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对约翰·霍普金斯大学西德尼·基梅尔综合癌症中心(SKCCC)的内科肿瘤学家钱宁·帕勒博士进行关键的额外培训。帕勒博士利用之前的培训，在前列腺癌(PCA)治疗研究方面开发了一个扩展计划。PCA最初对雄激素剥夺疗法高度敏感，但所有患者最终都进展到去势抵抗状态。在这一点上，患者接受一系列有效的单一药物，包括激素疗法、化疗和免疫疗法。在目前的治疗模式中，患者按顺序接受这些疗法中的每一种作为单一药物，直到进展时，开出列表中的下一种药物。认识到这些限制 在这种循序渐进的治疗方法中，帕勒博士设定了一个目标，即设计合理的联合疗法，以克服耐药性机制，并提高患有前列腺癌的男性的存活率。鉴于免疫疗法在实体肿瘤治疗中的新兴作用，帕勒博士将继续接受免疫疗法方面的专门培训，就像免疫疗法适用于前列腺癌一样。她将重点放在联合疗法的设计上，还需要对生物标记物的开发、验证和纳入试验设计有深刻的理解。因此，拟议的第二阶段临床试验评估一种新型转化生长因子-β受体(转化生长因子-βR)抑制剂在阿比特龙治疗后的转移性去势抵抗前列腺癌中克服对苯扎鲁胺的耐药性，将成为帕勒博士获得额外的指导和实践培训的平台，以便利用一组生物标记物实施结合免疫治疗和肿瘤组织免疫标记物评估的综合疗法。帕勒博士还将完成一系列关于肿瘤学和免疫学分子标记的课程。此外，她还组建了一支由多学科导师组成的优秀团队，为她的培训和研究提供便利。SKCCC临床研究副主任Michael Carducci博士是国际知名的前列腺癌治疗专家，她将继续担任她的主要导师。他将监督整个培训和研究计划。基于PCA的免疫疗法专家查尔斯·德雷克博士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记物开发方面的专业知识。研究计划集中在上皮-间充质转化(EMT)的标志物(AIM 1)、促炎细胞因子和T细胞的数量和功能(AIM 2)以及循环肿瘤细胞(CTCs)中雄激素受体剪接变异体7(AR-V7)的水平(AIM 3)。这项研究将在有和没有转化生长因子-β受体抑制的苯扎鲁胺临床试验的背景下，评估这些标志物与放射学无进展生存率的相关性。建议的研究将提供关于抑制转化生长因子-β受体的免疫学效应的数据。该团队预计，PCa采用的免疫逃逸机制将限制这些影响，并计划研究转化生长因子-β受体抑制与免疫检查点抑制剂在R01应用中的组合。

 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.