Targeting Genetic and Metabolic Alterations in Distinct Subtypes of RCC

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Over the past three decades, it has become increasingly clear that a number of histologically, genetically and clinically distinct tumors arise from the kidney. Consequently, the classification of kidney cancers has evolved considerably, with a number of new entities now recognized and classified primarily based on genetic alterations underlying these tumors. However, our therapeutic approach to these tumors is only beginning to account for the diversity underlying these tumors, with most approaches until now being developed primarily to treat patients with the most common RCC variant (clear cell RCC), with often modest activity in other forms of RCC. We aim to understand the key drivers and vulnerabilities associated with distinct variants of kidney cancer and help develop approaches that target these vulnerabilities. Our efforts are focused largely on the following RCC variants. 1) Fumarate deficient (FH-deficient) kidney cancer / Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC): HLRCC, an autosomal dominant inherited condition, predisposes to the development of a distinct RCC variant that metastasizes early and is difficult to treat, with most patients dying from their cancer. Until recently, there were no effective treatments for treating this condition. Preclinical work performed at the NCI identified HIF upregulation, impaired Krebs cycle, mitochondrial dysfunction, and a reliance on aerobic glycolysis as key characteristics of these tumors. I conducted a phase 2 study evaluating the combination of bevacizumab, a VEGF targeted antibody, and erlotinib, a tyrosine kinase inhibitor targeting EGFR, in an effort to target key vulnerabilities in these tumors. Data from this study were published recently (New England Journal of Medicine, 2025) and demonstrated the activity of this combination in advanced HLRCC-associated kidney cancer, with an overall response rate of 72%, a median PFS of 21 months and a median OS of 44 months. Based on these data, this regimen is considered a standard of care option in this patient population. The regimen also has some activity in patients with sporadic forms of papillary RCC (ORR 35%, median PFS 8.8 months), with a subset of patients achieving durable responses. Unfortunately, most patients eventually develop progressive disease and die from their disease. In an effort to improve the clinical outcomes in these patients, particularly the complete response/durable remission rates, I have designed and lead an ongoing ETCTN/CTEP sponsored multicenter phase 2 study evaluating the addition of the PDL1 antibody, atezolizumab, to bevacizumab/erlotinib. The study also includes a cohort of patients with sporadic papillary RCC, who may benefit from this approach. The study is currently enrolling patients into both cohorts. Additional efforts in the laboratory focus on preclinical studies exploiting additional vulnerabilities in FH-deficient tumors such as defects in DNA damage repair. 2) Papillary RCC: As currently defined by the WHO classification, this entity is comprised largely of tumors previously classified as type 1 papillary RCC. These tumors are characterized by activating mutations in the MET (15-20% of patients) and gain of chromosome 7 (~ 70% of cases). I co-led the first study to evaluate the activity of MET directed therapy in these tumors; this study, a phase 2 study of the multitargeted TKI, foretinib, demonstrated that this approach had modest activity in and unselected cohort of patients with papillary RCC, but had significantly higher activity (ORR 50%) in a subset of patients with activating MET mutations (JCO, 2013). Efforts to identify alternative treatment approaches are ongoing in my laboratory. One approach, inhibition of hsp 90, has demonstrated activity in preclinical models of papillary RCC (Journal of Experimental Clinical Cancer Research, 2022). Inhibition of the cdk 4/6 pathway also appears to have activity in these tumors as demonstrated in ongoing preclinical studies and has led to the initiation of a phase 1/2 study of the combination of palbociclib and sasanlimab that I lead. 3) Translocation RCC: This subtype of RCC predominantly affects children and young adults and is characterized by aberrant fusion proteins resulting from translocation of a variety of transcription factors (TFE3, TFEB, MiTF). The mechanisms by which these fusion proteins drive cancer are under study. There are currently no treatment approaches of proven benefit for patients with advanced translocation TRCC. A number of approaches are being studied in my laboratory, in collaboration with academic and industry partners. I have also helped establish a coalition of adult and pediatric oncologists as well as other disease experts and advocacy groups to increase awareness of this disease and to help accelerate basic science, translational and clinical research in efforts in this area.