Slow-Cycling Prostate Cancer Cells in Therapy Resistance, Disease Relapse, and Metastasis
Abstract
Likely Contributions of This Study to a 2022 Overarching Challenge: This project directly tackles the Overarching Challenge, Define the biology of prostate cancer progression to lethal prostate cancer to reduce death, and has the potential to identify novel a prostate cancer (PCa) cell Achilles heel for new clinical trials. What Types of Patients Will It Help and How? This study is pertinent to treatment-naïve advanced and metastatic PCa patients and especially mCRPC patients. mCRPC still claims the lives of >32,000 Americans each year, representing a huge health care burden. Why Is mCRPC So Lethal? Patients with advanced/metastatic PCa are treated with androgen receptor (AR)-targeting therapies such as androgen-deprivation therapy (ADT) and enzalutamide (Enza), as well as chemotherapeutic drugs such as docetaxel. However, therapeutic responses are generally short-lived, and tumors enter an adaptation/dormancy period with clinically defined minimal residual disease (MRD), and most treated PCa patients will eventually develop therapy resistance with recurrent CRPC in the prostate and, more frequently, in metastatic sites. This pattern of treatment response/MRD/tumor recurrence in PCa patients is remarkably similar to breast cancer patients treated with anti-estrogens/chemotherapeutic drugs. In the case of breast cancer, there is now strong evidence for a population of dormant slow-cycling cells (SCCs) to survive therapeutics, populate the MRD, and mediate disease recurrence and metastasis. However, in the case of PCa patients, it is generally unclear which PCa cells survive ADT and chemotherapeutic drugs and enter the adaptation/dormancy phase and which PCa cells come out of the MRD and mediate tumor relapse and metastatic dissemination. Here we propose that Dormant (slow-cycling) PCa cells with prostate cancer stem cell (PCSC) properties preferentially survive treatments (ADT and chemodrugs) and mediate therapy resistance, tumor recurrence and metastatic dissemination, which is also our overarching hypothesis for the current DOD IDA project. This hypothesis was based on: (1) our >20 years of focused studies on various PCa cell populations that have implicated functionally defined stem-like PCa cells (i.e., PCSCs) in mediating therapy resistance, CRPC, and metastasis; (2) our observations that the PCSC pool is heterogeneous, with only a small subset of very dormant PCSCs being able to generate and propagate CRPC; and (3) our recent studies in a genetic mouse model demonstrating very dormant luminal epithelial progenitor cells being inherently castration-resistant. By overcoming technical hurdles, we have now developed a novel genetic mouse model called trigenic Hi-Myc that allows identification, purification, and prospective studies of LIVE PCa slow-cycling cells (PSCCs) from both intact and castrated mouse prostate. We propose to test our overarching hypothesis in the novel trigenic Hi-Myc tumor model (Aim 1) as well as in human PCa xenograft and PDX models (Aim 2). What Are the Potential Clinical Applications, Benefits, and Risks? There are several potential clinical applications. For example, the dormancy gene signature derived from this study may be used in patients’ biopsies to help assess whether the patient on treatment has entered the adaptation/dormancy stage. The gene expression profiles identified herein to be specific to PSCCs may be utilized to gauge the probability of when/whether the responsive tumors may eventually stop responding and mediate recurrence. In the long term, the Achilles heel of PSCCs identified in this study will likely be clinically actionable targets. What Is the Projected Time to Achieve a Patient-Related Outcome? We estimate it to be within 5-7 years. This estimation is based on the timeline of several of our lab studies that have been translated to novel clinical trials (e.g., NCT03751436). What Are the Interim Outcomes? By integrating the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310163
Entities
People
- Dean Tang
Organizations
- United States Army