University of Texas Southwestern Medical Center SPORE in Kidney Cancer

总体汇总 肾细胞癌（RCC）在德克萨斯州尤其普遍，转移后可致命。为了解决这一未满足的问题， 根据医疗需求，UTSW肾癌孢子已经开发出一个全面的治疗方案， （靶向治疗和免疫治疗）和创新（代谢导向）领域。可以说，最 RCC的重要驱动因子是HIF 2 α。在UTSW发现，被认为是不可用的，结构研究 揭示了一个漏洞，该漏洞通过化学筛选被利用，导致Peloton的成立 UTSW生物中心的治疗学以及PT 2385和PT 2977的开发。在过去的融资中 在此期间，项目1的研究人员验证了HIF 2 α作为靶点，确定了依赖性的推定生物标志物， 进行了1期试验，确定了耐药突变，并将HIF 2 α确定为核心依赖性。 最终，Peloton被默克公司收购，PT 2977（也是 Belzutifan）获得了FDA的批准。在接下来的时间里，一个创新的基于siRNA的第二代 针对野生型和耐药突变型HIF 2 α的抑制剂将与基础- 打破成像放射性示踪剂，使患者的HIF 2 α评价。项目2调查人员利用一个深刻的 肾细胞癌与代谢的关系使用开创性的同位素标记的营养输液，项目3的研究人员 在1-5年期间确定谷氨酰胺是促进患者RCC生长的关键营养素。在7-12年，他们 将部署经认证的体内代谢实验室，以靶向谷氨酰胺旁路途径，可能解释 最近转氨酶抑制剂的失败最后，通过利用突破奖认可的研究， UTSW导致一种新的先天免疫系统激活药物，项目3研究人员提出了一种范式转变 在涉及适应性和先天性臂的协调激活的免疫疗法开发中（当它发生时 生理上）。加上以前受到赞扬的发展和职业发展计划，SPORE 调查人员得到四个核心的支持。一个前瞻性的行政核心（核心A）作为一个枢纽。一 病理核心（核心B）带来了承担最大和最复杂的RCC肿瘤银行之一， 支持国家努力的专门知识。数据分析核心（核心C）协助统计支持， 生物信息学和数据管理与一个前卫的工具，自动提取信息， 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）提供支持技术，包括拥有IND的创新示踪剂， 不合格的专业知识。根据西蒙斯综合癌症中心肾癌项目， 它的合作历史，跨学科的癌症研究，孢子项目和核心提供了一个引擎， 发现、创新和翻译支持国家和国际努力，以促进患者护理， 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.