Kidney Cancer Genomic Studies Reveal New Targets and Complexities

Jane de Lartigue, PhD
Published: Monday, Mar 14, 2016
Renal cell carcinoma Kidney cancer is not a single disease, but a collection of histologically heterogeneous cancers that vary widely in their clinical course and response to treatment. Until recently, however, clinical trials have enrolled all types of patients and drugs have been broadly applied. Genome sequencing studies are beginning to match distinct genomic profiles to different subtypes, driving a dramatic shift in our understanding of these diseases and how to treat them.

Researchers have uncovered substantial genomic heterogeneity, even within the same tumor, and have made important discoveries hinting at the important roles of chromatin modification and cancer cell metabolism in driving tumor formation. Although these malignancies present unique challenges, capitalizing on these findings could offer the potential for durable disease control and a brighter future.

Kidney Cancer’s Histologic Diversity

Kidney cancers account for about 4% of all adult malignancies. The most common form, renal cell carcinoma (RCC), can be further subdivided on the basis of histologic morphology into a number of different subtypes. The vast majority (60%-80%) are clear cell RCC (ccRCC), with the remainder broadly classed as non-ccRCC.

Further adding to the complexity, non-ccRCC tumors encompass additional histologic groups: papillary RCC (pRCC; 10%-15%), chromophobe RCC (5%), and collecting duct carcinoma (1%). More recently, rarer subtypes have been discovered, including translocation-linked, mucinous tubular, and spindle- type RCC in addition to tubulocystic carcinoma, collectively accounting for less than 1% of cases, but responsible for some particularly devastating outcomes. There also are typically benign epithelial tumors such as renal oncocytoma (5%), which can be difficult to distinguish from chromophobe RCC. All forms of kidney cancer have proved difficult to treat, notoriously resistant to chemotherapy, with surgical resection providing the only potentially curative option if patients can be identified at an early stage. Around 30% of patients present with metastatic disease, with a further one-third developing metastases after surgical resection.

Targeting Key Drivers

Genetically speaking, kidney cancers can be either inherited or sporadic. Although less than 10% of kidney cancer cases are considered to have an inherited basis, the study of the four major autosomal dominant inherited kidney cancer syndromes has been pivotal to our understanding of the development and progression of this disease. Indeed, the some of the major drivers of inherited syndromes are common to many sporadic cases. These syndromes are the von Hippel-Lindau (VHL) syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC), hereditary papillary renal cancer (HPRC), and Birt-Hogg-Dubé syndrome (BHD).

Mutations in the VHL gene that are behind the hereditary risk of kidney cancer in patients with that syndrome are the most common. More than 90% of cases of ccRCC, both inherited and sporadic, exhibit deregulation of the VHL pathway. The VHL gene encodes a protein that forms a central part of an E3 ubiquitin ligase complex. This complex “tags” target proteins in the cell with ubiquitin molecules that signal to the proteasomal machinery that the proteins need to be destroyed and removed from the cell. Among VHL’s target proteins are the hypoxia-inducible factors (HIFs), primarily HIF-1α, oxygen-sensing transcription factors that mediate the expression of a number of genes in the nucleus that have hallmark roles in carcinogenesis.

One such HIF-target gene is VEGF, which has a well-known role in regulating angiogenesis. Thus, in the presence of a defective VHL gene, HIF-1α is no longer disposed of as it should be, leading to its accumulation and corresponding increases in the expression of downstream genes like VEGF. As researchers have worked to dissect the molecular pathways of kidney carcinogenesis, it has been shown that increased expression of HIF-1α and VEGF is highly dependent on the upstream activity of another well-known oncogenic signaling network, the PI3K/mTOR pathway.

Drugs targeting both the VEGF and PI3K/ mTOR pathways were already in development for other types of cancer and these discoveries paved the way for a decade of advancements in the treatment of metastatic RCC.

Drugs Approved for Kidney Cancer

The FDA has approved seven targeted therapies for kidney cancer since 2005. These include four multikinase inhibitors that inhibit the VEGF receptor (VEGFR) among other targets—sunitinib (Sutent), pazopanib (Votrient), sorafenib (Nexavar), and axitinib (Inlyta)—and the monoclonal antibody bevacizumab (Avastin). Two mTOR inhibitors, temsirolimus (Torisel) and everolimus (Afinitor), are approved as first- and second-line therapy, respectively.

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