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.

项目概要 HIF2α 可以说是透明细胞肾细胞癌 (ccRCC) 的最重要驱动因素，透明细胞肾细胞癌是最常见的肾脏疾病 癌症类型。在 UT 西南医学中心 (UTSW) 发现，被认为是不可成药的、结构性的 研究揭示了一个漏洞，该漏洞被利用导致小分子抑制剂的鉴定和 生物技术公司 Peloton Therapeutics, Inc. 成立，该公司开发了多种类似物（PT2385、 PT2399 和 PT2977）。 PT 药物与 HIF2α 结合，导致其与其必需伙伴 HIF1β 解离， 从而抑制 HIF2 介导的转录。上一资助期间的临床前和临床工作 显着推进了该领域。使用移植到小鼠体内的患者 ccRCC 的肿瘤移植（TG）模型，我们 表明：HIF2 是一个有效的目标；大约 50% 的 ccRCC 依赖于 HIF2； HIF2敏感肿瘤 以高 HIF2α 为特征，这可以作为生物标志物；并且抵抗力的发展是由于 获得性 HIF2α 突变。此外，我们还主导了 1 期试验，结果表明 PT2385 效果良好 耐受且活跃。此外，我们还发现：(i) PT2385 特异性靶向患者肿瘤中的 HIF2（但 不是 HIF1)； (ii) HIF2靶向导致HIF2靶基因的抑制； (iii) 长期治疗导致 我们预测在 TG 中获得抗性突变。这些数据将 HIF2α 确定为第一个核心依赖项 在ccRCC。该计划的成功最终以 PT2977（belzutifan）获得 FDA 批准而告终。对于 下一个资助期，我们寻求共同开发：(i) 一种基于 siRNA 的 HIF2α 药物 (siHIF2α)，该药物既针对野生型 和耐药突变体 HIF2α； (ii) 一种分子成像工具，可实现非侵入性 HIF2α 监测 患者。 siHIF2α 由 Arrowhead Pharmaceuticals Inc. 开发，是一种合成的、稳定的、化学修饰的、 双链 RNAi 触发器特异性靶向与整合素高亲和力配体缀合的 HIF2α mRNA αvβ3 和 αvβ5 在 ccRCC 中广泛表达。 siHIF2α将与新型成像工具共同开发 我们生成的用于 HIF2α 定量，并将用于测量 siRNA 介导的靶标 消耗。我们利用 PT2385 的高特异性，并通过取代天然氟原子将其转化为 进入 PET 放射性示踪剂 ([18F]PT2385)。自一年前最初提交以来，我们收到了 IND ([18F]PT2385)，获得IRB批准，并开始人体剂量测定研究。我们还改进了 siHIF2α 对最后一个计划队列的 1 期试验显示出良好的耐受性，表明 siHIF2α 下调 HIF2α 患者肿瘤活检，并提供活性的初步证据。成功发射HIF2α 抑制剂，现已 FDA 批准，我们建议开发针对野生型和药物的第二代抑制剂 HIF2α 耐药。如果成功，这可能会产生一种治疗 ccRCC 的新药，并且可能是第一个基于 siRNA 的药物 肿瘤学治疗。