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

 描述（由申请人提供）：拟议的职业发展和研究计划将支持约翰霍普金斯西德尼金梅尔综合癌症中心（SKCCC）的医学肿瘤学家钱宁帕勒博士的关键额外培训。Paller博士利用以前的培训来开发前列腺癌（PCa）治疗研究的扩展计划。前列腺癌最初对雄激素剥夺治疗高度敏感，但所有患者最终都会发展为去势抵抗状态。在这一点上，患者接受一系列有效的单一药物，包括激素治疗，化疗和免疫治疗。在当前的治疗范例中，患者作为单一药剂依次接受这些疗法中的每一种，直到在进展时开出列表中的下一种药剂。认识到局限性 Paller博士的目标是设计合理的联合疗法，克服耐药机制，提高前列腺癌患者的生存率。鉴于免疫疗法在治疗实体瘤中的新兴作用，Paller博士将继续接受免疫疗法的具体培训，因为它适用于PCa。她对联合治疗设计的关注还需要对生物标志物的开发、验证和纳入试验设计有深刻的理解。因此，拟定的II期临床试验评价了一种新型TGF-β受体（TGF-βR）抑制剂在阿比特龙治疗后转移性去势抵抗性PCa中克服对Enzalutamide耐药性的作用，将作为Paller博士在实施联合治疗（将联合收割机免疫治疗与利用一组生物标志物进行的肿瘤组织免疫标志物评估相结合）方面获得额外教学和实践培训的平台。Paller博士还将完成一些关于肿瘤学和免疫学分子标记物的课程。此外，她还组建了一支由多学科导师组成的优秀团队，以促进她的培训和研究。Michael Carducci博士是SKCCC临床研究副主任，是国际知名的PCa治疗专家，他将继续担任她的主要导师。他将监督整个培训和研究计划。Charles Drake博士是基于PCA的免疫疗法专家，他将监督她的免疫学培训。SKCCC生物统计学主任加里罗斯纳博士将补充他在生物标志物开发方面的专业知识。该研究计划侧重于上皮间质转化（EMT）（目标1），促炎细胞因子和T细胞数量和功能（目标2），以及循环肿瘤细胞（CTC）中雄激素受体剪接变体7（AR-V7）水平（目标3）的标志物。该研究将在Enzalutamide联合和不联合TGF-βR抑制的临床试验中评估标志物与放射学无进展生存期的相关性。拟议的研究将提供有关TGF-βR抑制的免疫学效应的数据。研究小组预计，PCa采用的免疫逃逸机制将限制这些影响，并计划在R 01应用中研究TGF-βR抑制与免疫检查点抑制剂的组合。

 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.