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.

总体总结 肾细胞癌 (RCC) 在德克萨斯州尤其常见，一旦发生转移，就会致命。 医疗需求，UTSW 肾癌 SPORE 开发了一套经过验证的综合治疗方案 （靶向治疗和免疫治疗）和创新（代谢导向）领域可以说是最多的。 RCC 的重要驱动因素是 UTSW 发现的 HIF2α，并被视为不可成药的结构研究。 揭示了一个通过化学筛选被利用的漏洞，导致 Peloton 的成立 UTSW BioCenter 的治疗以及 PT2385 和 PT2977 的开发 在之前的资助期间。 在此期间，项目 1 的研究人员验证了 HIF2α 作为目标，确定了假定的依赖性生物标志物， 进行了 1 期试验，确定了耐药突变，并将 HIF2α 确立为核心依赖性。 Peloton 被默克 (Merck) 收购，PT2977（也 belzutifan）在接下来的一段时间内获得了 FDA 的批准，这是一种基于 siRNA 的第二代创新产品。 针对野生型和耐药突变型 HIF2α 的抑制剂将与地面药物共同开发 突破性成像放射性示踪剂能够对患者进行 HIF2α 评估。 项目 3 的研究人员使用开创性的同位素标记的营养输注来研究 RCC 和新陈代谢之间的联系。 他们在第 1-5 年确定谷氨酰胺是促进患者肾细胞癌生长的关键营养素。在第 7-12 年，他们确定了这一点。 将部署经过验证的体内代谢实验室来瞄准谷氨酰胺旁路途径，这可能解释 最后，通过利用突破奖认可的研究来解决谷氨酰胺酶抑制剂最近的失败。 UTSW 开发出一种新的先天免疫系统激活药物，项目 3 研究人员提出范式转变 在免疫疗法的开发中，涉及适应性臂和先天臂的协调激活（当它发生时） 与之前推荐的发展和职业提升计划一起，SPORE 调查人员得到四个核心的支持，一个具有前瞻性的行政核心（核心 A）充当枢纽。 病理学核心（核心 B）带来了最大、最复杂的 RCC 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）协助统计支持， 生物信息学和数据管理，使用先进的工具自动从生物信息中提取信息 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，包括持有 IND 的创新示踪剂，以及 以西蒙斯综合癌症中心肾癌项目为基础， 其合作、跨学科癌症研究的历史、SPORE 项目和核心提供了一个引擎 发现、创新和转化支持国家和国际努力促进患者护理， 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