Slow-cycling cells, therapy resistance and clinical implications in prostate cancer Project Summary/Abstract Accumulating evidence suggests the existence of slow-cycling cells (SCCs) in cancer cell cultures, xenograft tumors, and human clinical tumor specimens. Although SCCs are thought to be insensitive to anticancer therapies and contribute to later disease progression and metastasis, few studies have focused on and developed systems to study SCCs. Despite an initial favorable response to initial hormone therapy, almost all prostate cancer (PCa) patients eventually develop progressive castration-resistant prostate cancer (CRPC). Mechanisms underlying CRPC development and maintenance remain poorly understood. Our meticulous studies on PCa cell heterogeneity, combined with preliminary studies on PCa SCCs lead to hypothesis that SCCs survive androgen deprivation therapy (ADT) and repopulate CRPC. By developing innovative experimental strategies to purify out SCCs live from human PCa cell cultures and xenograft tumors, and establishing a unique transgenic mouse model of label-retaining cells (LRCs), we are poised to systematically investigate SCCs and test our hypothesis in a nave tumor microenvironment under both physiological and androgen-ablation conditions. Through a spectrum of in vitro and in vivo biological assays, we will comprehensively examine the functional properties and the clinical implications of SCCs in PCa, especially in castration resistance. By performing gene expression analysis coupled with functional assays, we will find potential therapeutic targets that could lead to elimination of this `hard-to-kill' population. Our studies will not only fill critical gap knowledge of quiescent cancer cell biology but also provide clinical insights into how we can target them for better patient outcomes. The long-term goal of this project is to identify treatment options by combining ADT and SCC-specific therapies to eventually eliminate CRPC in patients.

Public Health Relevance

Slow-cycling cells, therapy resistance and clinical implications in prostate cancer Project Narrative Slow-cycling cells (SCCs) preexist in human primary prostate tumors, but direct studies examining whether these cells resist current therapies (androgen deprivation therapy (ADT) in particular) and mediate later tumor relapse and metastasis is lacking. These studies will systematically investigate the functional properties, therapy resistance, as well as clinical implications of SCCs in prostate cancer at both cell biology and molecular biology levels. We anticipate this work will identify new actionable targets for the stubborn SCCs, and by combining ADT (which mainly kills fast proliferating cells) and SCC-specific therapies, we can expect to eventually eliminate CRPC in patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1)
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Arya, Suresh
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Roswell Park Cancer Institute Corp
United States
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Zhang, Dingxiao; Zhao, Shuhong; Li, Xinyun et al. (2018) Prostate Luminal Progenitor Cells in Development and Cancer. Trends Cancer 4:769-783
Zhang, Dingxiao; Tang, Dean G (2018) ""Splice"" a way towards neuroendocrine prostate cancer. EBioMedicine 35:12-13