Abstract SY13-03: Signal pathways in prostate cancer stem cells

Abstract

Abstract New therapeutic strategies are needed to treat prostate cancer as it progresses to the castration resistant stage following treatment with drugs to reduce androgen production or interfere with androgen receptor function. Genetic analyses of DNA alterations and RNA expression show that multiple pathways can be involved in this cancer progression. An understanding of the cellular components needed to initiate prostate cancer and sustain it during the process of metastasis may help to elucidate new pathways for therapy. We have developed techniques to transform mouse and human benign prostate epithelial basal stem cells and define them as one cell of origin which can respond to multiple stimuli to produce cancers which are capable of maturing to more differentiated cell types including luminal, squamous and neuroendocrine phenotypes. Different subtypes of cells with the properties of cancer stem cells capable of transplantation of the cancer phenotype have been defined. Current work is focusing on the activation of specific kinase driven pathways to provide new targets for therapy in metastatic prostate cancer. We previously demonstrated that castration resistant prostate cancer (CRPC) tissues exhibit increased tyrosine phosphorylation, suggesting that enhanced tyrosine kinase activity may contribute to advanced disease. To identify specific kinase activation patterns in metastatic CRPC, we utilized phospho-tyrosine peptide enrichment and quantitative mass spectrometry using tissue from CRPC patients obtained at rapid autopsy. Evaluation of these rare metastatic CRPC samples for tyrosine phosphorylation and kinases revealed activated SRC, EGFR, RET, ALK, and other targets. Importantly, these kinase activation patterns exhibited intrapatient similarity and interpatient heterogeneity implying clonal origins of these lesions. To evaluate the function of these kinases in metastatic CRPC, we are analyzing their role during specific steps of the metastatic cascade. We hope our approach will improve an understanding of the mechanistic role of kinase activation in prostate cancer and identify promising therapeutic strategies targeting non-mutated kinases for metastatic CRPC. Citation Format: Owen N. Witte. Signal pathways in prostate cancer stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY13-03. doi:10.1158/1538-7445.AM2014-SY13-03