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。大华大学分子治疗学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，针对传统癌基因和改变的代谢途径的各种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期研究正在研究针对这些肿瘤的靶向方法。中期分析显示，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65%）和持久的缓解。基于贝伐单抗和厄洛替尼在2期试验中所看到的前所未有的疗效，人们正在努力进一步评估该方案作为家族性和散发性乳头状肾癌患者可行和有效的标准治疗选择。作为该策略的一部分，该研究已经扩大，以确认最初看到的反应率，并试图识别分子标记，可能有助于识别散发乳头状RCC患者最有可能从该方法中获益。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；vandetanib联合二甲双胍在散发性乳头状RCC患者以及克雷布斯循环改变患者（即FH和SDH失活突变患者）中的1/2期试验已经启动，目前正在累积患者。此外，我们计划评估一种新型谷氨酰胺酶抑制剂CB-839在肿瘤中的疗效，该酶被认为在维持细胞生物能量学和大分子合成中发挥关键作用。为此，我们正在参与该药物与cabozantinib联合用于晚期RCC患者的1期研究3)靶向mTOR通路的Birt Hogg Dube和散发的疏色性RCC中，疏色性肾癌约占所有RCC诊断的5%。虽然大多数憎色性肿瘤是零星发生的，但这些肿瘤也发生在家族性肾癌综合征（BHD）患者中。BHD患者有发展为各种组织学亚型的双侧多灶性肾肿瘤的风险，包括嫌色、混合嫌色/嗜瘤细胞肿瘤和透明细胞肾细胞癌。这些肿瘤是FLCN基因种系失活突变的结果，通常伴随着第二次体细胞攻击，导致卵泡蛋白失活。利用bhd肿瘤细胞系以及FLCN缺失的动物模型，我们的研究小组已经证明FLCN缺失与mTOR及其下游效应物的激活有关。一些散发的憎色性RCC肿瘤，在组织学上与BHD无法区分，也与mTOR的激活有关，这引起了对该途径抑制剂的临床评估的兴趣。一项研究mTOR抑制剂依维莫司在bhd相关肾肿瘤患者和转移性散发性色素恐惧肿瘤患者中的疗效和耐受性的2期试验正在进行中。BHD和散发性恐色性RCC患者将被纳入独立队列，并将平行纳入患者。VHL是一种家族性癌症综合征，其特点是易发展为双侧多灶透明细胞RCC以及其他器官的肿瘤。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。PT2385是首个临床可用的HIF2抑制剂，我们已经在vhl相关RCC患者中启动了该药物的2期研究

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 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 is being studied in an ongoing phase 2 study of bevacizumab and erlotinib. Interim analyses have shown a high response rate (ORR approximately 65% in those with fumarate hydratase mutations) and durable responses in many patients, including those with some forms of sporadic papillary RCC. Based on the unprecedented efficacy seen in the phase 2 trial of bevacizumab and erlotinib, efforts are afoot to further evaluate this regimen as a feasible and effective standard of care option in patients with familial as well as sporadic forms of papillary RCC. As part of this strategy, the study has been expanded in order to confirm the response rates seen initially as well as to attempt to identify molecular markers that may help identify sporadic papillary RCC patients most likely to benefit from this approach. 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; a phase 1/2 trial of vandetanib in combination with metformin in patients with sporadic papillary RCC as well as those with altered Krebs cycle (i.e, those with inactivating FH and SDH mutations) has been initiated and is currently accruing patients. In addition, we plan to evaluate the efficacy of a novel glutaminase inhibitor, CB-839, in tumors where this enzyme is believed to play a key role in maintaining cellular bioenergetics and macromolecule synthesis. To this end, we are participating in a phase 1 study of the agent in combination with cabozantinib in patients with advanced RCC 3) Targeting the mTOR Pathway in Birt Hogg Dube and Sporadic Chromophobe RCC Chromophobe kidney cancer accounts for approximately 5% of all RCC diagnoses. Although the majority of chromophobe tumors arise sporadically, these tumors also occur in patients with the familial kidney cancer syndrome, BHD. Patients with BHD are at risk for the development of bilateral multifocal renal tumors of various histologic subtypes, including chromophobe, mixed chomophobe/oncocytic tumors and clear cell RCC. These tumors are the result of germline inactivating mutations in the FLCN gene, usually accompanied by a second, somatic hit resulting in inactivation of folliculin. Using cell lines derived from BHD-tumors as well as animal models of FLCN deficiency, our group has demonstrated that FLCN loss is associated with activation of mTOR and its downstream effectors. Some sporadic chromophobe RCC tumors, which are indistinguishable histologically from those seen in BHD, are also associated with activation of mTOR, kindling interest in clinical evaluation of inhibitors of this pathway. A phase 2 trial to study the efficacy and tolerability of the mTOR inhibitor everolimus in pateints with BHD-associated renal tumors and in patients with metastatic sporadic chormophobe tumors his ongoing. Patients with BHD and sporadic chromophobe RCC will be accrued to independent cohorts and will accrue patients in parallel. 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. PT2385 is the first clinically available HIF2 inhibitor and we have initiated a phase 2 study with this agent in patients with VHL-associated RCC