Background
Identifying OS stem cell populations as therapeutic targets
Marker | Function, clinical relevance | References |
---|---|---|
Sarcosphere | Chemoresistance (e.i., doxorubicin and cisplatin etc.,) overexpressing Oct3/4, and Stat3 | |
CD133 | Sphere formation, self-renewal ability, multipotency, tumorigenicity, inclusion of SP cells, upregulating stemness genes of Nestin, Sox2, OCT3/4, and Nanog | |
CD117/Stro-1 | Chemoresistance features, higher level of self-renewal, tumorigenicity, multipotent invasive, metastasis, inducing ABCG2 and CXCR4 overexpression | |
ALDH | Differentiation, self-renewal ability, tumorigenicity, metastatic potential, over-expressing Oct3/4, Nanog, Sox2, and Stat3 | |
CD271 | Tumorigenicity, self-renewal, differentiation, and the advantage of sarcospheres formation | |
Side population | Clonogenicity, drug resistance, self-renewal capacity, and tumor-initiating capacity in CSCs and invasiveness | |
CD44 | Sphere-forming, invasiveness, Tumorigenic and metastatic property | [39] |
MSC antigen Sca-1 | Overexpression of Sca-1 and Sox2 cells can be capable of self-renewal in OS-stem cells | |
CD248 | Tumorigenicity and invasiveness | [26] |
ABCA5 | Considered as putative biomarkers and overexpressed in spheres | [43] |
CD47 | Its CD47 blockade was linked to inhibition of tumor growth., invasion, prognostic factor, and immunotherapeutic target | |
Oct3/4 | Tumorigenic, self-renewal capability and metastatic potential | |
ABCG2 and CXCR4 | Metastasis-associated marker CXCR4 and drug-resistance marker ABCG2 | |
Sox2 | Tumorigenicity, Sphere formation, invasiveness, and cancer cell migration | |
Nestin | CD133, Oct3/4, Sox2, Nanog, nestin Coexpression of Nes+/CD133+ cells; presence of cells with a stem-like phenotype |
Markers for isolation of OSCs
CD133
CD271
ALDH
Other OSC phenotype-associated factors
CD47 as immunotherapeutic target
Sca-1 stem cell antigen as effective OSC marker
Side population (SP) cells
Nestin identification in CSCs from OS
MicroRNA therapeutic targets
Sphere-forming assays
Signaling pathways and epigenetic regulators
The role of MAPK/ERK signaling pathway in OS stem-like cells
Hedgehog
Targeting Wnt/β-catenin
Therapeutic | Function of molecules | Study type and model | Mechanism | References |
---|---|---|---|---|
BYL719 | A new specific PI3Kα inhibitor | Different murine preclinical models of osteosarcoma | Tumor development and tumor ectopic bone formation by decreasing Ki67+ cells and tumor vascularization | Gobin et al. [53] |
LY294002 | An inhibitor of phosphoinositide 3-kinases (PI3Ks) | Human osteosarcoma CSCs, in vitro study | Prevent phosphorylation of PKB/Akt via inhibition of PI3K phosphorylation activity, leading to G0/G1 cell cycle arrest and apoptosis | Gong et al. [108] |
BRM270 as a compound from 7 seven sian medicinal plants | NF-κB inhibitor | An in vivo tumor metastasis model of nude mice for osteosarcoma | A NF-κB inhibitor via acting as a suppressor of NF-κB signaling cascade in multidrug resistance -induced stem like cancer-initiating cells | Kwon et al. [194] |
parthenolide | NF-κB inhibitor and oxidative stress inducer | LM7 osteosarcoma cells, in vitro treatments | Parthenolide and ionizing radiation leads cell death in osteosarcoma cells, resulting in reduction in the viability of both the osteosarcoma cells and CD133+ CSCs | Zuch et al. [110] |
MC1742 and MC2625 | HDAC inhibitors | CSCs, in vitro study | Can elevate acetyl-H3 and acetyl-tubulin levels, inhibited CSC sphere growth via apoptosis induction in osteosarcoma and Ewing sarcoma | Di Pompo et al. [195] |
Bufalin | – | In vitro study, and in vivo (nude mice model) | Inhibits the differentiation and proliferation of CSCs from C1OS via targeting miR-148 Downregulate proliferation marker Ki67, resulting in inhibition of sphere forming and proliferation in human OSCs derived from the MG63 cell line | |
Salinomycin | Antibacterial and coccidiostat agent | Both in vitro and in vivo study (nude mice model) | Suppress the sarcosphere formation, expressions of Oct4 and Sox2. Inhibit Wnt/β-catenin pathway via degradation of β-catenin and can act as inhibitor of OSCs | Tang et al. [86] |
CESPa | Nanoparticle | Both in vitro and in vivo study (mic model) | Effective inhibitor of tumor growth with promising efficacy in osteosarcoma-bearing mice, effectively target CSCs of osteosarcoma and cancer cells | Chen et al. [196] |
Ap-SAL-NPb | Nanoparticle | Both in vitro and in vivo study (mic model) | Ap-SAL-NP kill CD133+ osteosarcoma CSCs | Ni et al. [197] |
EGFR-SNPs | Nanoparticle | In vitro drug assessment | EGFR-SNPs decrease the osteosarcoma sphere-forming and CD133+ osteosarcoma CSCs while comparing with salinomycin and SNPs. Effectively enhance delivery of salinomycin to osteosarcoma cells | Yu et al. [198] |
5-Azacytidine | DNA methyltransferase (DNMT) inhibitor | Osteosarcoma cell lines Saos-2 and MG63 | Induce an increase of stemness features of OS cells in context of CD133, Sox2, OCT4 and Nanog overexpression, as well as high sarcospheres-forming efficiency | Tirino et al. [199] |
Notch
PI3K signaling
NF-κB signaling pathway
SDF-1 (cxcl12) cxcr4
Targeting the tumor microenvironment of CSCs
Molecular imaging
Circulating tumor cells
Circulating DNA
An overview of therapeutic strategies for targeting OSCs
Status | Conditions | Interventions | Phase | Last update posted |
---|---|---|---|---|
Unknown | Osteosarcoma | Drug: Chemotherapy Drug: Endostar (drug type: VEGFR inhibitor) | Phase 2 | September 3, 2014 |
Completed | Osteosarcoma | Drug: sorafenibb (multi target inhibitor: PRGFR/VEGFR inhibitor) | Phase 2 | March 28, 2013 |
Recruiting | Soft tissue sarcoma Bone sarcoma | Sunitinib [Sutent] (multitarget inhibitors: (e.i.,PDGF-Rs, VEGFRs) | Phase 1 | September 11, 2017 |
Metastatic osteosarcoma Relapsed osteosarcoma | Drug: Sorafenibb (multitarget inhibitors; PRGFR/VEGFR inhibitor) Drug: Everolimus (mTOR inhibitor) | Phase 2 | June 17, 2015 | |
Completed | Sarcoma | Drug: RG1507 (IGF1-R inhibitors) | Phase 2 | April 4, 2017 |
Completed | Sarcoma | Drug: RG1507(IGF1-R inhibitors) | Phase 2 | April 4, 2017 |
Unknown | Osteosarcoma | Dietary supplement: Curcumin powder (WNT/β-catenin inhibitor) Dietary Supplement: Ashwagandha extract | Phase 1 Phase 2 | June 23, 2011 |
Completed | Osteosarcoma | Drug: Saracatinib a Src inhibitor of c-Src) Drug: Placebo | Phase 2 | May 11, 2018 |
Terminated | Osteosarcoma Metastatic osteosarcoma | Drug: Pazopanibc (drug type: multitarget inhibitors: VEGFR inhibitor) | Phase 2 | June 26, 2018 |
Unknown | Refractory or relapsed osteosarcoma | Drug: Everolimus (mTOR inhibitor) | Phase 2 | August 7, 2013 |
Completed | Osteosarcoma Metastasis | Drug: Apatinib (YN968D1, tyrosine kinase inhibitor and VEGFR2 inhibitor) | Phase 2 Phase 3 | April 23, 2018 |
Active, not recruiting | Osteosarcoma Malignant fibrous histiocytoma (MFH) of bone | Biological: Bevacizumab (drug type: monoclonal antibody; target: VEGF-A) Drug: Cisplatin Drug: Doxorubicin (and 5 more…) | Phase 2 | June 14, 2018 |
Completed | Sarcoma | Biological: trastuzumab (drug type: monoclonal antibody; target: ERBB2) Procedure: conventional surgery | Phase 2 | June 21, 2013 |
Terminated | Osteosarcoma Sarcoma, Ewing’s Peripheral neuroectodermal tumor | Biological: Robatumumab (SCH 717454; IGF1-R inhibitors ) | Phase 2 | June 7, 2017 |
Recruiting | Metastatic Ewing sarcoma Metastatic osteosarcoma Recurrent Ewing sarcoma (and 7 more…) | Drug: Cabozantinib S-malate (small molecule receptor tyrosine kinase (RTK) inhibitor) | Phase 2 | May 24, 2018 |
Recruiting | Ewing sarcomas Chondrosarcomas Osteosarcomas Chondroma | Drug: Regorafenib (multi-kinase inhibitor Drug: Placebo | Phase 2 | August 16, 2018 |
Completed | Metastatic soft-tissue sarcomas Metastatic bone sarcomas | Drug: Ridaforolimus (mTOR inhibitor) Drug: Placebo | Phase 3 | February 13, 2015 |
Recruiting | Adult liposarcoma Metastatic liposarcoma Metastatic osteosarcoma (and 4 more…) | Drug: Pazopanibc hydrochloride (multitarget inhibitors; target: PDGFR, c-Kit,) Drug: Oral Topotecan hydrochloride | Phase 2 | January 9, 2018 |
Completed has results | Metastatic osteosarcoma Recurrent adult soft tissue sarcoma Recurrent osteosarcoma (and 2 more…) | Biological: Cixutumumab ( drug type: monoclonal antibody; target: IGF1R) Drug: Temsirolimus | Phase 2 | July 30, 2015 |
Completed | Childhood malignant fibrous histiocytoma of bone Sarcoma | Drug: Imatiniba mesylate (PDGFR inhibitor) | Phase 2 | June 19, 2013 |
Completed | Glioblastoma Rhabdomyosarcomas Neuroblastoma Osteosarcoma | Drug: Irinotecan (Camptosar), Gefitinib (ZD1839: Drug type: EGFR inhibitor )or (Iressa) | Phase 1 | April 17, 2012 |
Terminated has results | Sarcoma | Drug: Sorafenibb (PRGFR/VEGFR inhibitor) Drug: Ifosfamide | Phase 2 | November 24, 2015 |
Recruiting | Liposarcoma Osteogenic sarcoma Ewing/Ewing-like sarcoma Rhabdomyosarcoma | Drug: Regorafenib Drug: Placebo | Phase 2 | July 18, 2018 |
Completed | Leiomyosarcoma Liposarcoma Osteosarcoma (and 2 more…) | Drug: Ridaforolimus (mTOR inhibitor) | Phase 2 | February 13, 2015 |
Completed | Sarcoma | Drug: RG1507 (drug type: monoclonal antibody; Target: IGF1R ) | Phase 2 | April 4, 2017 |
Withdrawn | Sarcoma Neuroblastoma Wilms tumor (and 2 more…) | Drug: Pazopanibc (drug type: VEGFR inhibitor), (GW786034) | Phase 1 | July 2, 2017 |
Completed has results | Metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor Metastatic osteosarcoma Recurrent adult soft tissue sarcoma (and 6 more…) | Drug: Sorafenibb tosylate (multitarget inhibitors: PRGFR/VEGFR inhibitor) Procedure: Therapeutic conventional surgery Other: Laboratory biomarker analysis (and 3 more…) | Phase 2 | April 30, 2014 |
Recruiting | Glioma Rhabdomyosarcoma Osteosarcoma (and 5 more…) | Biological: Erlotinib (drug type: PDGFR Inhibitor) Drug: Temozolomide | Phase 2 | February 15, 2018 |
Status | Conditions | Interventions | Phase | Last update posted |
---|---|---|---|---|
Recruiting | Osteosarcoma | Drug: Avelumab (monoclonal antibody) | Phase 2 | June 25, 2018 |
Recruiting | Osteosarcoma | Drug: Pembrolizumab (IgG4 isotype antibody) | Phase 2 | April 5, 2018 |
Recruiting | Metastatic osteosarcoma | Drug: Sm-EDTMP Other: Autologous stem cell infusion Radiation: External beam radiotherapy | Phase 2 | February 14, 2018 |
Unknown | Osteosarcoma | Drug: Zoledronic acid (type of drug: bisphosphonates; target: Osteoclasts) Drug: Standard chemotherapy | Phase 2 Phase 3 | June 23, 2011 |
Active, not recruiting | Recurrent osteosarcoma | Drug: Glembatumumab Vedotin Antibody–drug conjugate Other: Laboratory biomarker analysis Other: Pharmacological study | Phase 2 | May 7, 2018 |
Completed | Osteosarcoma | Drug: Cisplatin Drug: Doxorubicin Drug: Methotrexate Administration of Pamidronate (drug type: bisphosphonates; target: osteoclasts) with chemotherapy | Phase 2 | January 20, 2016 |
Recruiting | Recurrent osteosarcoma | Biological: Humanized anti-GD2 antibody (drug type: monoclonal antibody; target: immune system) Drug: GM-CSF | Phase 2 | August 2, 2018 |
Active, not recruiting | Childhood osteosarcoma Metastatic osteosarcoma Recurrent osteosarcoma (and 3 more…) | Biological: Denosumab (drug type: monoclonal antibody; target: RANKL) | Phase 2 | August 7, 2018 |
Completed | Sarcoma | Zoledronic acid (type of drug: bisphosphonates; target: osteoclasts Drug: cisplatin Drug: Dexrazoxane hydrochloride Drug: doxorubicin hydrochloride (and 10 more…) | Phase 1 | July 4, 2014 |
Completed | Neuroblastoma Melanoma Osteosarcoma Ewing sarcoma | Biological: Anti-GD2 antibody (drug type: monoclonal antibody; target: immune system) | Phase 1 | |
Terminated | Sarcoma | Zoledronic acid (type of drug: bisphosphonates; target: osteoclasts Drug: Cisplatin Drug: Doxorubicin hydrochloride Drug: Etoposide (and 4 more…) | Phase 3 | June 22, 2016 |
Recruiting | Desmoplastic small round cell tumor Disseminated neuroblastoma Metastatic osteosarcoma (and 2 more…) | Biological: IL-2 Biological: GD2Bi-aATC (drug type: cells Biological: GM-CSF Evaluations of immune responses | Phase 1 Phase 2 | December 4, 2017 |
Completed | Osteosarcoma | Drug: c (type of target: Monocyte/macrophage activator glycopeptide) Drug: Ifosfamide | Phase 2 | March 22, 2017 |
Not yet recruiting | Bone sarcoma Soft tissue sarcoma | Biological: NY-ESO-1 (target: immunotherapy; TCR affinity enhancing specific T cell therapy) | Phase 2 | March 16, 2018 |
Ewing sarcoma Osteosarcoma Rhabdomyosarcoma | Biological: Expanded, activated NK cells | Phase 1 Phase 2 | November 6, 2017 | |
Active, not recruiting | Soft tissue sarcoma Bone sarcoma | Drug: Pembrolizumab: MK-3475 (cancer immunotherapy: target: PD-1 ) | Phase 2 | July 25, 2018 |
Recruiting | Recurrent malignant solid neoplasm Recurrent osteosarcoma Refractory malignant solid neoplasm Refractory osteosarcoma | Biological: Anti-SEMA4D monoclonal antibody VX15/2503 | Phase 1 Phase 2 | August 9, 2018 |
Recruiting | Ewing sarcoma Osteosarcoma Rhabdomyosarcoma | Biological: Expanded, activated NK cells (target: Immune system) | Phase 1 Phase 2 | November 6, 2017 |
Completed | Sarcoma Osteosarcoma Neuroblastoma Melanoma | Biological: Anti-GD2-CAR engineered T cells Drug: AP1903 Drug: Cyclophosphamide | Phase 1 | July 6, 2018 |
Recruiting | Ewing sarcoma Neuroblastoma Rhabdomyosarcoma (and 2 more…) | Procedure: Allogeneic HCT Drug: Donor NK Cell Infusion (target: immune system) | Phase 2 | June 1, 2018 |
Active, not recruiting | Neuroblastoma Ewing sarcoma Rhabdomyosarcoma (and 2 more…) | Procedure: haploidentical stem cell transplantation and NK cell therapy (target: Immune system) | Phase 2 | October 18, 2016 |
Recruiting | Neuroblastoma Rhabdomyosarcoma Osteosarcoma (and 3 more…) | Drug: Enoblituzumab (monoclonal antibody) | Phase 1 | August 7, 2018 |
Not yet recruiting | Soft tissue sarcoma Bone sarcoma Chondrosarcoma (and 5 more…) | Drug: Ipilimumab (Drug type: monoclonal antibody; target: CTLA-4 receptor) Drug: Nivolumab (IgG4 anti-PD-1 monoclonal antibody; target: PD-1 | Phase 2 | November 1, 2017 |