University of Texas Southwestern Medical Center SPORE in Kidney Cancer

总体摘要 尤其在得克萨斯州，肾细胞癌(RCC)在转移时是致命的。来解决这个未得到满足的问题 医疗需要，UTSW肾癌孢子已经制定了一个全面的治疗计划在经过验证 (靶向治疗和免疫治疗)和创新(新陈代谢导向)领域。可以说，世界上最 RCC的重要驱动因素是HIF2α。在UTSW发现，并被认为是不可用药的结构研究 揭示了一个漏洞，该漏洞被通过化学筛选而被利用，导致了佩洛顿的建立 UTSW生物中心的治疗和PT2385和PT2977的开发。在之前的资助期间 期间，项目1调查人员验证了HIF2α作为靶点，确定了推测的依赖生物标志物， 进行了1期试验，确定了耐药突变，并将hif2α确立为核心依赖项。 垂直协作和项目成功的顶峰是，Peloton被默克公司和PT2977(也是 名为belzutifan)获得了FDA的批准。在接下来的一段时间里，基于siRNA的创新第二代 针对野生型和抗性突变体hif2α的抑制剂将与一种地面- 破碎性成像放射性示踪剂使患者能够进行HIF2α评估。项目2调查人员利用一种深刻的 肾细胞癌与新陈代谢之间的联系。使用开创性的同位素标记营养输液，项目3的研究人员 在1-5年间确定谷氨酰胺是促进患者肾细胞癌生长的关键营养物质。在7-12年级，他们 将在体内代谢实验室中部署经过验证的谷氨酰胺旁路，可能会解释 最近谷氨酰胺酶抑制剂的失败。最后，通过利用突破奖认可的研究， UTSW导致一种新的先天性免疫系统激活药物，项目3的研究人员提出了一种范式转变 在免疫疗法的发展中，涉及适应性和先天手臂的协调激活(当它发生时 生理上)。连同之前受到表彰的发展和职业提升计划，孢子 调查人员由四个核心支持。一个具有前瞻性的行政核心(核心A)是一个枢纽。一个 病理核心(核心B)带来了最大和最复杂的肾癌肿瘤库之一和 支持国家努力的专业知识。数据分析核心(核心C)协助提供统计支持， 生物信息学，以及使用前卫工具进行数据管理，该工具自动从 电子病历，自我更新，并将这些信息链接到实验基因组学和肿瘤库。 成像核心(核心D)提供使能技术，包括IND持有的创新示踪剂，以及 不合格的专业知识。建立在西蒙斯综合癌症中心肾癌计划和 它的合作、跨学科的癌症研究、孢子项目和核心的历史为 发现、创新和翻译支持国家和国际推动患者护理的努力， 研究和教育。

Overall Summary Particularly prevalent in Texas, renal cell carcinoma (RCC) is lethal when metastatic. To address this unmet medical need, the UTSW Kidney Cancer SPORE has developed a comprehensive therapeutic program in proven (targeted therapies and immunotherapy) and innovative (metabolism-directed) areas. Arguably, the most important driver of RCC is HIF2α. Discovered at UTSW, and regarded as undruggable, structural studies revealed a vulnerability that was exploited through a chemical screen leading to the founding of Peloton Therapeutics in the UTSW BioCenter and the development of PT2385 and PT2977. During the previous funding period, Project 1 investigators validated HIF2α as a target, identified putative biomarkers of dependency, executed a phase 1 trial, identified resistance mutations, and established HIF2α as a core dependency. Culminating the vertical collaboration and program success, Peloton was acquired by Merck, and PT2977 (also called belzutifan) gained FDA approval. During the next period, an innovative siRNA-based, second-generation inhibitor targeting both wild-type and resistant mutant HIF2α will be co-developed together with a ground- breaking imaging radiotracer enabling HIF2α evaluation in patients. Project 2 investigators exploit a profound link between RCC and metabolism. Using pioneering isotope-labeled nutrient infusions, Project 3 investigators established during years 1-5 that glutamine is a key nutrient fueling RCC growth in patients. In years 7-12, they will deploy the authenticated In Vivo Metabolism Lab to target glutamine bypass pathways, likely explaining the recent failure of glutaminase inhibitors. Finally, by leveraging Breakthrough Prize-recognized research at UTSW leading to a new innate immune system-activating drug, Project 3 investigators propose a paradigm shift in immunotherapy development involving the coordinated activation of the adaptive and innate arms (as it occurs physiologically). Together with previously commended development and career-enhancing programs, SPORE investigators are supported by four Cores. A forward-looking Administrative Core (Core A) serves as a hub. A Pathology Core (Core B) brings to bear one of the largest and most sophisticated RCC tumor banks and expertise supporting national efforts. A Data Analytics Core (Core C) assists with statistical support, bioinformatics, and data management with an avant-garde tool that automatically extracts information from the electronic medical record, self-updates, and links this information to experimental genomics and the tumor bank. An Imaging Core (Core D) delivers enabling technologies, including IND-holding innovative tracers, and unqualified expertise. Building upon the Simmons Comprehensive Cancer Center Kidney Cancer Program and its history of collaborative, interdisciplinary cancer research, SPORE Projects and Cores provide an engine of discovery, innovation, and translation supporting national and international efforts to advance patient care, research, and education.