Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende
Erweiterte Suche
Anmelden
nach oben
Current Oncology Reports
Erschienen in: Current Oncology Reports 2/2013

01.04.2013 | Evolving Therapies (RM Bukowski, Section Editor)

Targeting the Adrenal Gland in Castration-Resistant Prostate Cancer: A Case for Orteronel, a Selective CYP-17 17,20-Lyase Inhibitor

verfasst von: Hui Zhu, Jorge A. Garcia

Erschienen in: Current Oncology Reports | Ausgabe 2/2013

Einloggen, um Zugang zu erhalten

Abstract

Androgen and the androgen receptor (AR) pathway remain the key targets for emerging new therapies against castration-resistant prostate cancer (CRPC). Adrenal androgens and intratumoral testosterone production appear to be sufficient to activate AR in the castration-resistant setting. This process re-engages AR and allows it to continue to be the primary target responsible for prostate cancer progression. Adrenal androgen production can be blocked by inhibiting cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17), a key enzyme for androgen synthesis in adrenal glands and peripheral tissues. Therapeutic CYP17 inhibition by ketoconazole or by the recently approved adrenal inhibitor abiraterone acetate is the only available choice to target this pathway in CRPC. A new CYP17 inhibitor, with more selective inhibition of 17,20-lyase over 17α-hydroxylase, orteronel (TAK-700), is currently undergoing phase III clinical trials in pre- and postchemotherapy CRPC. In a completed phase II trial in CRPC patients, orteronel demonstrated its efficacy by lowering the levels of circulating androgens, reducing prostate-specific antigen (PSA) levels, and decreasing the levels of circulating tumor cells. Ongoing studies evaluating orteronel in CRPC will further define its safety and role in the management of this disease.
Literatur
1.
Huggins C. Effect of orchiectomy and irradiation on cancer of the prostate. Ann Surg. 1942;115:1192–200.PubMedCrossRef
2.
Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med. 1989;321:419–24.PubMedCrossRef
3.
Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med. 1998;339:1036–42.PubMedCrossRef
4.
• de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005. This phase III trial demonstrated the overall survival benefit of abiraterone acetate in docetaxel-refractory CRPC patients and led to its FDA approval.PubMedCrossRef
5.
Chatterjee B. The role of the androgen receptor in the development of prostatic hyperplasia and prostate cancer. Mol Cell Biochem. 2003;253:89–101.PubMedCrossRef
6.
Denis LJ, Griffiths K. Endocrine treatment in prostate cancer. Semin Surg Oncol. 2000;18:52–74.PubMedCrossRef
7.
Mohler JL, Gregory CW, Ford 3rd OH, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004;10:440–8.PubMedCrossRef
8.
Brinkmann AO, Blok LJ, de Ruiter PE, et al. Mechanisms of androgen receptor activation and function. J Steroid Biochem Mol Biol. 1999;69:307–13.PubMedCrossRef
9.
Quigley CA, De Bellis A, Marschke KB, et al. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev. 1995;16:271–321.PubMed
10.
Pratt WB, Toft DO. Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev. 1997;18:306–60.PubMedCrossRef
11.
Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1:34–45.PubMedCrossRef
12.
Nelson PS, Clegg N, Arnold H, et al. The program of androgen-responsive genes in neoplastic prostate epithelium. Proc Natl Acad Sci USA. 2002;99:11890–5.PubMedCrossRef
13.
Harper ME, Pike A, Peeling WB, Griffiths K. Steroids of adrenal origin metabolized by human prostatic tissue both in vivo and in vitro. J Endocrinol. 1974;60:117–25.PubMedCrossRef
14.
Koh E, Kanaya J, Namiki M. Adrenal steroids in human prostatic cancer cell lines. Arch Androl. 2001;46:117–25.PubMedCrossRef
15.
Titus MA, Schell MJ, Lih FB, et al. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11:4653–7.PubMedCrossRef
16.
Nishiyama T, Hashimoto Y, Takahashi K. The influence of androgen deprivation therapy on dihydrotestosterone levels in the prostatic tissue of patients with prostate cancer. Clin Cancer Res. 2004;10:7121–6.PubMedCrossRef
17.
Mizokami A, Koh E, Fujita H, et al. The adrenal androgen androstenediol is present in prostate cancer tissue after androgen deprivation therapy and activates mutated androgen receptor. Cancer Res. 2004;64:765–71.PubMedCrossRef
18.
Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66:2815–25.PubMedCrossRef
19.
Suzuki K, Nishiyama T, Hara N, et al. Importance of the intracrine metabolism of adrenal androgens in androgen-dependent prostate cancer. Prostate Cancer Prostatic Dis. 2007;10:301–6.PubMedCrossRef
20.
Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68:6407–15.PubMedCrossRef
21.
Yamaoka M, Hara T, Hitaka T, et al. Orteronel (TAK-700), a novel non-steroidal 17,20-lyase inhibitor: effects on steroid synthesis in human and monkey adrenal cells and serum steroid levels in cynomolgus monkeys. J Steroid Biochem Mol Biol. 2012;129:115–28.PubMedCrossRef
22.
O'Donnell A, Judson I, Dowsett M, et al. Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer. 2004;90:2317–25.PubMed
23.
Koivisto P, Kononen J, Palmberg C, et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 1997;57:314–9.PubMed
24.
Visakorpi T, Hyytinen E, Koivisto P, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet. 1995;9:401–6.PubMedCrossRef
25.
Gregory CW, Johnson Jr RT, Mohler JL, et al. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 2001;61:2892–8.PubMed
26.
Palmberg C, Koivisto P, Kakkola L, et al. Androgen receptor gene amplification at primary progression predicts response to combined androgen blockade as second line therapy for advanced prostate cancer. J Urol. 2000;164:1992–5.PubMedCrossRef
27.
Gaddipati JP, McLeod DG, Heidenberg HB, et al. Frequent detection of codon 877 mutation in the androgen receptor gene in advanced prostate cancers. Cancer Res. 1994;54:2861–4.PubMed
28.
Taplin ME, Bubley GJ, Ko YJ, et al. Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist. Cancer Res. 1999;59:2511–5.PubMed
29.
Veldscholte J, Berrevoets CA, Ris-Stalpers C, et al. The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. J Steroid Biochem Mol Biol. 1992;41:665–9.PubMedCrossRef
30.
Culig Z, Steiner H, Bartsch G, Hobisch A. Interleukin-6 regulation of prostate cancer cell growth. J Cell Biochem. 2005;95:497–505.PubMedCrossRef
31.
Culig Z, Hobisch A, Cronauer MV, et al. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res. 1994;54:5474–8.PubMed
32.
Hobisch A, Eder IE, Putz T, et al. Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor. Cancer Res. 1998;58:4640–5.PubMed
33.
Singh RK, Sudhakar A, Lokeshwar BL. Role of chemokines and chemokine receptors in prostate cancer development and progression. J Cancer Sci Ther. 2010;2:89–94.PubMedCrossRef
34.
Wu JD, Haugk K, Woodke L, et al. Interaction of IGF signaling and the androgen receptor in prostate cancer progression. J Cell Biochem. 2006;99:392–401.PubMedCrossRef
35.
Zhao XY, Malloy PJ, Krishnan AV, et al. Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nat Med. 2000;6:703–6.PubMedCrossRef
36.
Medema RH, Kops GJ, Bos JL, Burgering BM. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature. 2000;404:782–7.PubMedCrossRef
37.
Graff JR, Konicek BW, McNulty AM, et al. Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem. 2000;275:24500–5.PubMedCrossRef
38.
Sarker D, Reid AH, Yap TA, de Bono JS. Targeting the PI3K/AKT pathway for the treatment of prostate cancer. Clin Cancer Res. 2009;15:4799–805.PubMedCrossRef
39.
Humphrey PA, Zhu X, Zarnegar R, et al. Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am J Pathol. 1995;147:386–96.PubMed
40.
• Hussain M, Smith MR, Sweeney C, et al. Cabozantinib (XL184) in metastatic castration-resistant prostate cancer (mCRPC): results from a phase II randomized discontinuation trial. J Clin Oncol. 2011;29:abstr 4516. This early-phase study demonstrated clinical efficacy of XL184 in metastatic CRPC patients.
41.
Ruijter E, van de Kaa C, Miller G, et al. Molecular genetics and epidemiology of prostate carcinoma. Endocr Rev. 1999;20:22–45.PubMedCrossRef
42.
Marcelli M, Ittmann M, Mariani S, et al. Androgen receptor mutations in prostate cancer. Cancer Res. 2000;60:944–9.PubMed
43.
Cher ML, Bova GS, Moore DH, et al. Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping. Cancer Res. 1996;56:3091–102.PubMed
44.
Palmberg C, Koivisto P, Hyytinen E, et al. Androgen receptor gene amplification in a recurrent prostate cancer after monotherapy with the nonsteroidal potent antiandrogen Casodex (bicalutamide) with a subsequent favorable response to maximal androgen blockade. Eur Urol. 1997;31:216–9.PubMed
45.
Tilley WD, Buchanan G, Hickey TE, Bentel JM. Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clin Cancer Res. 1996;2:277–85.PubMed
46.
Taplin ME, Bubley GJ, Shuster TD, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med. 1995;332:1393–8.PubMedCrossRef
47.
Culig Z, Hobisch A, Hittmair A, et al. Expression, structure, and function of androgen receptor in advanced prostatic carcinoma. Prostate. 1998;35:63–70.PubMedCrossRef
48.
Craft N, Chhor C, Tran C, et al. Evidence for clonal outgrowth of androgen-independent prostate cancer cells from androgen-dependent tumors through a two-step process. Cancer Res. 1999;59:5030–6.PubMed
49.
Puche C, Jose M, Cabero A, Meseguer A. Expression and enzymatic activity of the P450c17 gene in human adipose tissue. Eur J Endocrinol. 2002;146:223–9.PubMedCrossRef
50.
Attard G, Reid AH, Olmos D, de Bono JS. Antitumor activity with CYP17 blockade indicates that castration-resistant prostate cancer frequently remains hormone driven. Cancer Res. 2009;69:4937–40.PubMedCrossRef
51.
Arth GE, Patchett AA, Jefopoulus T, et al. Steroidal androgen biosynthesis inhibitors. J Med Chem. 1971;14:675–9.PubMedCrossRef
52.
Chart JJ, Sheppard H. Pharmacology and biochemistry of some amphenone analogues and other adrenal cortical inhibitors. J Med Pharm Chem. 1959;1:407–41.PubMedCrossRef
53.
Gaunt R, Steinetz BG, Chart JJ. Pharmacologic alteration of steroid hormone functions. Clin Pharmacol Ther. 1968;9:657–81.PubMed
54.
DeFelice R, Johnson DG, Galgiani JN. Gynecomastia with ketoconazole. Antimicrob Agents Chemother. 1981;19:1073–4.PubMedCrossRef
55.
Trachtenberg J, Pont A. Ketoconazole therapy for advanced prostate cancer. Lancet. 1984;2:433–5.PubMedCrossRef
56.
De Coster R, Caers I, Coene MC, et al. Effects of high dose ketoconazole therapy on the main plasma testicular and adrenal steroids in previously untreated prostatic cancer patients. Clin Endocrinol (Oxf). 1986;24:657–64.CrossRef
57.
Mahler C, Verhelst J, Denis L. Ketoconazole and liarozole in the treatment of advanced prostatic cancer. Cancer. 1993;71:1068–73.PubMedCrossRef
58.
Small EJ, Baron AD, Fippin L, Apodaca D. Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal. J Urol. 1997;157:1204–7.PubMedCrossRef
59.
Small EJ, Baron A, Bok R. Simultaneous antiandrogen withdrawal and treatment with ketoconazole and hydrocortisone in patients with advanced prostate carcinoma. Cancer. 1997;80:1755–9.PubMedCrossRef
60.
Small EJ, Halabi S, Dawson NA, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004;22:1025–33.PubMedCrossRef
61.
Reid AH, Attard G, Danila DC, et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010;28:1489–95.PubMedCrossRef
62.
Attard G, Belldegrun AS, de Bono JS. Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU Int. 2005;96:1241–6.PubMedCrossRef
63.
Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol. 2010;28:1481–8.PubMedCrossRef
64.
Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol. 2010;28:1496–501.PubMedCrossRef
65.
Yamaoka M, Hara T, Kusaka M. Overcoming persistent dependency on androgen signaling after progression to castration-resistant prostate cancer. Clin Cancer Res. 2010;16:4319–24.PubMedCrossRef
66.
Dreicer R, Agus DB, MacVicar GR, et al. Safety, pharmacodynamics, and efficacy of TAK-700 in metastatic castration-resistant prostate cancer: a phase I/II, open-label study. J Clin Oncol. 2010;28:abstr 3084.
67.
• Agus DB, Stadler WM, Shevrin DH, et al. Safety, efficacy, and pharmacodynamics of the investigational agent TAK-700 in metastatic castration-resistant prostate cancer (mCRPC): updated data from a phase I/II study. J Clin Oncol. 2011;29:abstr 4531. This early-phase study demonstrated clinical efficacy and safety of orteronel in metastatic CRPC patients.
68.
Vasaitis T, Belosay A, Schayowitz A, et al. Androgen receptor inactivation contributes to antitumor efficacy of 17{alpha}-hydroxylase/17,20-lyase inhibitor 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer. Mol Cancer Ther. 2008;7:2348–57.PubMedCrossRef
69.
Kaku T, Hitaka T, Ojida A, et al. Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer. Bioorg Med Chem. 2011;19:6383–99.PubMedCrossRef
70.
Rowlands MG, Barrie SE, Chan F, et al. Esters of 3-pyridylacetic acid that combine potent inhibition of 17 alpha-hydroxylase/C17,20-lyase (cytochrome P45017 alpha) with resistance to esterase hydrolysis. J Med Chem. 1995;38:4191–7.PubMedCrossRef
71.
Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26:4563–71.PubMedCrossRef
72.
Haidar S, Ehmer PB, Barassin S, et al. 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. 2003;84:555–62.PubMedCrossRef
73.
Salem M, Garcia JA. Abiraterone acetate, a novel adrenal inhibitor in metastatic castration-resistant prostate cancer. Curr Oncol Rep. 2011;13:92–6.PubMedCrossRef
74.
Galsky MD, Small AC, Tsao CK, Oh WK. Clinical development of novel therapeutics for castration-resistant prostate cancer: historic challenges and recent successes. CA Cancer J Clin. 2012;62:299–308.PubMedCrossRef
75.
Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–90.PubMedCrossRef
76.
• Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet. 2010;375:1437–46. This early-phase study demonstrated clinical efficacy and safety of MDV3100 in metastatic CRPC patients.PubMedCrossRef
77.
• Scher H, Fizari K, Saad F, et al. Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer postdocetaxel: results from the phase III AFFIRM study. J Clin Oncol. 2012;30 Suppl 5:LBA1. This phase III trial demonstrated the overall survival benefit of MDV3100 in docetaxel-refractory CRPC patients.
Metadaten
Titel
Targeting the Adrenal Gland in Castration-Resistant Prostate Cancer: A Case for Orteronel, a Selective CYP-17 17,20-Lyase Inhibitor
verfasst von
Hui Zhu
Jorge A. Garcia
Publikationsdatum
01.04.2013
Verlag
Current Science Inc.
Erschienen in
Current Oncology Reports / Ausgabe 2/2013
Print ISSN: 1523-3790
Elektronische ISSN: 1534-6269
DOI
https://doi.org/10.1007/s11912-013-0300-1

Weitere Artikel der Ausgabe 2/2013

Current Oncology Reports 2/2013 Zur Ausgabe

Evolving Therapies (RM Bukowski, Section Editor)

Foretinib (XL880): c-MET Inhibitor with Activity in Papillary Renal Cell Cancer

Head and Neck Cancers (EY Hanna, Section Editor)

Assessment of Treatment Response after Chemoradiation of Head and Neck Cancer

Evolving Therapies (RM Bukowski, Section Editor)

Tasquinimod: A Novel Angiogenesis Inhibitor–Development in Prostate Cancer

Gastrointestinal Cancers (BG Czito, Section Editor)

Pathological Complete Response After Neoadjuvant Therapy for Rectal Cancer and the Role of Adjuvant Therapy

Head and Neck Cancers (EY Hanna, Section Editor)

Efficacy of Neck Dissection in the Management of Isolated Nodal Recurrence after Head and Neck Cancer Treatment

Head and Neck Cancers (EY Hanna, Section Editor)

Transoral Microsurgery for Treatment of Laryngeal and Pharyngeal Cancers

Neu im Fachgebiet Onkologie

Erhöhte Mortalität bei postpartalem Brustkrebs

07.05.2024 Mammakarzinom Nachrichten

Auch für Trägerinnen von BRCA-Varianten gilt: Erkranken sie fünf bis zehn Jahre nach der letzten Schwangerschaft an Brustkrebs, ist das Sterberisiko besonders hoch.

Hypertherme Chemotherapie bietet Chance auf Blasenerhalt

07.05.2024 Harnblasenkarzinom Nachrichten

Eine hypertherme intravesikale Chemotherapie mit Mitomycin kann für Patienten mit hochriskantem nicht muskelinvasivem Blasenkrebs eine Alternative zur radikalen Zystektomie darstellen. Kölner Urologen berichten über ihre Erfahrungen.

Ein Drittel der jungen Ärztinnen und Ärzte erwägt abzuwandern

07.05.2024 Medizinstudium Nachrichten

Extreme Arbeitsverdichtung und kaum Supervision: Dr. Andrea Martini, Sprecherin des Bündnisses Junge Ärztinnen und Ärzte (BJÄ) über den Frust des ärztlichen Nachwuchses und die Vorteile des Rucksack-Modells.

Bessere Prognose mit links- statt rechtsseitigem Kolon-Ca.

06.05.2024 Kolonkarzinom Nachrichten

Menschen mit linksseitigem Kolonkarzinom leben im Mittel zweieinhalb Jahre länger als solche mit rechtsseitigem Tumor. Auch aktuell ist das Sterberisiko bei linksseitigen Tumoren US-Daten zufolge etwa um 11% geringer als bei rechtsseitigen.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen
Bildnachweise