Abstract CN04-03: Targeting the metabolic basis of kidney cancer

Renal cell carcinoma (RCC) affects nearly 300,000 people worldwide each year and is responsible for over 100,000 deaths each year. RCC is not a single disease; it is made up of a number of different types of cancer, with different histologies and clinical courses, responding differently to therapy and caused by different genes. There are currently 17 genes known to cause RCC, 14 of which are associated with inherited forms of the disease. Study of the RCC gene pathways has shown that RCC is fundamentally a metabolic disease. Much of what is known about the genetic basis of RCC has been learned from studying RCC-predisposition families. von Hippel-Lindau (VHL) is a hereditary cancer syndrome in which affected individuals are at risk for the development of tumors in a number of organs, including the kidneys. Patients affected with VHL are at risk for the development of bilateral, multifocal, clear cell renal cell carcinoma. Genetic linkage analysis in VHL families was performed to identify the VHL gene on the short arm of chromosome 3. VHL gene mutation that segregates with the disease is identified in 100% of VHL families. VHL gene mutation or methylation is also found in a high percentage of tumors from patients with sporadic, nonfamilial clear cell RCC. The product of the VHL gene, pVHL, has been found to form a complex with elongin C, elongin B, Cul2, and RBX1 to target the hypoxia-induced factors, HIF1/2, for oxygen-dependent ubiquitin-mediated degradation. Although 9 targeted therapeutic agents have been approved by the FDA for the treatment of patients with advanced RCC, many patients eventually progress and may succumb to this disease. High-grade, high-stage, low-survival clear cell RCC has been shown to be characterized by a pattern consistent with aerobic glycolysis, reduced oxidative phosphorylation, and a dependence on the pentose phosphate shunt. Clinical trials targeting the metabolic basis of clear cell RCC, including targeting HIF2 transcription, are currently under way. Hereditary papillary renal cell carcinoma (HPRC) is a hereditary cancer syndrome in which affected individuals are at risk for the development of bilateral, multifocal type 1 papillary RCC. HPRC is characterized by germline mutation of the MET proto-oncogene. MET gene alteration or amplification is found in a high percentage of tumors from patients with nonhereditary, sporadic Type 1 papillary renal cell carcinoma (PRCC). Clinical trials are currently under way targeting the MET pathway in patients with Type 1 PRCC. Birt-Hogg-Dube is an inherited form of chromophobe RCC (ChRCC) in which affected individuals are at risk for the development of bilateral multifocal chromophobe and hybrid oncocytic RCC. Genetic linkage analysis identified the FLCN as the Birt-Hogg-Dube gene. The product of the FLCN gene, folliculin, forms a complex with the FLCN binding proteins, FNIP1/2, and the gamma subunit of AMPK. Inactivation of the FLCN has been shown to result in activation of mTORC1/mTORC2. A clinical trial is currently being conducted to evaluate the effect of targeting the mTORC1 pathway in patients with Birt-Hogg-Dube-associated renal tumors. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for the development of cutaneous and uterine leiomyomas and an aggressive form of Type 2 PRCC. HLRCC is characterized by mutation of the gene for the Krebs cycle enzyme, fumarate hydratase (FH). HLRCC-associated type 2 PRCC has been shown to be characterized by a Warburg shift to aerobic glycolysis with decreased oxidative phosphorylation and a glutamine-dependent reductive carboxylation. Clinical trials are currently under way evaluating the effect of agents targeting the FH pathway in patients with HLRCC-associated RCC. SDH-RCC is an inherited from of renal cell carcinoma that occurs in families with germline mutation of succinate dehydrogenase (SDH) B,C, or D genes. Similar to FH-deficient RCC, SDH-RCC is characterized by a metabolic shift to aerobic glycolysis, significantly impaired oxidative phosphorylation (consistent with complex 2 dysfunction), and a glutamine-dependent reductive carboxylation. SDH-RCC renal tumors are malignant and have a propensity to spread when they are small. Understanding the metabolic basis of renal cell carcinoma has the potential to provide the foundation for the development of more effective forms of therapy for patients with these cancers.References: 1. 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Sourbier C, Ricketts CJ, Matsumoto S, Ghosh S, Chen V, Srivastava G, Tong WH, Mannes PZ, Yang Y, Wei MH, Vocke CD, Merino M, Srinivasan R, Pendergast AM, Krishna M, Mitchell JB, Rouault TA, Neckers L, Linehan WM. Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer. Cancer Cell 2014;26:840-50. 6. Linehan WM, Spellman PT, Ricketts CJ, et al. Comprehensive molecular characterization of papillary renal cell carcinoma. N Engl J Med 2016;374:135-45. 7. Saxena N, Maio N, Crooks DR, Ricketts CJ, Yang Y, Wei MH, Fan TW, Lane AN, Sourbier C, Singh A, Killian JK, Meltzer PS, Vocke CD, Rouault TA, Linehan WM. SDHB-deficient cancers: The role of mutations that impair iron sulfur cluster delivery. J Natl Cancer Inst 2016;108. Citation Format: W. Marston Linehan. Targeting the metabolic basis of kidney cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr CN04-03.