University of Texas Southwestern Medical Center SPORE in Kidney Cancer

德克萨斯大学西南医学中心 SPORE 在肾癌中的应用

• 批准号: 10706530
• 负责人: James Brugarolas
• 金额: $ 217.34万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706530
• 关键词: Accounting; Address; Angiogenesis Inhibitors; Antigen Presentation; Area; Bioinformatics; Biological Markers; Biotechnology; Bypass; Carbon; Cell Proliferation; Cell Survival; Cessation of life; Chemicals; Citric Acid Cycle; Clear Cell; Clear cell renal cell carcinoma; Collaborations; Comprehensive Cancer Center; Computerized Medical Record; Core Facility; Data Analytics; Dependence; Development; Diagnosis; Disease; Drug Screening; Education; Enzymes; Evaluation; Failure; Foundations; Funding; Generations; Genes; Genomics; Germ-Line Mutation; Glutaminase; Glutamine; Glycogen; Growth; Heart failure; Hypertension; Image; Immune checkpoint inhibitor; Immune system; Immunotherapy; In complete remission; Individual; Inflammation; Infusion procedures; Innate Immune System; International; Isotope Labeling; KDR gene; Link; Lipids; Medical; Medical center; Metabolic; Metabolism; Modeling; Nitrogen; Nivolumab; Nutrient; Pathology; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Phosphotransferases; Physiological; Prize; Process; Production; Proteinuria; Radiation; Recording of previous events; Renal Cell Carcinoma; Renal carcinoma; Research; Research Personnel; Resistance; STING agonists; Sagittaria; Small Interfering RNA; Structure; Survival Rate; Technology; Texas; Therapeutic; Toxic effect; Tracer; Translating; Translations; Tumor Bank; Tumor Promotion; Tyrosine Kinase Inhibitor; Universities; Update; VHL mutation; Vascular Endothelial Growth Factors; angiogenesis; anticancer research; arm; career; clinical practice; data management; immunogenic; in vivo; inhibitor; innovation; mortality; mutant; novel therapeutic intervention; novel therapeutics; palliative; patient population; phase I trial; predictive marker; programs; radiotracer; real time monitoring; resistance mutation; safety and feasibility; side effect; stemness; success; targeted treatment; tool; transcription factor; tumor; tumorigenesis

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.

总结 在德克萨斯州特别普遍，转移性时肾细胞癌（RCC）是致命的。解决这个尚未满足的 医疗需求，UTSW肾脏癌孢子已经开发了一项全面的治疗计划 （有针对性的疗法和免疫疗法）以及创新（代谢指导）的区域。可以说，最多 RCC的重要驱动力是HIF2α。在UTSW发现，被认为是不可能的，结构性研究 揭示了通过化学屏幕探索的脆弱性，导致Peloton建立 UTSW BioCenter中的治疗剂以及PT2385和PT2977的开发。在以前的资金中 期间，项目1研究人员将HIF2α验证为目标，确定了依赖性的假定生物标志物， 执行了1期试验，确定了电阻突变，并确定了HIF2α作为核心依赖性。 默克和PT2977收购了Peloton的最终垂直协作和计划成功的最终 称为Belzutifan）获得了FDA批准。在下一个时期，创新的基于siRNA的第二代 靶向野生型和抗性突变体HIF2α的抑制剂将与地面共同开发 打破成像放射性示踪剂，使患者可以评估HIF2α。项目2调查人员利用了深刻的 RCC与代谢之间的联系。使用开拓性的同位素标记的营养输注，项目3调查人员 在1 - 5年内建立，谷氨酰胺是患者RCC增长的关键营养素。在7 - 12年中，他们 将部署身份验证的体内代谢实验室以靶向谷氨酰胺旁路途径，可能解释 谷氨酰胺酶抑制剂最近失效。最后，通过利用突破性奖励认可的研究 UTSW导致新的先天免疫系统激活药物，项目3调查人员提出范式转变 在免疫疗法开发中涉及适应性和先天臂的协调激活（因为它发生 物理上）。连同先前传达的发展和职业增强计划，孢子 研究人员得到了四个核心的支持。前瞻性管理核心（核心A）用作集线器。一个 病理核心（核心B）带来最大，最复杂的RCC肿瘤库之一， 支持国家努力的专业知识。数据分析核心（核心C）有助于统计支持， 生物信息学和使用前卫工具的数据管理，该工具自动从该工具中提取信息 电子病历，自我升级并将这些信息与实验基因组学和肿瘤库联系起来。 成像核心（核心D）提供促成技术，包括辅助创新示踪剂和 不合格的专业知识。基于西蒙斯综合癌症中心肾癌计划和 其协作，跨学科癌症研究，孢子项目和核心的历史提供了 发现，创新和翻译支持国家和国际努力促进患者护理的努力， 研究和教育。

项目成果

Quantitative Methods in Abdominal MRI: Perfusion Imaging.

• DOI: 10.1097/rmr.0000000000000145
• 发表时间: 2017-12
• 期刊: Topics in magnetic resonance imaging : TMRI
• 作者: Madhuranthakam AJ;Yuan Q;Pedrosa I
• 通讯作者: Pedrosa I

Stereotactic Ablative Radiation for Systemic Therapy-naïve Oligometastatic Kidney Cancer.

• DOI: 10.1016/j.euo.2022.06.008
• 发表时间: 2022-12
• 期刊: EUROPEAN UROLOGY ONCOLOGY
• 影响因子: 8.2
• 作者: Hannan, Raquibul;Christensen, Michael;Christie, Alana;Garant, Aurelie;Pedrosa, Ivan;Robles, Liliana;Mannala, Samantha;Wang, Chiachien;Hammers, Hans;Arafat, Waddah;Courtney, Kevin;Bowman, Isaac A.;Sher, David;Ahn, Chul;Cole, Suzanne;Choy, Hak;Timmerman, Robert;Brugarolas, James
• 通讯作者: Brugarolas, James

Magnetic Resonance Imaging Radiomics Analyses for Prediction of High-Grade Histology and Necrosis in Clear Cell Renal Cell Carcinoma: Preliminary Experience.

• DOI: 10.1016/j.clgc.2020.05.011
• 发表时间: 2021-03
• 期刊: Clinical genitourinary cancer
• 影响因子: 3.2
• 作者: Dwivedi DK;Xi Y;Kapur P;Madhuranthakam AJ;Lewis MA;Udayakumar D;Rasmussen R;Yuan Q;Bagrodia A;Margulis V;Fulkerson M;Brugarolas J;Cadeddu JA;Pedrosa I
• 通讯作者: Pedrosa I

What morphology can teach us about renal cell carcinoma clonal evolution.

哪些形态学可以告诉我们肾细胞癌克隆进化。

• 发表时间: 2020
• 期刊: Kidney cancer journal : official journal of the Kidney Cancer Association
• 作者: Kapur,Payal;Christie,Alana;Rajaram,Satwik;Brugarolas,James
• 通讯作者: Brugarolas,James

HIF2 Inactivation and Tumor Suppression with a Tumor-Directed RNA-Silencing Drug in Mice and Humans.

• DOI: 10.1158/1078-0432.ccr-22-0963
• 发表时间: 2022-12-15
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Ma, Yuanqing;Joyce, Allison;Brandenburg, Olivia;Saatchi, Faeze;Stevens, Christina;Tcheuyap, Vanina Toffessi;Christie, Alana;Do, Quyen N.;Fatunde, Oluwatomilade;Macchiaroli, Alyssa;Wong, So C.;Woolford, Layton;Yousuf, Qurratulain;Miyata, Jeffrey;Carrillo, Deyssy;Onabolu, Oreoluwa;McKenzie, Tiffani;Mishra, Akhilesh;Hardy, Tanner;He, Wei;Li, Daniel;Ivanishev, Alexander;Zhang, Qing;Pedrosa, Ivan;Kapur, Payal;Schluep, Thomas;Kanner, Steven B.;Hamilton, James;Brugarolas, James
• 通讯作者: Brugarolas, James