Novel Approaches to Targeting Cancers Associated with VHL Mutations

HIF2的上调是VHL失活的结果，似乎对散发性ccRCC（体细胞VHL改变）以及VHL患者的各种肿瘤（种系VHL改变）的发展至关重要。最近，HIF2的小分子抑制剂已经在临床前模型中进行了评估，目前正在进行临床评估。为了测试HIF2 α抑制剂的疗效，将进行许多临床研究，包括VHL患者的单药研究和散发性ccRCC的单药研究。此外，各种组合策略将在临床前模型中进行评估，并在适当的情况下在临床中进行评估。正在进行的或计划中的研究包括：1)评估VHL中HIF2 α的小分子抑制剂：目前对VHL相关恶性肿瘤患者的治疗包括监测和手术/局灶治疗，以尽量减少转移和/或局部并发症的风险。VHL患者在其一生中经历多次外科手术，并伴有显著的发病率。为了探索手术以外的全身治疗方案，我们在VHL相关肾肿瘤患者中开展了一项PT2385的2期研究，PT2385是一种新型小分子HIF2抑制剂。由于参加该药物临床试验的患者的药代动力学参数存在很大差异，因此在累积了4名患者后，尽管看到了令人鼓舞的早期活动迹象，但该研究停止了。第二代选择性HIF2 - α抑制剂PT2977/MK6482/belzutifan比PT2385更有效，具有更好的药理特性，由我们的制药合作伙伴开发，用于进一步的临床评估。我是一项新的多中心二期研究的共同负责人，该研究将该药物用于vhl相关的RCC；我们小组在帮助设计这项研究中发挥了重要作用。该研究的数据在2021年ASCO年会上公布，并随后发表在《新英格兰医学杂志》（2021年11月）上，证明了该药物在vhl相关肾肿瘤患者中的活性和安全性。vhl相关肾肿瘤患者的总体缓解率为49%，另有11%的患者表现出尚未证实的缓解。该研究是FDA批准belzutifan用于与VHL相关的器官局限性肾脏、胰腺和中枢神经系统肿瘤患者的基础。2)评估hif2 - α抑制剂在散发性ccRCC中的作用：Peloton公司在先前接受免疫治疗和VEGFR靶向治疗的晚期ccRCC患者中进行的一项PT2977的2期研究显示，ORR约为25%。对这些药物的耐药性机制目前尚不清楚，需要进一步研究。为了更好地了解PT2977和其他新的HIF2抑制剂对肿瘤和肿瘤微环境的影响，临床前研究正在考虑进行临床研究，以便开发合理的、基于机制的联合方法。利用其他HIF2抑制剂的其他研究以及针对ccRCC新靶点的研究也正在设计中，预计将在未来几个月内开放。这项工作部分将在David McDermott博士和Marston Linehan博士共同开发的u01资助下完成：开发VHL突变恶性肿瘤的翻译管道（1U01CA236489-01）。

Upregulation of HIF2 is well studied consequence of VHL inactivation and appears to be critical for development of sporadic ccRCC (somatic VHL alteration) as well as a variety of tumors in patients with VHL (germline VHL alterations). Recently, small molecule inhibitors of HIF2 have been evaluated in preclinical models and are currently undergoing clinical evaluation. To test the efficacy of HIF2 alpha inhibitors a number of clinical studies will be performed, including single agent studies in VHL patients, and single agent studies in sporadic ccRCC. Additionally, a variety of combination strategies will be evaluated in preclinical models and, if appropriate, in the clinic. Ongoing/planned studies include: 1) Evaluation of small molecule inhibitors of HIF2 alpha in VHL: The current management of patients with VHL associated malignancies involves surveillance and surgical/focal therapy to minimize the rsik of metastases and/or local complications. Patients with VHL undergo multiple surgical procedures during their lifetime with significant attendant morbidity. To explore systemic therapy alternatives to surgery, we conducted a phase 2 study of PT2385, a novel small molecule HIF2 inhibitor in patients with VHL associated renal tumors. Due to wide variability in pharmacokinetic parameters in patients enrolled on clinical trials of this agent, this study was halted after four patients were accrued, although encouraging signs of early activity were seen. A second generation, selective HIF2 -alpha inhibitor, PT2977/MK6482/belzutifan, that is more potent than PT2385 and is associated with better pharmacologic properties, was developed by our pharma collaborators for further clinical evaluation. I am co-leader of a new, multicenter, phase 2 study of this agent in VHL-associated RCC; our group was instrumental in helping design this study. Data from this study, demonstrating the activity and safety of this agent in patients with VHL-associated renal tumors, were presented at the 2021 ASCO Annual meeting and subsequently published in the New England Journal of Medicine (Nov, 2021) The overall response rate in patients with VHL-associated renal tumors was 49%, with an additional 11% of patients demonstrating a response that is yet to be confirmed. The study was the basis for the FDA approval of belzutifan for patients with organ confined renal, pancreatic and CNS tumors associated with VHL. 2) Evaluation of HIF2-alpha inhibitors in sporadic ccRCC: A phase 2 study of PT2977 conducted by Peloton, Inc, in patients with advanced ccRCC who had progressed on prior immunotherapy and VEGFR targeted therapy revealed an ORR of approximately 25%. The mechanisms underlying resistance to these agents is poorly understood at this time and warrant further study. Clinical studies to better understand the effects of PT2977 as well as other new HIF2 inhibitors on tumors and the tumor microenvironment are under consideration as are preclinical studies to enable the development of rational, mechanism based combination approaches. Additional studies utilizing other HIF2 inhibitors as well as studies targeting novel targets in ccRCC are also being designed and are expected to open to accrual in the next several months. This work will partly be done under the aegis of a UO1 grant developed with Dr. David McDermott and Dr. Marston Linehan: Developing a Translation Pipeline for VHL Mutant Malignancies (1U01CA236489-01).