Project 1: Targeting HIF2 in Renal Cell Carcinoma

项目 1：针对肾细胞癌中的 HIF2

• 批准号: 10708828
• 负责人: James Brugarolas
• 金额: $ 33.93万
• 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/10708828
• 关键词: Affinity; Binding; Biological Markers; Biopsy; Biotechnology; Chemicals; Chemistry; Clear cell renal cell carcinoma; Clinical; Clinical Trials; Collaborations; DNA Binding; Data; Dependence; Dissociation; Dose Limiting; Down-Regulation; Drug Targeting; Drug resistance; Evaluation; FDA approved; Fluorine; Funding; Future; Generations; Genes; Genetic Transcription; HIF1A gene; Human; Hypoxia Inducible Factor; Imaging Device; Institutional Review Boards; Integrin alphaVbeta3; Ligands; Malignant Neoplasms; Measurable; Measures; Mediating; Medical center; Messenger RNA; Modeling; Monitor; Mus; Mutation; Nature; Neoplasm Transplantation; Oncology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase I Clinical Trials; Positron-Emission Tomography; Proteins; RNA Interference; Radiology Specialty; Renal Cell Carcinoma; Renal carcinoma; Reporting; Resistance; Resistance development; Sagittaria; Small Interfering RNA; Specificity; Testing; Texas; Therapeutic; Toxic effect; Transplantation; Universities; Visualization; Work; analog; biomarker identification; cancer type; cohort; dosimetry; experimental study; imaging biomarker; implantation; in vivo; inhibitor; innovation; mRNA Transcript Degradation; manufacture; molecular imaging; mutant; novel; novel therapeutics; phase 1 study; phase I trial; pre-clinical; programs; radioligand; radiotracer; resistance mutation; small molecule inhibitor; standard of care; success; therapeutic siRNA; transcriptome sequencing; tumor; tumor growth

Project Summary HIF2α is arguably the most important driver of clear cell renal cell carcinoma (ccRCC), the most common kidney cancer type. Discovered at UT Southwestern Medical Center (UTSW) and regarded as undruggable, structural studies revealed a vulnerability that was exploited leading to the identification of small molecule inhibitors and the founding of a biotech company, Peloton Therapeutics, Inc., which developed several analogues (PT2385, PT2399 and PT2977). PT drugs bind to HIF2α leading to its dissociation from its obligatory partner HIF1β, thereby inhibiting HIF2-mediated transcription. Preclinical and clinical work during the previous funding period advanced the field significantly. Using tumorgraft (TG) models of patient ccRCCs transplanted in mice, we showed that: HIF2 is a valid target; approximately 50% of ccRCC are dependent on HIF2; HIF2-sensitive tumors are characterized by high HIF2α, which may serve as a biomarker; and resistance develops as a result of acquired HIF2α mutations. In addition, we led accrual to the phase 1 trial, which showed that PT2385 was well tolerated and active. Furthermore, we showed that: (i) PT2385 specifically targeted HIF2 in patient tumors (but not HIF1); (ii) HIF2 targeting resulted in inhibition of HIF2 target genes; and (iii) prolonged therapy led to the acquisition of resistance mutations we predicted in TGs. These data identified HIF2α as the first core dependency in ccRCC. The success of the program culminated with the approval by the FDA of PT2977 (belzutifan). For the next funding period, we seek to co-develop: (i) an siRNA-based HIF2α drug (siHIF2α) that targets both wild-type and resistant-mutant HIF2α; and (ii) a molecular imaging tool that can enable non-invasive HIF2α monitoring in patients. Developed by Arrowhead Pharmaceuticals Inc., siHIF2α is a synthetic, stabilized, chemically modified, double-stranded RNAi trigger specifically targeting HIF2α mRNA conjugated to a high-affinity ligand for integrins αvβ3 and αvβ5, which are broadly expressed in ccRCC. siHIF2α will be co-developed with a novel imaging tool we generated to enable HIF2α quantification, and which will be deployed to measure siRNA-mediated target depletion. We leveraged the high specificity of PT2385 and by substituting a native fluorine atom converted it into a PET radiotracer ([18F]PT2385). Since the original submission a year ago, we received an IND for ([18F]PT2385), obtained IRB approval, and began dosimetry studies in humans. We also advanced the siHIF2α phase 1 trial to the last planned cohort revealing good tolerability, showing that siHIF2α downregulates HIF2α in patient tumor biopsies, and providing preliminary evidence of activity. Having successfully launched a HIF2α inhibitor, now FDA approved, we propose to develop a second-generation inhibitor targeting wild-type and drug- resistant HIF2α. If successful, this may lead to a new drug for ccRCC and possibly the first siRNA-based therapeutic in oncology.

项目摘要 HIF 2 α可以说是肾透明细胞癌（ccRCC）最重要的驱动因素， 癌症类型。在UT西南医学中心（UTSW）发现，被认为是不可药用的，结构性的 研究揭示了一个漏洞，该漏洞被利用，导致识别小分子抑制剂， 成立了一家生物技术公司，Peloton Therapeutics，Inc.，其开发了几种类似物（PT 2385， PT 2399和PT 2977）。PT药物与HIF 2 α结合，导致其与其强制性伴侣HIF 1 β解离， 从而抑制HIF 2介导的转录。上一个资助期的临床前和临床工作 大大推进了这一领域。使用移植到小鼠中的患者ccRCC的肿瘤移植物（TG）模型，我们 表明：HIF 2是一个有效的靶点;大约50%的ccRCC依赖于HIF 2; HIF 2敏感性肿瘤 以高HIF 2 α为特征，这可能是一种生物标志物;耐药性的产生是由于 获得性HIF 2 α突变。此外，我们将纳入1期试验，该试验显示PT 2385 宽容和积极。此外，我们发现：（i）PT 2385特异性靶向患者肿瘤中的HIF 2（但 非HIF 1）;（ii）HIF 2靶向导致HIF 2靶基因的抑制;和（iii）延长治疗导致 获得我们在TG中预测的耐药突变。这些数据将HIF 2 α确定为第一个核心依赖性。 在ccRCC。该计划的成功最终获得了FDA对PT 2977（Belzutifan）的批准。为 下一个资助期，我们寻求共同开发：（i）一种基于siRNA的HIF 2 α药物（siHIF 2 α）， 和耐药突变型HIF 2 α;和（ii）一种分子成像工具，可以实现非侵入性HIF 2 α监测， 患者由箭头制药公司开发，siHIF 2 α是一种合成的，稳定的，化学修饰的， 特异性靶向HIF 2 α mRNA的双链RNAi触发剂与整合素的高亲和力配体偶联 αvβ3和αvβ5在ccRCC中广泛表达。siHIF 2 α将与一种新型成像工具共同开发 我们产生的，使HIF 2 α定量，并将部署到测量siRNA介导的目标， 耗尽我们利用PT 2385的高特异性，通过取代天然氟原子， PET放射性示踪剂（[18F] PT 2385）。自一年前首次提交以来，我们收到了IND， （[18F] PT 2385），获得IRB批准，并开始人体剂量测定研究。我们还将siHIF 2 α 最后一个计划队列的I期试验显示了良好的耐受性，表明siHIF 2 α下调HIF 2 α， 患者肿瘤活检，并提供活性的初步证据。在成功发射了HIF 2 α之后， 抑制剂，现在FDA批准，我们建议开发第二代抑制剂靶向野生型和药物- 抗HIF 2 α。如果成功，这可能会导致一种用于ccRCC的新药，并可能是第一种基于siRNA的药物。 治疗肿瘤。