Targeting Genetic and Metabolic Alterations in Distinct Subtypes of RCC

肾癌是由一系列广泛的组织学和遗传多样性肿瘤组成的，这些肿瘤出现在肾脏中。通过独特的临床和组织学特征来区分的几种亚型的RCC，现在被确认。此外，通过研究RCC的家族形式以及最近的大规模基因组分析，发现了与这些独特的RCC亚型相关的各种遗传改变。个体RCC亚型中不同分子通路的鉴定为我们评估这些患者的个体化、基于机制的治疗策略提供了基础。我们小组正在寻求多种方法，重点如下：1)针对乳头状肾细胞癌的Met途径：乳头状肾细胞癌占所有肾癌的10-15%，由一组异质性恶性肿瘤组成，其特征是组织病理学评估中存在乳头状瘤。大华大学分子癌症治疗项目的主要科学兴趣是更好地表征各种亚型乳头状细胞癌的分子和机制基础。作为开发基于机制的乳头状RCC治疗策略的专门转化工作的一部分，各种针对传统癌基因和改变代谢途径的系统方法正在进行评估。原癌基因MET的种系激活突变是遗传性乳头状肾细胞癌（HPRC）家族双侧多灶1型乳头状肿瘤发展的基础。此外，MET通路似乎在散发性乳头状RCC患者中被激活。为了确定MET作为有效治疗靶点的相关性，我们帮助设计并进行了MET酪氨酸激酶抑制剂foretinib（一种对VEGFR2具有额外活性的药物）在乳头状RCC患者中的首次试验。这一概念验证的多中心二期试验的数据发表在《临床肿瘤学杂志》上，并证明了该方法在乳头状RCC中的有效性，特别是在MET种系激活突变的患者中。然而，该药物的剂量受到与VEFGR抑制相关的毒性的限制，并且尚不清楚该药物是否达到了最佳的MET抑制。我们假设选择性MET抑制剂可能在可接受的毒性下提供最大的目标抑制。这一假设正在INC280（一种选择性的第二代MET抑制剂）的二期试验中进行评估。2)针对乳头状RCC的代谢改变：乳头状RCC中第二个被充分研究的生化改变是有氧糖酵解的优先利用和氧化应激反应机制的激活，这在遗传性平滑肌瘤病和肾细胞癌（HLRCC）患者的肿瘤中得到了最好的表征，这些患者携带克雷伯斯循环酶富马酸水合酶基因的种系失活突变。一项正在进行的贝伐单抗和厄洛替尼的2期研究研究了靶向治疗这些肿瘤的方法。这项研究的数据显示，在许多患者中，包括一些散发性乳头状肾细胞癌患者，高缓解率（富马酸水合酶突变患者的ORR约为72%）和持久的缓解。该方案现在被广泛认为是晚期FH缺陷肾癌患者的标准治疗方案，也用于散发性乳头状肾细胞癌患者。鉴别分子标记物的尝试正在进行中，这些分子标记物可能有助于鉴别散发的乳头状RCC患者最有可能从这种方法中获益。各种其他方法也正在研究中，以利用某些形式的乳头状RCC对有氧糖酵解的依赖性。3)靶向mTOR治疗birt - hogg - dube相关性肾细胞癌：Birt-Higg-Dube相关性肾细胞癌患者表现为双侧多灶性肿瘤，组织学形态多样，最常见的是嗜色肿瘤/嗜癌细胞瘤。肿瘤抑制基因FLCN的种系改变是这种疾病的标志。在Marston Linehan博士的实验室进行的临床前研究发现，mTOR通路的上调是FLCN改变导致肿瘤发生的一种潜在机制；此外，在一个小鼠模型中，西罗莫司抑制mTOR部分逆转了与肾脏FLCN选择性失活相关的表型。基于这些数据，2015年在bhd相关肾肿瘤患者中启动了mTOR抑制剂依维莫司的2期研究。然而，由于低累积，该研究被关闭，这在很大程度上是由于患有这种罕见实体的患者不愿意接受依维莫司相关的潜在毒性。4)靶向VHL通路：VHL是一种家族性癌症综合征，以双侧多灶透明细胞RCC和其他器官肿瘤的发展倾向为特征。虽然对这些患者有明确的手术护理标准，特别是在局部疾病的情况下，但显然有必要探索替代方案，使这些患者免于与重复手术相关的发病率。为此，大华银行启动了首个针对VHL患者的全身治疗临床试验。热休克蛋白90抑制剂（17 AAG）的二期试验旨在治疗伴有VHL的局部肾肿瘤的手术前患者，该试验是与CTEP和Len Neckers博士合作开发的，Len Neckers博士的实验室工作为这类药物在透明细胞RCC中的评估提供了临床前数据支持。随后的一项评估vandetanib （VEGFR和EGFR双重抑制剂）疗效的2期研究于2008年启动，迄今为止仍是VHL患者中最大的试验；这项研究的数据表明，虽然vandetanib是有效的，但相关的副作用对这些患者的生活质量有重大影响，这些患者大多是局部肿瘤，通常适合手术治疗。各种临床前研究正在进行中，以评估各种亚型RCC的新方法，并有望指导这些恶性肿瘤患者的未来研究。HIF2的上调是VHL失活的结果，似乎对RCC的发展至关重要。最近，HIF2的小分子抑制剂已经进行了临床前评估，目前正在进行临床评估。我们启动了一项针对VHL相关肾肿瘤患者的新型小分子HIF2抑制剂PT2385的2期研究。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，我们的制药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，具有更可预测和统一的药理学特性。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；该研究的数据表明，该药物在VHL相关肾肿瘤中的活性最近在2021年ASCO年会上公布。这项研究的结果也是FDA正在加速审查的NDA的基础。

Kidney cancer is comprised of a wide array of histologically and genetically diverse tumors that arise in the kidney. Several subtypes of RCC, distinguishable by unique clinical and histological features, are now recognized. Additionally, by studying familial forms of RCC and more recently, by large scale genomic analysis, a variety of genetic alterations associated with these unique RCC subtypes have been unearthed. The identification of distinct molecular pathways in individual RCC subtypes has served as the foundation for our approach to the evaluation of individualized, mechanism based treatment strategies for these patients. Our group is pursuing a variety of approaches as highlighted below: 1) Targeting the Met pathway in papillary RCC: Papillary RCC, accounting for 10-15% of all kidney cancers, is comprised of a heterogeneous group of malignancies characterized by the presence of papillae on histopathologic evalaution. A major scientific interest within the UOB Molecular Cancer Therapeutics program is to better characterize the molecular and mechanistic basis of the various subtypes of papillary RCC. As part of a dedicated translational effort to develop mechanism-based therapeutic strategies for papillary RCC, a variety of systemic approaches targeting both conventional oncogenes and altered metabolic pathways are being evaluated. Germline activating mutations in the proto-oncogene MET are the basis for the development of bilateral multifocal type 1 papillary tumors in families with a condition termed Hereditary Papillary Renal Cell Cancer (HPRC). In addition, the MET pathway appears to be activated in a subset of patients with sporadic papillary RCC. To determine the relevance of MET as a valid therapeutic target, we helped design and conduct the first trial of a MET tyrosine kinase inhibitor, foretinib (an agent with additional activity against VEGFR2), in patients with papillary RCC. Data from this proof of concept, multicenter phase 2 trial were published in the Journal of Clinical Oncology, and demonstrated the efficacy of this approach in papillary RCC, particularly in patients with germline activating mutations in MET. However, dosing of this agent was limited by toxicity related to VEFGR inhibition and it is unclear if optimal MET inhibition was achieved with this drug. We hypothesized that selective MET inhibitors might provide maximal target inhibition with acceptable toxicity. This hypothesis is being evaluated in a phase 2 trial of INC280, a selective, second generation MET inhibitor. 2) Targeting Metabolic Alterations in Papillary RCC: A second well studied biochemical alteration in papillary RCC is the preferential utilization of aerobic glycolysis and activation of an oxidative stress response mechanism, best characterized in tumors from patients with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), who carry germline inactivating mutations in the gene for the Krebs' cycle enzyme fumarate hydratase. A targeted approach to these tumors was studied in an ongoing phase 2 study of bevacizumab and erlotinib. Data from this study have shown a high response rate (ORR approximately 72% in those with fumarate hydratase mutations) and durable responses in many patients, including those with some forms of sporadic papillary RCC. This regimen is now widely regarded as the standard of care for patients with advanced FH deficient kidney cancer, and is also used in patients with sporadic papillary RCC. Attempts to identify molecular markers that may help identify sporadic papillary RCC patients most likely to benefit from this approach are ongoing. A variety of other approaches are also being investigated in a bid to exploit the dependence of some forms of papillary RCC on aerobic glycolysis. 3) Targeting mTOR in Birt-Hogg-Dube-Associated RCC: Patients with Birt-Higg-Dube associated renal cell cancer present with bilateral multifocal tumors of varied histologies, with the most common histology being hybrid chromophobe tumors/oncocytomas. Germline alterations in the tumor suppressor gene FLCN are the hallmark of this condition. Preclinical studies conducted in Dr. Marston Linehan's lab identified upregulation of the mTOR pathway as one potential mechanism leading to tumorigenesis as a consequrnve of FLCN alterations; furthermore, mTOR inhibition with sirolimus partially reversed the phenotype associated with selective inactivation of FLCN in the kidneys in one mouse model. Based on these data, a phase 2 study of the mTOR inhibitor, everolimus, was initiated in patients with BHD-associated renal tumors in 2015. However, the study was closed due to low accrual, owing to a significant extent to the reluctance of patients with this rare entity to accept the potential toxicity associated with everolimus. Additional studies to identify other potential targets in BHD-associated tumors as well as sporadic chromophobe tumors are underway 4) Targeting the VHL Pathway: VHL is a familial cancer syndrome characterized by a propensity for the development of bilateral multifocal clear cell RCC as well as tumors in several other organs. While there is a well-defined surgical standard of care for these patients, particularly in the setting of localized disease, there is clearly a need to explore alternatives which would spare these patients the morbidity associated with repeated surgery. Towards this end, the first clinical trial utilizing systemic therapy directed at VHL patients was initiated in the UOB. This phase 2 trial of the heat shock protein 90 inhibitor, 17 AAG, was designed to treat presurgical patients with localized renal tumors associated with VHL and was developed in collaboration with CTEP and Dr. Len Neckers, whose laboratory work provided the preclinical data supporting the evaluation of this class of agents in clear cell RCC. A subsequent phase 2 study evaluating the efficacy of vandetanib, a dual VEGFR and EGFR inhibitor, was initiated in 2008 and remains the largest trial in VHL patients to date; data from this study suggest that while vandetanib is active, the associated side effects have a significant impact on quality of life of these patients with mostly localized tumors generally amenable to surgical management. A variety of preclinical studies are ongoing to evaluate novel approaches in the various subtypes of RCC and are expected to guide future studies in patients with these malignancies. Upregulation of HIF2 is well studied consequence of VHL inactivation and appears to be critical for development of RCC.Recently, small molecule inhibitors of HIF2 have been evaluated preclinically and are currently undergoing clinical evaluation.We initiated 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, a second generation, selective HIF2 -alpha inhibitor, PT2977/MK6482, that is more potent than PT2385 and is associated with more predictable and uniform pharmacologic properties, was developed by our pharma collaborators. I am co-leader of a new, multicenter, phase 2 study of this agent in VHL-associated RCC; data from this study, demonstrating the activity of this agent in VHL associated renal tumors were recently presented at the 2021 ASCO Annual Meeting. Results from this study are also the basis for an NDA that is undergoing expedited review by the FDA.