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BMI-1 Targeting Interferes with Patient-Derived Tumor-Initiating Cell Survival and Tumor Growth in Prostate Cancer.

ABSTRACT: Current prostate cancer management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TIC-tailored therapies appears to be a promising approach.We have previously developed a combined immunophenotypic and time-of-adherence assay to identify CD49bhiCD29hiCD44hi cells as human prostate TICs. We utilized this assay with patient-derived prostate cancer cells and xenograft models to characterize the effects of pharmacologic inhibitors of BMI-1.We demonstrate that in cell lines and patient-derived TICs, BMI-1 expression is upregulated and associated with stem cell-like traits. From a screened library, we identified a number of post-transcriptional small molecules that target BMI-1 in prostate TICs. Pharmacologic inhibition of BMI-1 in patient-derived cells significantly decreased colony formation in vitro and attenuated tumor initiation in vivo, thereby functionally diminishing the frequency of TICs, particularly in cells resistant to proliferation- and androgen receptor-directed therapies, without toxic effects on normal tissues.Our data offer a paradigm for targeting TICs and support the development of BMI-1-targeting therapy for a more effective prostate cancer treatment. Clin Cancer Res; 22(24); 6176-91. ©2016 AACR.

SUBMITTER: Bansal N

PROVIDER: S-EPMC5159329 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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BMI-1 Targeting Interferes with Patient-Derived Tumor-Initiating Cell Survival and Tumor Growth in Prostate Cancer.

Bansal Nitu N Bartucci Monica M Yusuff Shamila S Davis Stephani S Flaherty Kathleen K Huselid Eric E Patrizii Michele M Jones Daniel D Cao Liangxian L Sydorenko Nadiya N Moon Young-Choon YC Zhong Hua H Medina Daniel J DJ Kerrigan John J Stein Mark N MN Kim Isaac Y IY Davis Thomas W TW DiPaola Robert S RS Bertino Joseph R JR Sabaawy Hatem E HE

Clinical cancer research : an official journal of the American Association for Cancer Research 20160615 24

<h4>Purpose</h4>Current prostate cancer management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TIC-tailored therapies appears to be a promising approach.<h4>Experimental design</h4>We have previously developed a combined immunophenotypic and time-of-adherence assay to identify CD49b<sup>h ...[more]

PMID: 27307599

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Project description:With the advent of potent second-line anti-androgen therapy, we and others have observed an increased incidence of androgen receptor (AR)-null small cell or neuroendocrine prostate cancer (SCNPC) in metastatic castration-resistant prostate cancer (mCRPC). Additionally, we have detected upregulated expression of MET and RET transcripts in SCNPC metastases relative to adenocarcinoma. Our study was designed to determine the effect of cabozantinib, a multi-targeted tyrosine kinase inhibitor that inhibits MET, RET and VEGFR2, on SCNPC patient-derived xenografts (PDX) in vivo. Surveillance of SU2C and University of Washington rapid autopsy mCRPC cohorts through RNA-Seq revealed that increased MET expression significantly correlated with loss of AR expression and activity. In vitro treatment of SCNPC PDX cells with AMG 337 had no impact on cell viability in LuCaP 93 (MET+/RET+) and LuCaP 173.1 (MET-/RET-), whereas cabozantinib decreased cell viability in LuCaP 93, but not in LuCaP 173.1. Notably, tumor volume was significantly decreased (p<0.001) with cabozantinib treatment in SCID mice bearing LuCaP 93 and LuCaP 173.1 tumors. Tissue analysis indicated that tumor cell proliferation was not inhibited by cabozantinib, but that cabozantinib decreased microvessel density (CD31) in LuCaP 93 (p<0.001) and LuCaP 173.1 (p<0.01) tumors. RNA-Seq and gene set enrichment analysis determined that hypoxia and glycolysis pathways were increased in cabozantinib treated tumors relative to control tumors. Thus, cabozantinib inhibited tumor growth in MET+/RET+ LuCaP 93 and MET-/RET- LuCaP 173.1 tumors in vivo and this activity was independent of MET or RET expression in LuCaP 173.1. Our data suggest that the most likely mechanism of tumor growth suppression is through disruption of the stromal architecture and cabozantinib may represent a potential therapy for patients with metastatic disease in tumor phenotypes that have a significant dependence on the tumor vasculature for survival and proliferation.

Dataset Information

BMI-1 Targeting Interferes with Patient-Derived Tumor-Initiating Cell Survival and Tumor Growth in Prostate Cancer.

Publications

BMI-1 Targeting Interferes with Patient-Derived Tumor-Initiating Cell Survival and Tumor Growth in Prostate Cancer.

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