AUA 2018: Whitmore Lecture - Genetic Basis of Kidney Cancer

San Francisco, CA ( W. Marston Linehan, MD of the National Cancer Institute, unfortunately, could not attend the session in person but gave a video talk on inherited forms of renal carcinoma.  There are 4 known forms of inherited renal carcinoma, including Von Hippel Lindau (VHL) for clear cell RCC, hereditary papillary renal carcinoma for type 1 papillary RCC, Birt Hogg Dube for chromophobe RCC, and hereditary Leiomyomatosis renal cell carcinoma for type 2 papillary RCC.

VHL gene mutation was discovered in 1993 at the NCI. Mutations are seen in anywhere from 90-95% of clear cell renal cell carcinoma (ccRCC) cases. VHL clinical features include tumors developing in both kidneys, adrenal glands, pancreas, brain or spine, eyes, or inner ears. Further study of downstream effectors of the VHL complex led to the discovery of HIF, mTOR, VEGFR, PDGFR, and EGFR, each of which has been selectively targeted. As a result, we now have seven drugs that act on different parts of the VHL pathway: bevacizumab, pazopanib, axitinib, sunitinib, sorafenib, temsirolimus, and everolimus. 

Linehan emphasized the importance of using a phenotype to genotype strategy in curing patients with rare disease. Once we identify therapies that have promising results for select patients, whole genome sequencing can be carried out to find and target mutated genes, further illuminating important clinical pathways.

Linehan then shifted to describing the NIH experience with hereditary papillary renal cell carcinoma (HPRC), an autosomal dominant disease which causes papillary type 1 RCC. The gene is MET, which is activated by HIF. The tyrosine kinase domain is mutated in these patients resulting in a constitutively active signal. The mutation is present in about 13% of sporadic papRCC. Because of this finding, Foretinib (which is a dual VEGF and MET inhibitor) showed a dramatic response on therapy. In addition, all 39 patients on the Foretinib study had tumor shrinkage. The Phase II study was published in 2012.

Lastly, Linehan discussed treatment of hereditary leiomyomatosis renal cell carcinoma (HLRCC), and the importance of understanding the role of fumarate hydratase (FH). This syndrome manifests in cutaneous leiomyoma, uterine leiomyomas (fibroids) and papillary type 2 RCC. Mutational inactivation of FH leads to VHL-independent upregulation of HIF and their downstream transcriptional targets, such as VEGF and EGFR. The NCI urologic oncology team, led by the work of Ramaprasad Srinivasan, approached treatment by targeting VEGF and EGFR using bevacizumab and erlotinib.

In conclusion, kidney cancer is not a single gene disease, rather it is affected by a collection of genes, and we need to focus on targeting each one separately. Doing so will give us the potential to develop new treatments and learn how to utilize combination strategies so that we can improve survival in kidney cancer patients.

Presented by: W. Marston Linehan, MD, National Cancer Institute National Cancer Institute, Rockville, MD USA

Written by:  Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA
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