors. Pharmacol Res 94:9–25PubMedCrossRef Roskoski R Jr (2015) Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors. Pharmacol Res 94:9–25PubMedCrossRef
136.
Zurück zum Zitat Rucci N, Recchia I, Angelucci A, Alamanou M, Del Fattore A, Fortunati D, Susa M, Fabbro D, Bologna M, Teti A (2006) Inhibition of protein kinase c-Src reduces the incidence of breast cancer metastases and increases survival in mice: implications for therapy. J Pharmacol Exp Ther 318:161–172PubMedCrossRef Rucci N, Recchia I, Angelucci A, Alamanou M, Del Fattore A, Fortunati D, Susa M, Fabbro D, Bologna M, Teti A (2006) Inhibition of protein kinase c-Src reduces the incidence of breast cancer metastases and increases survival in mice: implications for therapy. J Pharmacol Exp Ther 318:161–172PubMedCrossRef
138.
Zurück zum Zitat Campone M, Bondarenko I, Brincat S, Hotko Y, Munster PN, Chmielowska E, Fumoleau P, Ward R, Bardy-Bouxin N, Leip E, Turnbull K, Zacharchuk C, Epstein RJ (2012) Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy. Ann Oncol 23:610–617PubMedCrossRef Campone M, Bondarenko I, Brincat S, Hotko Y, Munster PN, Chmielowska E, Fumoleau P, Ward R, Bardy-Bouxin N, Leip E, Turnbull K, Zacharchuk C, Epstein RJ (2012) Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy. Ann Oncol 23:610–617PubMedCrossRef
139.
Zurück zum Zitat Yu EY, Massard C, Gross ME, Carducci MA, Culine S, Hudes G, Posadas EM, Sternberg CN, Wilding G, Trudel GC, Paliwal P, Fizazi K (2011) Once-daily dasatinib: expansion of phase II study evaluating safety and efficacy of dasatinib in patients with metastatic castration-resistant prostate cancer. Urology 77:1166–1171PubMedPubMedCentralCrossRef Yu EY, Massard C, Gross ME, Carducci MA, Culine S, Hudes G, Posadas EM, Sternberg CN, Wilding G, Trudel GC, Paliwal P, Fizazi K (2011) Once-daily dasatinib: expansion of phase II study evaluating safety and efficacy of dasatinib in patients with metastatic castration-resistant prostate cancer. Urology 77:1166–1171PubMedPubMedCentralCrossRef
140.
Zurück zum Zitat Yu EY, Duan F, Muzi M, Deng X, Chin BB, Alumkal JJ, Taplin ME, Taub JM, Herman B, Higano CS, Doot RK, Hartfeil D, Febbo PG, Mankoff DA (2015) Castration-resistant prostate cancer bone metastasis response measured by 18F-fluoride PET after treatment with dasatinib and correlation with progression-free survival: results from American College of Radiology Imaging Network 6687. J Nucl Med 56:354–360PubMedPubMedCentralCrossRef Yu EY, Duan F, Muzi M, Deng X, Chin BB, Alumkal JJ, Taplin ME, Taub JM, Herman B, Higano CS, Doot RK, Hartfeil D, Febbo PG, Mankoff DA (2015) Castration-resistant prostate cancer bone metastasis response measured by 18F-fluoride PET after treatment with dasatinib and correlation with progression-free survival: results from American College of Radiology Imaging Network 6687. J Nucl Med 56:354–360PubMedPubMedCentralCrossRef
141.
Zurück zum Zitat Mitri Z, Nanda R, Blackwell K, Costelloe CM, Hood I, Wei C, Brewster AM, Ibrahim NK, Koenig KB, Hortobagyi GN, Van Poznak C, Rimawi MF, Moulder-Thompson S, Translational Breast Cancer Research Consortium (2016) TBCRC-010: phase I/II study of dasatinib in combination with zoledronic acid for the treatment of breast cancer bone metastasis. Clin Cancer Res 22:5706–5712PubMedCrossRef Mitri Z, Nanda R, Blackwell K, Costelloe CM, Hood I, Wei C, Brewster AM, Ibrahim NK, Koenig KB, Hortobagyi GN, Van Poznak C, Rimawi MF, Moulder-Thompson S, Translational Breast Cancer Research Consortium (2016) TBCRC-010: phase I/II study of dasatinib in combination with zoledronic acid for the treatment of breast cancer bone metastasis. Clin Cancer Res 22:5706–5712PubMedCrossRef
142.
Zurück zum Zitat Rabbani SA, Valentino ML, Arakelian A, Ali S, Boschelli F (2010) SKI-606 (Bosutinib) blocks prostate cancer invasion, growth, and metastasis in vitro and in vivo through regulation of genes involved in cancer growth and skeletal metastasis. Mol Cancer Ther 9:1147–1157PubMedCrossRef Rabbani SA, Valentino ML, Arakelian A, Ali S, Boschelli F (2010) SKI-606 (Bosutinib) blocks prostate cancer invasion, growth, and metastasis in vitro and in vivo through regulation of genes involved in cancer growth and skeletal metastasis. Mol Cancer Ther 9:1147–1157PubMedCrossRef
143.
Zurück zum Zitat Yang JC, Bai L, Yap S, Gao AC, Kung HJ, Evans CP (2010) Effect of the specific Src family kinase inhibitor saracatinib on osteolytic lesions using the PC-3 bone model. Mol Cancer Ther 9:1629–1637PubMedCrossRef Yang JC, Bai L, Yap S, Gao AC, Kung HJ, Evans CP (2010) Effect of the specific Src family kinase inhibitor saracatinib on osteolytic lesions using the PC-3 bone model. Mol Cancer Ther 9:1629–1637PubMedCrossRef
144.
Zurück zum Zitat Antonarakis ES, Heath EI, Posadas EM, Yu EY, Harrison MR, Bruce JY, Cho SY, Wilding GE, Fetterly GJ, Hangauer DG, Kwan MF, Dyster LM, Carducci MA (2013) A phase 2 study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer. Cancer Chemother Pharmacol 71:883–892PubMedPubMedCentralCrossRef Antonarakis ES, Heath EI, Posadas EM, Yu EY, Harrison MR, Bruce JY, Cho SY, Wilding GE, Fetterly GJ, Hangauer DG, Kwan MF, Dyster LM, Carducci MA (2013) A phase 2 study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer. Cancer Chemother Pharmacol 71:883–892PubMedPubMedCentralCrossRef
145.
Zurück zum Zitat Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192PubMedCrossRef Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192PubMedCrossRef
146.
Zurück zum Zitat Colucci S, Brunetti G, Oranger A, Mori G, Sardone F, Specchia G, Rinaldi E, Curci P, Liso V, Passeri G, Zallone A, Rizzi R, Grano M (2011) Myeloma cells suppress osteoblasts through sclerostin secretion. Blood Cancer J 1:e27PubMedPubMedCentralCrossRef Colucci S, Brunetti G, Oranger A, Mori G, Sardone F, Specchia G, Rinaldi E, Curci P, Liso V, Passeri G, Zallone A, Rizzi R, Grano M (2011) Myeloma cells suppress osteoblasts through sclerostin secretion. Blood Cancer J 1:e27PubMedPubMedCentralCrossRef
147.
Zurück zum Zitat Mendoza-Villanueva D, Zeef L, Shore P (2011) Metastatic breast cancer cells inhibit osteoblast differentiation through the Runx2/CBFbeta-dependent expression of the Wnt antagonist, sclerostin. Breast Cancer Res 13:R106PubMedPubMedCentralCrossRef Mendoza-Villanueva D, Zeef L, Shore P (2011) Metastatic breast cancer cells inhibit osteoblast differentiation through the Runx2/CBFbeta-dependent expression of the Wnt antagonist, sclerostin. Breast Cancer Res 13:R106PubMedPubMedCentralCrossRef
148.
Zurück zum Zitat Kyvernitakis I, Rachner TD, Urbschat A, Hars O, Hofbauer LC, Hadji P (2014) Effect of aromatase inhibition on serum levels of sclerostin and dickkopf-1, bone turnover markers and bone mineral density in women with breast cancer. J Cancer Res Clin Oncol 140:1671–1680PubMedCrossRef Kyvernitakis I, Rachner TD, Urbschat A, Hars O, Hofbauer LC, Hadji P (2014) Effect of aromatase inhibition on serum levels of sclerostin and dickkopf-1, bone turnover markers and bone mineral density in women with breast cancer. J Cancer Res Clin Oncol 140:1671–1680PubMedCrossRef
149.
Zurück zum Zitat Terpos E, Christoulas D, Katodritou E, Bratengeier C, Gkotzamanidou M, Michalis E, Delimpasi S, Pouli A, Meletis J, Kastritis E, Zervas K, Dimopoulos MA (2012) Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: reduction post-bortezomib monotherapy. Int J Cancer 131:1466–1471PubMedCrossRef Terpos E, Christoulas D, Katodritou E, Bratengeier C, Gkotzamanidou M, Michalis E, Delimpasi S, Pouli A, Meletis J, Kastritis E, Zervas K, Dimopoulos MA (2012) Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: reduction post-bortezomib monotherapy. Int J Cancer 131:1466–1471PubMedCrossRef
150.
Zurück zum Zitat Eda H, Santo L, Wein MN, Hu DZ, Cirstea DD, Nemani N, Tai YT, Raines SE, Kuhstoss SA, Munshi NC, Kronenberg HM, Raje NS (2016) Regulation of sclerostin expression in multiple myeloma by Dkk-1; a potential therapeutic strategy for myeloma bone disease. J Bone Miner Res 31:1225–1234PubMedPubMedCentralCrossRef Eda H, Santo L, Wein MN, Hu DZ, Cirstea DD, Nemani N, Tai YT, Raines SE, Kuhstoss SA, Munshi NC, Kronenberg HM, Raje NS (2016) Regulation of sclerostin expression in multiple myeloma by Dkk-1; a potential therapeutic strategy for myeloma bone disease. J Bone Miner Res 31:1225–1234PubMedPubMedCentralCrossRef
151.
Zurück zum Zitat Garcia-Fontana B, Morales-Santana S, Varsavsky M, Garcia-Martin A, Garcia-Salcedo JA, Reyes-Garcia R, Munoz-Torres M (2014) Sclerostin serum levels in prostate cancer patients and their relationship with sex steroids. Osteoporos Int 25:645–651PubMedCrossRef Garcia-Fontana B, Morales-Santana S, Varsavsky M, Garcia-Martin A, Garcia-Salcedo JA, Reyes-Garcia R, Munoz-Torres M (2014) Sclerostin serum levels in prostate cancer patients and their relationship with sex steroids. Osteoporos Int 25:645–651PubMedCrossRef
152.
Zurück zum Zitat Yavropoulou MP, van Lierop AH, Hamdy NAT, Rizzoli R, Papapoulos SE (2012) Serum sclerostin levels in Paget’s disease and prostate cancer with bone metastases with a wide range of bone turnover. Bone 51:153–157PubMedCrossRef Yavropoulou MP, van Lierop AH, Hamdy NAT, Rizzoli R, Papapoulos SE (2012) Serum sclerostin levels in Paget’s disease and prostate cancer with bone metastases with a wide range of bone turnover. Bone 51:153–157PubMedCrossRef
153.
Zurück zum Zitat Larson SR, Zhang X, Dumpit R, Coleman I, Lakely B, Roudier M, Higano CS, True LD, Lange PH, Montgomery B, Corey E, Nelson PS, Vessella RL, Morrissey C (2013) Characterization of osteoblastic and osteolytic proteins in prostate cancer bone metastases. Prostate 73:932–940PubMedPubMedCentralCrossRef Larson SR, Zhang X, Dumpit R, Coleman I, Lakely B, Roudier M, Higano CS, True LD, Lange PH, Montgomery B, Corey E, Nelson PS, Vessella RL, Morrissey C (2013) Characterization of osteoblastic and osteolytic proteins in prostate cancer bone metastases. Prostate 73:932–940PubMedPubMedCentralCrossRef
154.
Zurück zum Zitat Hudson BD, Hum NR, Thomas CB, Kohlgruber A, Sebastian A, Collette NM, Coleman MA, Christiansen BA, Loots GG (2015) SOST inhibits prostate cancer invasion. PLoS ONE 10:e0142058PubMedPubMedCentralCrossRef Hudson BD, Hum NR, Thomas CB, Kohlgruber A, Sebastian A, Collette NM, Coleman MA, Christiansen BA, Loots GG (2015) SOST inhibits prostate cancer invasion. PLoS ONE 10:e0142058PubMedPubMedCentralCrossRef
155.
Zurück zum Zitat Jiang Y, Dai J, Zhang H, Sottnik JL, Keller JM, Escott KJ, Sanganee HJ, Yao Z, McCauley LK, Keller ET (2013) Activation of the wnt pathway through AR79, a GSK3ß inhibitor, promotes prostate cancer growth in soft tissue and bone. Mol Cancer Res 11:1597–1610PubMedCrossRef Jiang Y, Dai J, Zhang H, Sottnik JL, Keller JM, Escott KJ, Sanganee HJ, Yao Z, McCauley LK, Keller ET (2013) Activation of the wnt pathway through AR79, a GSK3ß inhibitor, promotes prostate cancer growth in soft tissue and bone. Mol Cancer Res 11:1597–1610PubMedCrossRef
156.
Zurück zum Zitat Veverka V, Henry AJ, Slocombe PM, Ventom A, Mulloy B, Muskett FW, Muzylak M, Greenslade K, Moore A, Zhang L, Gong J, Qian X, Paszty C, Taylor RJ, Robinson MK, Carr MD (2009) Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation. J Biol Chem 284:10890–10900PubMedPubMedCentralCrossRef Veverka V, Henry AJ, Slocombe PM, Ventom A, Mulloy B, Muskett FW, Muzylak M, Greenslade K, Moore A, Zhang L, Gong J, Qian X, Paszty C, Taylor RJ, Robinson MK, Carr MD (2009) Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation. J Biol Chem 284:10890–10900PubMedPubMedCentralCrossRef
157.
Zurück zum Zitat Nioi P, Taylor S, Hu R, Pacheco E, He YD, Hamadeh H, Paszty C, Pyrah I, Ominsky MS, Boyce RW (2015) Transcriptional profiling of laser capture microdissected subpopulations of the osteoblast lineage provides insight into the early response to sclerostin antibody in rats. J Bone Miner Res 30:1457–1467PubMedCrossRef Nioi P, Taylor S, Hu R, Pacheco E, He YD, Hamadeh H, Paszty C, Pyrah I, Ominsky MS, Boyce RW (2015) Transcriptional profiling of laser capture microdissected subpopulations of the osteoblast lineage provides insight into the early response to sclerostin antibody in rats. J Bone Miner Res 30:1457–1467PubMedCrossRef
158.
Zurück zum Zitat Taylor S, Ominsky MS, Hu R, Pacheco E, He YD, Brown DL, Aguirre JI, Wronski TJ, Buntich S, Afshari CA, Pyrah I, Nioi P, Boyce RW (2016) Time-dependent cellular and transcriptional changes in the osteoblast lineage associated with sclerostin antibody treatment in ovariectomized rats. Bone 84:148–159PubMedCrossRef Taylor S, Ominsky MS, Hu R, Pacheco E, He YD, Brown DL, Aguirre JI, Wronski TJ, Buntich S, Afshari CA, Pyrah I, Nioi P, Boyce RW (2016) Time-dependent cellular and transcriptional changes in the osteoblast lineage associated with sclerostin antibody treatment in ovariectomized rats. Bone 84:148–159PubMedCrossRef
159.
Zurück zum Zitat Reagan MR, McDonald M, Terry R, Pettitt J, Le L, Mohanty S, Kneissel M, Kramer I, Brooks D, Bouxsein M, Rosen CJ, Ghobrial IM, Croucher P (2015) Anti-sclerostin treatment prevents multiple myeloma induced bone loss and reduces tumor burden. Blood 126:119 Reagan MR, McDonald M, Terry R, Pettitt J, Le L, Mohanty S, Kneissel M, Kramer I, Brooks D, Bouxsein M, Rosen CJ, Ghobrial IM, Croucher P (2015) Anti-sclerostin treatment prevents multiple myeloma induced bone loss and reduces tumor burden. Blood 126:119
160.
Zurück zum Zitat McClung MR, Grauer A, Boonen S, Bolognese MA, Brown JP, Diez-Perez A, Langdahl BL, Reginster J-, Zanchetta JR, Wasserman SM, Katz L, Maddox J, Yang Y-, Libanati C, Bone HG (2014) Romosozumab in postmenopausal women with low bone mineral density. New Engl J Med 370:412–420PubMedCrossRef McClung MR, Grauer A, Boonen S, Bolognese MA, Brown JP, Diez-Perez A, Langdahl BL, Reginster J-, Zanchetta JR, Wasserman SM, Katz L, Maddox J, Yang Y-, Libanati C, Bone HG (2014) Romosozumab in postmenopausal women with low bone mineral density. New Engl J Med 370:412–420PubMedCrossRef
161.
Zurück zum Zitat Recker RR, Benson CT, Matsumoto T, Bolognese MA, Robins DA, Alam J, Chiang AY, Hu L, Krege JH, Sowa H, Mitlak BH, Myers SL (2015) A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. J Bone Miner Res 30:216–224PubMedCrossRef Recker RR, Benson CT, Matsumoto T, Bolognese MA, Robins DA, Alam J, Chiang AY, Hu L, Krege JH, Sowa H, Mitlak BH, Myers SL (2015) A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. J Bone Miner Res 30:216–224PubMedCrossRef
162.
Zurück zum Zitat Lewiecki EM (2014) Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases. Ther Adv Musculoskelet Dis 6:48–57PubMedPubMedCentralCrossRef Lewiecki EM (2014) Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases. Ther Adv Musculoskelet Dis 6:48–57PubMedPubMedCentralCrossRef
163.
Zurück zum Zitat Voorzanger-Rousselot N, Goehrig D, Journe F, Doriath V, Body JJ, Clezardin P, Garnero P (2007) Increased Dickkopf-1 expression in breast cancer bone metastases. Br J Cancer 97:964–970PubMedPubMedCentralCrossRef Voorzanger-Rousselot N, Goehrig D, Journe F, Doriath V, Body JJ, Clezardin P, Garnero P (2007) Increased Dickkopf-1 expression in breast cancer bone metastases. Br J Cancer 97:964–970PubMedPubMedCentralCrossRef
164.
Zurück zum Zitat Heath DJ, Chantry AD, Buckle CH, Coulton L, Shaughnessy JD, Evans HR, Snowden JA, Stover DR, Vanderkerken K, Croucher PI (2009) Inhibiting Dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. J Bone Miner Res 24:425–436PubMedCrossRef Heath DJ, Chantry AD, Buckle CH, Coulton L, Shaughnessy JD, Evans HR, Snowden JA, Stover DR, Vanderkerken K, Croucher PI (2009) Inhibiting Dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. J Bone Miner Res 24:425–436PubMedCrossRef
165.
Zurück zum Zitat Rachner TD, Gobel A, Benad-Mehner P, Hofbauer LC, Rauner M (2014) Dickkopf-1 as a mediator and novel target in malignant bone disease. Cancer Lett 346:172–177PubMedCrossRef Rachner TD, Gobel A, Benad-Mehner P, Hofbauer LC, Rauner M (2014) Dickkopf-1 as a mediator and novel target in malignant bone disease. Cancer Lett 346:172–177PubMedCrossRef
166.
Zurück zum Zitat Goldstein SD, Trucco M, Bautista Guzman W, Hayashi M, Loeb DM (2016) A monoclonal antibody against the Wnt signaling inhibitor dickkopf-1 inhibits osteosarcoma metastasis in a preclinical model. Oncotarget 7:21114–21123PubMedPubMedCentralCrossRef Goldstein SD, Trucco M, Bautista Guzman W, Hayashi M, Loeb DM (2016) A monoclonal antibody against the Wnt signaling inhibitor dickkopf-1 inhibits osteosarcoma metastasis in a preclinical model. Oncotarget 7:21114–21123PubMedPubMedCentralCrossRef
167.
Zurück zum Zitat Iyer SP, Beck JT, Stewart AK, Shah J, Kelly KR, Isaacs R, Bilic S, Sen S, Munshi NC (2014) A phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events. Br J Haematol 167:366–375PubMedCrossRef Iyer SP, Beck JT, Stewart AK, Shah J, Kelly KR, Isaacs R, Bilic S, Sen S, Munshi NC (2014) A phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events. Br J Haematol 167:366–375PubMedCrossRef
168.
Zurück zum Zitat Florio M, Gunasekaran K, Stolina M, Li X, Liu L, Tipton B, Salimi-Moosavi H, Asuncion FJ, Li C, Sun B, Tan HL, Zhang L, Han CY, Case R, Duguay AN, Grisanti M, Stevens J, Pretorius JK, Pacheco E, Jones H, Chen Q, Soriano BD, Wen J, Heron B, Jacobsen FW, Brisan E, Richards WG, Ke HZ, Ominsky MS (2016) A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. Nat Commun 7:11505PubMedPubMedCentralCrossRef Florio M, Gunasekaran K, Stolina M, Li X, Liu L, Tipton B, Salimi-Moosavi H, Asuncion FJ, Li C, Sun B, Tan HL, Zhang L, Han CY, Case R, Duguay AN, Grisanti M, Stevens J, Pretorius JK, Pacheco E, Jones H, Chen Q, Soriano BD, Wen J, Heron B, Jacobsen FW, Brisan E, Richards WG, Ke HZ, Ominsky MS (2016) A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. Nat Commun 7:11505PubMedPubMedCentralCrossRef
170.
Zurück zum Zitat Kitagawa Y, Dai J, Zhang J, Keller JM, Nor J, Yao Z, Keller ET (2005) Vascular endothelial growth factor contributes to prostate cancer-mediated osteoblastic activity. Cancer Res 65:10921–10929PubMedCrossRef Kitagawa Y, Dai J, Zhang J, Keller JM, Nor J, Yao Z, Keller ET (2005) Vascular endothelial growth factor contributes to prostate cancer-mediated osteoblastic activity. Cancer Res 65:10921–10929PubMedCrossRef
171.
Zurück zum Zitat Nakashiro K, Hayashi Y, Oyasu R (2003) Immunohistochemical expression of hepatocyte growth factor and c-Met/HGF receptor in benign and malignant human prostate tissue. Oncol Rep 10:1149–1153PubMed Nakashiro K, Hayashi Y, Oyasu R (2003) Immunohistochemical expression of hepatocyte growth factor and c-Met/HGF receptor in benign and malignant human prostate tissue. Oncol Rep 10:1149–1153PubMed
172.
Zurück zum Zitat Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH (2011) Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 10:2298–2308PubMedCrossRef Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH (2011) Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 10:2298–2308PubMedCrossRef
173.
Zurück zum Zitat Nguyen HM, Ruppender N, Zhang X, Brown LG, Gross TS, Morrissey C, Gulati R, Vessella RL, Schimmoller F, Aftab DT, Corey E (2013) Cabozantinib inhibits growth of androgen-sensitive and castration-resistant prostate cancer and affects bone remodeling. PLoS ONE 8:e78881PubMedPubMedCentralCrossRef Nguyen HM, Ruppender N, Zhang X, Brown LG, Gross TS, Morrissey C, Gulati R, Vessella RL, Schimmoller F, Aftab DT, Corey E (2013) Cabozantinib inhibits growth of androgen-sensitive and castration-resistant prostate cancer and affects bone remodeling. PLoS ONE 8:e78881PubMedPubMedCentralCrossRef
174.
Zurück zum Zitat Dai J, Zhang H, Karatsinides A, Keller JM, Kozloff KM, Aftab DT, Schimmoller F, Keller ET (2014) Cabozantinib inhibits prostate cancer growth and prevents tumor-induced bone lesions. Clin Cancer Res 20:617–630PubMedCrossRef Dai J, Zhang H, Karatsinides A, Keller JM, Kozloff KM, Aftab DT, Schimmoller F, Keller ET (2014) Cabozantinib inhibits prostate cancer growth and prevents tumor-induced bone lesions. Clin Cancer Res 20:617–630PubMedCrossRef
175.
Zurück zum Zitat Varkaris A, Corn PG, Parikh NU, Efstathiou E, Song JH, Lee Y, Aparicio A, Hoang AG, Gaur S, Thorpe L, Maity SN, Bar Eli M, Czerniak BA, Shao Y, Alauddin M, Lin S, Logothetis CJ, Gallick GE (2016) Integrating murine and clinical trials with cabozantinib to understand roles of MET and VEGFR2 as targets for growth inhibition of prostate cancer. Clin Cancer Res 22:107PubMedCrossRef Varkaris A, Corn PG, Parikh NU, Efstathiou E, Song JH, Lee Y, Aparicio A, Hoang AG, Gaur S, Thorpe L, Maity SN, Bar Eli M, Czerniak BA, Shao Y, Alauddin M, Lin S, Logothetis CJ, Gallick GE (2016) Integrating murine and clinical trials with cabozantinib to understand roles of MET and VEGFR2 as targets for growth inhibition of prostate cancer. Clin Cancer Res 22:107PubMedCrossRef
176.
Zurück zum Zitat Watanabe K, Hirata M, Tominari T, Matsumoto C, Fujita H, Yonekura K, Murphy G, Nagase H, Miyaura C, Inada M (2016) The MET/vascular endothelial growth factor receptor (VEGFR)-targeted tyrosine kinase inhibitor also attenuates FMS-dependent osteoclast differentiation and bone destruction induced by prostate cancer. J Biol Chem 291:20891–20899PubMedPubMedCentralCrossRef Watanabe K, Hirata M, Tominari T, Matsumoto C, Fujita H, Yonekura K, Murphy G, Nagase H, Miyaura C, Inada M (2016) The MET/vascular endothelial growth factor receptor (VEGFR)-targeted tyrosine kinase inhibitor also attenuates FMS-dependent osteoclast differentiation and bone destruction induced by prostate cancer. J Biol Chem 291:20891–20899PubMedPubMedCentralCrossRef
177.
Zurück zum Zitat Fujita H, Gomori A, Fujioka Y, Kataoka Y, Tanaka K, Hashimoto A, Suzuki T, Ito K, Haruma T, Yamamoto-Yokoi H, Harada N, Sakuragi M, Oda N, Matsuo K, Inada M, Yonekura K (2016) High potency VEGFRs/MET/FMS triple blockade by TAS-115 concomitantly suppresses tumor progression and bone destruction in tumor-induced bone disease model with lung carcinoma cells. PLoS ONE 11:e0164830PubMedPubMedCentralCrossRef Fujita H, Gomori A, Fujioka Y, Kataoka Y, Tanaka K, Hashimoto A, Suzuki T, Ito K, Haruma T, Yamamoto-Yokoi H, Harada N, Sakuragi M, Oda N, Matsuo K, Inada M, Yonekura K (2016) High potency VEGFRs/MET/FMS triple blockade by TAS-115 concomitantly suppresses tumor progression and bone destruction in tumor-induced bone disease model with lung carcinoma cells. PLoS ONE 11:e0164830PubMedPubMedCentralCrossRef
178.
Zurück zum Zitat Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, Krainer M, Bergman A, Hoelzer W, De Wit R, Bogemann M, Saad F, Cruciani G, Thiery-Vuillemin A, Feyerabend S, Miller K, Houede N, Hussain S, Lam E, Polikoff J, Stenzl A, Mainwaring P, Ramies D, Hessel C, Weitzman A, Fizazi K (2016) Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol 34:3005–3013PubMedCrossRef Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, Krainer M, Bergman A, Hoelzer W, De Wit R, Bogemann M, Saad F, Cruciani G, Thiery-Vuillemin A, Feyerabend S, Miller K, Houede N, Hussain S, Lam E, Polikoff J, Stenzl A, Mainwaring P, Ramies D, Hessel C, Weitzman A, Fizazi K (2016) Phase III study of cabozantinib in previously treated metastatic castration-resistant prostate cancer: COMET-1. J Clin Oncol 34:3005–3013PubMedCrossRef
180.
Zurück zum Zitat Graham TJ, Box G, Tunariu N, Crespo M, Spinks TJ, Miranda S, Attard G, de Bono J, Eccles SA, Davies FE, Robinson SP (2014) Preclinical evaluation of imaging biomarkers for prostate cancer bone metastasis and response to cabozantinib. J Natl Cancer Inst. doi:10.1093/jnci/dju033 PubMedCentral Graham TJ, Box G, Tunariu N, Crespo M, Spinks TJ, Miranda S, Attard G, de Bono J, Eccles SA, Davies FE, Robinson SP (2014) Preclinical evaluation of imaging biomarkers for prostate cancer bone metastasis and response to cabozantinib. J Natl Cancer Inst. doi:10.​1093/​jnci/​dju033 PubMedCentral
181.
182.
Zurück zum Zitat Stucci S, Tucci M, Passarelli A, Silvestris F (2015) Avβ3 integrin: pathogenetic role in osteotropic tumors. Crit Rev Oncol Hematol 96:183–193PubMedCrossRef Stucci S, Tucci M, Passarelli A, Silvestris F (2015) Avβ3 integrin: pathogenetic role in osteotropic tumors. Crit Rev Oncol Hematol 96:183–193PubMedCrossRef
183.
Zurück zum Zitat Davies J, Warwick J, Totty N, Philp R, Helfrich M, Horton M (1989) The osteoclast functional antigen, implicated in the regulation of bone resorption, is biochemically related to the vitronectin receptor. J Cell Biol 109:1817–1826PubMedCrossRef Davies J, Warwick J, Totty N, Philp R, Helfrich M, Horton M (1989) The osteoclast functional antigen, implicated in the regulation of bone resorption, is biochemically related to the vitronectin receptor. J Cell Biol 109:1817–1826PubMedCrossRef
184.
Zurück zum Zitat Zhao Y, Bachelier R, Treilleux I, Pujuguet P, Peyruchaud O, Baron R, Clement-Lacroix P, Clezardin P (2007) Tumor Avβ3 integrin is a therapeutic target for breast cancer bone metastases. Cancer Res 67:5821–5830PubMedCrossRef Zhao Y, Bachelier R, Treilleux I, Pujuguet P, Peyruchaud O, Baron R, Clement-Lacroix P, Clezardin P (2007) Tumor Avβ3 integrin is a therapeutic target for breast cancer bone metastases. Cancer Res 67:5821–5830PubMedCrossRef
185.
Zurück zum Zitat Carter RZ, Micocci KC, Natoli A, Redvers RP, Paquet-Fifield S, Martin AC, Denoyer D, Ling X, Kim SH, Tomasin R, Selistre-de-Araujo H, Anderson RL, Pouliot N (2015) Tumour but not stromal expression of β3 integrin is essential, and is required early, for spontaneous dissemination of bone-metastatic breast cancer. J Pathol 235:760–772PubMedCrossRef Carter RZ, Micocci KC, Natoli A, Redvers RP, Paquet-Fifield S, Martin AC, Denoyer D, Ling X, Kim SH, Tomasin R, Selistre-de-Araujo H, Anderson RL, Pouliot N (2015) Tumour but not stromal expression of β3 integrin is essential, and is required early, for spontaneous dissemination of bone-metastatic breast cancer. J Pathol 235:760–772PubMedCrossRef
186.
Zurück zum Zitat Gvozdenovic A, Boro A, Meier D, Bode-Lesniewska B, Born W, Muff R, Fuchs B (2016) Targeting αvβ3 and alphavbeta5 integrins inhibits pulmonary metastasis in an intratibial xenograft osteosarcoma mouse model. Oncotarget 7:55141–55154PubMedPubMedCentralCrossRef Gvozdenovic A, Boro A, Meier D, Bode-Lesniewska B, Born W, Muff R, Fuchs B (2016) Targeting αvβ3 and alphavbeta5 integrins inhibits pulmonary metastasis in an intratibial xenograft osteosarcoma mouse model. Oncotarget 7:55141–55154PubMedPubMedCentralCrossRef
187.
Zurück zum Zitat Yao H, Veine DM, Livant DL (2016) Therapeutic inhibition of breast cancer bone metastasis progression and lung colonization: breaking the vicious cycle by targeting α5β1 integrin. Breast Cancer Res Treat 157:489–501PubMedCrossRef Yao H, Veine DM, Livant DL (2016) Therapeutic inhibition of breast cancer bone metastasis progression and lung colonization: breaking the vicious cycle by targeting α5β1 integrin. Breast Cancer Res Treat 157:489–501PubMedCrossRef
188.
Zurück zum Zitat Rucci N, Capulli M, Olstad OK, Önnerfjord P, Tillgren V, Gautvik KM, Heinegård D, Teti A (2015) The α2β1 binding domain of chondroadherin inhibits breast cancer-induced bone metastases and impairs primary tumour growth: a preclinical study. Cancer Lett 358:67–75PubMedCrossRef Rucci N, Capulli M, Olstad OK, Önnerfjord P, Tillgren V, Gautvik KM, Heinegård D, Teti A (2015) The α2β1 binding domain of chondroadherin inhibits breast cancer-induced bone metastases and impairs primary tumour growth: a preclinical study. Cancer Lett 358:67–75PubMedCrossRef
189.
Zurück zum Zitat Gramoun A, Shorey S, Bashutski JD, Dixon SJ, Sims SM, Heersche JN, Manolson MF (2007) Effects of Vitaxin, a novel therapeutic in trial for metastatic bone tumors, on osteoclast functions in vitro. J Cell Biochem 102:341–352PubMedCrossRef Gramoun A, Shorey S, Bashutski JD, Dixon SJ, Sims SM, Heersche JN, Manolson MF (2007) Effects of Vitaxin, a novel therapeutic in trial for metastatic bone tumors, on osteoclast functions in vitro. J Cell Biochem 102:341–352PubMedCrossRef
190.
Zurück zum Zitat Bradley DA, Daignault S, Ryan CJ, Dipaola RS, Cooney KA, Smith DC, Small E, Mathew P, Gross ME, Stein MN, Chen A, Pienta KJ, Escara-Wilke J, Doyle G, Al-Hawary M, Keller ET, Hussain M (2011) Cilengitide (EMD 121974, NSC 707544) in asymptomatic metastatic castration resistant prostate cancer patients: a randomized phase II trial by the prostate cancer clinical trials consortium. Invest New Drugs 29:1432–1440PubMedCrossRef Bradley DA, Daignault S, Ryan CJ, Dipaola RS, Cooney KA, Smith DC, Small E, Mathew P, Gross ME, Stein MN, Chen A, Pienta KJ, Escara-Wilke J, Doyle G, Al-Hawary M, Keller ET, Hussain M (2011) Cilengitide (EMD 121974, NSC 707544) in asymptomatic metastatic castration resistant prostate cancer patients: a randomized phase II trial by the prostate cancer clinical trials consortium. Invest New Drugs 29:1432–1440PubMedCrossRef
191.
Zurück zum Zitat Kenny LM, Coombes RC, Oulie I, Contractor KB, Miller M, Spinks TJ, McParland B, Cohen PS, Hui AM, Palmieri C, Osman S, Glaser M, Turton D, Al-Nahhas A, Aboagye EO (2008) Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients. J Nucl Med 49:879–886PubMedCrossRef Kenny LM, Coombes RC, Oulie I, Contractor KB, Miller M, Spinks TJ, McParland B, Cohen PS, Hui AM, Palmieri C, Osman S, Glaser M, Turton D, Al-Nahhas A, Aboagye EO (2008) Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients. J Nucl Med 49:879–886PubMedCrossRef
192.
Zurück zum Zitat Zhang J, Niu G, Lang L, Li F, Fan X, Yan X, Yao S, Yan W, Huo L, Chen L, Li Z, Zhu Z, Chen X (2017) Clinical translation of a dual integrin αvβ3- and gastrin-releasing peptide receptor-targeting pet radiotracer, 68 Ga-BBN-RGD. J Nucl Med 58:228–234PubMedPubMedCentralCrossRef Zhang J, Niu G, Lang L, Li F, Fan X, Yan X, Yao S, Yan W, Huo L, Chen L, Li Z, Zhu Z, Chen X (2017) Clinical translation of a dual integrin αvβ3- and gastrin-releasing peptide receptor-targeting pet radiotracer, 68 Ga-BBN-RGD. J Nucl Med 58:228–234PubMedPubMedCentralCrossRef
193.
Zurück zum Zitat Gaddy-Kurten D, Coker JK, Abe E, Jilka RL, Manolagas SC (2002) Inhibin suppresses and activin stimulates osteoblastogenesis and osteoclastogenesis in murine bone marrow cultures. Endocrinology 143:74–83PubMedCrossRef Gaddy-Kurten D, Coker JK, Abe E, Jilka RL, Manolagas SC (2002) Inhibin suppresses and activin stimulates osteoblastogenesis and osteoclastogenesis in murine bone marrow cultures. Endocrinology 143:74–83PubMedCrossRef
194.
Zurück zum Zitat Chantry AD, Heath D, Mulivor AW, Pearsall S, Baud’huin M, Coulton L, Evans H, Abdul N, Werner ED, Bouxsein ML, Key ML, Seehra J, Arnett TR, Vanderkerken K, Croucher P (2010) Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo. J Bone Miner Res 25:2633–2646PubMedCrossRef Chantry AD, Heath D, Mulivor AW, Pearsall S, Baud’huin M, Coulton L, Evans H, Abdul N, Werner ED, Bouxsein ML, Key ML, Seehra J, Arnett TR, Vanderkerken K, Croucher P (2010) Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo. J Bone Miner Res 25:2633–2646PubMedCrossRef
195.
Zurück zum Zitat Kang HY, Huang HY, Hsieh CY, Li CF, Shyr CR, Tsai MY, Chang C, Chuang YC, Huang KE (2009) Activin A enhances prostate cancer cell migration through activation of androgen receptor and is overexpressed in metastatic prostate cancer. J Bone Miner Res 24:1180–1193PubMedCrossRef Kang HY, Huang HY, Hsieh CY, Li CF, Shyr CR, Tsai MY, Chang C, Chuang YC, Huang KE (2009) Activin A enhances prostate cancer cell migration through activation of androgen receptor and is overexpressed in metastatic prostate cancer. J Bone Miner Res 24:1180–1193PubMedCrossRef
196.
Zurück zum Zitat Vallet S, Mukherjee S, Vaghela N, Hideshima T, Fulciniti M, Pozzi S, Santo L, Cirstea D, Patel K, Sohani AR, Guimaraes A, Xie W, Chauhan D, Schoonmaker JA, Attar E, Churchill M, Weller E, Munshi N, Seehra JS, Weissleder R, Anderson KC, Scadden DT, Raje N (2010) Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proc Natl Acad Sci USA 107:5124–5129PubMedPubMedCentralCrossRef Vallet S, Mukherjee S, Vaghela N, Hideshima T, Fulciniti M, Pozzi S, Santo L, Cirstea D, Patel K, Sohani AR, Guimaraes A, Xie W, Chauhan D, Schoonmaker JA, Attar E, Churchill M, Weller E, Munshi N, Seehra JS, Weissleder R, Anderson KC, Scadden DT, Raje N (2010) Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proc Natl Acad Sci USA 107:5124–5129PubMedPubMedCentralCrossRef
198.
Zurück zum Zitat Silbermann R, Bolzoni M, Storti P, Guasco D, Bonomini S, Zhou D, Wu J, Anderson JL, Windle JJ, Aversa F, Roodman GD, Giuliani N (2014) Bone marrow monocyte-/macrophage-derived activin A mediates the osteoclastogenic effect of IL-3 in multiple myeloma. Leukemia 28:951–954PubMedCrossRef Silbermann R, Bolzoni M, Storti P, Guasco D, Bonomini S, Zhou D, Wu J, Anderson JL, Windle JJ, Aversa F, Roodman GD, Giuliani N (2014) Bone marrow monocyte-/macrophage-derived activin A mediates the osteoclastogenic effect of IL-3 in multiple myeloma. Leukemia 28:951–954PubMedCrossRef
199.
Zurück zum Zitat Abdulkadyrov KM, Salogub GN, Khuazheva NK, Sherman ML, Laadem A, Barger R, Knight R, Srinivasan S, Terpos E (2014) Sotatercept in patients with osteolytic lesions of multiple myeloma. Br J Haematol 165:814–823PubMedPubMedCentralCrossRef Abdulkadyrov KM, Salogub GN, Khuazheva NK, Sherman ML, Laadem A, Barger R, Knight R, Srinivasan S, Terpos E (2014) Sotatercept in patients with osteolytic lesions of multiple myeloma. Br J Haematol 165:814–823PubMedPubMedCentralCrossRef
200.
Zurück zum Zitat Scullen T, Santo L, Vallet S, Fulciniti M, Eda H, Cirstea D, Patel K, Nemani N, Yee A, Mahindra A, Raje N (2013) Lenalidomide in combination with an activin A-neutralizing antibody: preclinical rationale for a novel anti-myeloma strategy. Leukemia 27:1715–1721PubMedCrossRef Scullen T, Santo L, Vallet S, Fulciniti M, Eda H, Cirstea D, Patel K, Nemani N, Yee A, Mahindra A, Raje N (2013) Lenalidomide in combination with an activin A-neutralizing antibody: preclinical rationale for a novel anti-myeloma strategy. Leukemia 27:1715–1721PubMedCrossRef
Metadaten
Titel
Bone-Targeted Therapies in Cancer-Induced Bone Disease
verfasst von
Sofia Sousa
Philippe Clézardin
Publikationsdatum
27.10.2017
Verlag
Springer US
Erschienen in
Calcified Tissue International / Ausgabe 2/2018
Print ISSN: 0171-967X
Elektronische ISSN: 1432-0827
DOI
https://doi.org/10.1007/s00223-017-0353-5

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