Novel Approaches to Targeting Cancers Associated with VHL Mutations

HIF2的上调是VHL失活的重要结果，在散发性cRCC(体细胞性VHL改变)和VHL患者的多种肿瘤(生殖系VHL改变)的发生发展中起关键作用。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HIF2α抑制剂的疗效，将进行一系列临床研究，包括针对VHL患者的单药研究，以及对散发性肾癌的单药研究。此外，各种联合策略将在临床前模型中进行评估，如果合适，还将在临床上进行评估。正在进行/计划中的研究包括：1)评估HIF2α小分子抑制剂在VHL中的作用：目前对VHL相关恶性肿瘤患者的治疗包括监测和手术/局部治疗，以最大限度地减少转移和/或局部并发症的风险。VHL患者在一生中经历了多次手术，伴随着显著的发病率。为了探索手术以外的系统治疗方法，我们进行了PT2385的第二阶段研究，PT2385是一种新型小分子HIF2抑制剂，用于治疗VHL相关性肾肿瘤。由于参加该药临床试验的患者的药代动力学参数差异很大，这项研究在4名患者出现后停止，尽管看到了令人鼓舞的早期活动迹象。我们的药物合作伙伴开发了第二代选择性HIF2-α抑制剂PT2977/MK6482，它比PT2385更有效，并具有更好的药理学特性，用于进一步的临床评估。我是VHL相关肾癌中这种药物的新的多中心2期研究的共同负责人；我们团队在帮助设计这项研究方面发挥了重要作用。这项研究的数据展示了这种药物在VHL相关肾肿瘤患者中的活性和安全性，并在2020年ASCO年会上公布。VHL相关肾肿瘤患者的总体应答率为28%，另有13%的患者表现出尚未证实的应答。2)评估HIF2-α抑制剂在散发性肾癌中的作用：Peloton公司对PT2977进行的2期研究显示，在既往免疫治疗和VEGFR靶向治疗取得进展的晚期肾癌患者中，ORR约为25%。目前对这些药物的耐药机制尚不清楚，需要进一步研究。更好地了解PT2977对肿瘤和肿瘤微环境的影响的临床研究正在考虑中，临床前研究也在考虑中，以开发合理的、基于机制的组合方法。这项工作将在与David McDermott博士和Marston Linehan博士共同开发的UO1基金的支持下部分完成：为VHL突变恶性肿瘤开发翻译管道(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, 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 2020 ASCO Annual meeting. The overall response rate in patients with VHL-associated renal tumors was 28%, with an additional 13% of patients demonstrating a response that is yet to be confirmed. 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 on tumors and the tumor microenvironment are under consideration as are preclinical studies to enable the development of rational, mechanism based combination approaches. 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).