Identification, Characterization, and Therapeutic Targeting of a Population of Castration-Resistant Prostate Cancer Cells
Abstract
Prostate cancer (PCa) is the most common malignancy affecting men in the Western world, and the majority of advanced PCa patients will die of it due to the development of castration-resistant prostate cancer (CRPC) and metastasis. One of the four Prostate Cancer Research Program Challenges is "to develop effective treatments and address mechanisms of resistance for advanced PCa." My current postdoc fellowship project directly addresses this challenge by studying a PCa cell subpopulation that my past several years of studies have shown to mediate CRPC. Human cancers are heterogeneous containing many different kinds of cancer cells. Cancer cell heterogeneity can arise as a result of genetic diversity and/or epigenetic maturation of stem cell-like cancer cells called "cancer stem cells" (CSCs). Like their normal counterparts, CSCs also possess self-renewal capacity and the potential to give rise to all other differentiated cells with limited proliferative and tumorigenic ability. CSCs have been implicated in tumor initiation, progression, therapy resistance, and metastasis. PCa is also a heterogeneous malignancy containing various phenotypically different cancer cell types. Earlier work from Dr. Tang s group on CSCs has indicated that PCa also contains stem-like cancer cells, i.e., PCSCs. While I was working in Dr. Tang s lab as a graduate student, my projects focused on understanding the roles of PCSCs in tumor reconstitution, drug tolerance, and castration resistance. Recently, my colleagues and I have demonstrated that the PSA-/lo PCa cell population is highly enriched in CSCs, and of great clinical significance, PSA-/lo PCa cells can survive androgen deprivation and mediate tumor recurrence. Most interestingly, we have observed that the cells mediating CRPC within the PSA-/lo cellular pool bear the ALDH+CD44+alpha2beta1+ phenotype. However, it is still unclear whether the ALDH+CD44+alpha2beta1+ (TM+) cell population, in general, represents a cell-of-origin for all CRPC. This is a very important topic as it may help us to uncover the future therapeutic targets for CRPC patients. My current 2-year fellowship will further validate and characterize if the TM+ cells are highly enriched in PCSCs in androgen-deficient conditions in several androgen-independent tumor models I have recently established and importantly, in primary patient tumors. In addition, I will perform the unbiased drug library screening to find the potential chemicals that may specifically target TM+ CRPC cells. My ultimate goal is to understand the cell-of-origin for CRPC and identify the novel therapeutics that target PCSCs and CRPC cells. If successfully carried out, it will be of significant clinical relevance to better treat advanced PCa patients and better their future life.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510366
Entities
People
- Xin Chen
Organizations
- United States Army
- University of Texas at Austin