Overcoming drug resistance in metastatic castration resistant prostate cancer with a novel combination of TGF-beta inhibition and enzalutamide



 DESCRIPTION (provided by applicant): The proposed career development and research plan will support critical additional training for Dr. Channing Paller, a medical oncologist at the John Hopkins Sidney Kimmel Comprehensive Cancer Center (SKCCC). Dr. Paller has leveraged previous training to develop an expanding program in prostate cancer (PCa) therapeutics research. PCa is initially highly responsive to androgen deprivation therapy, but all patients eventually progress to a castration-resistant state. At that point patients receive a series of effective single agents, including hormone therapies, chemotherapies, and immunotherapies. In the current treatment paradigm, patients receive each of these therapies sequentially as single agents until, at progression, the next agent in the list is prescribed. Recognizing the limitations of this sequential therapeutic approach, Dr. Paller has set a goal to design rational combination therapies that will overcome resistance mechanisms and lead to improved survival of men suffering from PCa. Given the emerging role of immunotherapy in treating solid tumors, Dr. Paller will pursue specific training in immunotherapy as it applies to PCa. Her focus on the design of combination therapies will also require a firm understanding of biomarker development, validation, and incorporation into trial design. Thus, the proposed Phase II clinical trial evaluating a novel TGF-β receptor (TGF-βR) inhibitor in overcoming resistance to enzalutamide in metastatic castration-resistant PCa, post- abiraterone treatment, will serve as a platform for Dr. Paller to obtain additional didactic and hands-on training in implementing combination therapies that combine immunotherapy with immunological marker assessment in tumor tissue utilizing a panel of biomarkers. Dr. Paller will also complete a number of courses on molecular markers in oncology and on immunology. In addition, she has assembled an outstanding team of multidisciplinary mentors to facilitate her training and research. Dr. Michael Carducci, Associate Director of Clinical Research at SKCCC, is an internationally known expert on PCa therapeutics who will continue to serve as her primary mentor. He will oversee the overall training and research plans. Dr. Charles Drake, an expert in PCa-based immunotherapy, will oversee her immunology training. Dr. Gary Rosner, Director of Biostatistics at SKCCC, will add his expertise on biomarker development. The research plan focuses on markers of epithelial- mesenchymal transition (EMT) (Aim 1), pro-inflammatory cytokines and T-cell number and function (Aim 2), and androgen receptor splice variant 7 (AR-V7) levels in circulating tumor cells (CTCs) (Aim 3). The research will assess the markers' correlation with radiographic progression-free survival in the setting of a clinical trial of enzalutamide with and without TGF-βR inhibition. The proposed studies will provide data on the immunological effects of TGF-βR inhibition. The team anticipates that immune escape mechanisms employed by PCa will limit those effects and plans to study combinations of TGF-βR inhibition with immune checkpoint inhibitors in an R01 application.