Targeting Genetic and Metabolic Alterations in Distinct Subtypes of RCC

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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 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. Additionally, efforts to identify other targets and pharmacologic approaches are being explored in the laboratory, with recent data demonstrating the preclinical activity associated with hsp90 inhibition in papillary RCC 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 consequence 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/belzutifan, that is more potent than PT2385 and is associated with more predictable and uniform pharmacologic properties, was developed by our pharma collaborators. I co led a 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 published in the New England Journal of Medicine (Nov 2021). This study also provided the basis for the FDA approval of belzutifan in patients with organ confined VHL-associated renal, pancreatic and CNS tumors. This is the first systemic agent approved for use in patients with VHL and heralds a new paradigm for the management of VHL.