ORLANDO, FL, USA (UroToday.com) - Dr. Marston Linehan presented work from the Urologic Oncology Branch of the NIH on hereditary and sporadic kidney cancers.
He began by giving a now-familiar history of VHL biology. The gene was identified in 1993, and then was shown to be mutated in or silenced by methylation in 90% of sporadic disease. VHL acts as an oxygen sensor by mediating degradation of HIF1 and HIF2 transcription factors in aerobic conditions. When exposed to low oxygen tension or when VHL function is lost, HIF transcription factor concentration increases, activating genes involved in angiogenesis, paracrine growth, cell division, and glucose metabolism. Seven drugs now target the pathway starting with bevacizumab. Responses can be dramatic but unfortunately are not long-lived. He highlighted the TCGA data which showed PBRM1, SETD2, and BAP1 are mutated among 9 other ccRCC genes. As seen in the initial TCGA publication, high grade/high stage/low survival tumors undergo a Warburg shift to anaerobic glycolysis, and use glutamine differently as a metabolite, suggesting new avenues of research in targeting these tumors.
He 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 HGF. 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, vegf inhibitor + foretinib (which is a MET inhibitor) in one case study 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, and another study is going on with a second generation MET inhibitor.
The last disease he spoke about is HLRCC. These patients develop cutaneous and uterine leiomyoma and RCC. Fifty percent of women with the disorder had had a hysterectomy in their 20s. The first patient identified with the disease was an 18-year-old who was treated in 1989 and died about 9 months later. The family had several effected members, and all of the effected members died of metastatic type II papillary RCC. The gene responsible for the disease is fumarate hydratase (FH), and its mutation has been identified in 99% of patients with the disease. The mutation is inactivating, and the gene behaves as a tumor suppressor because replacement of the mutant allele in patient-derived cell lines completely blocks their oncogenic behavior. When FH is knocked out, the cell cannot metabolize acetyl-CoA through the tricarboxylic acid (or citric acid) cycle, again causing a Warburg shift. Because the cells are completely dependent on glucose, 18FDG-PET is an excellent way to image the disease. Additionally, fumarate is an oncogenic metabolite which builds up in the absence of FH: it is able to block prolyl-hydroxylase 2 (PHD2). PHD2 is required for HIF degradation by hydroxylating residues near the VHL-binding sites, linking this disease back to the oxygen-sensing pathway, and also lending itself to VHL-targeting therapies. A trial of bevacizumab + erlotinib showed these drugs were highly active, with some patients having durable responses (up to 8 years). In HLRCC patients, there is a 60% partial response, and in sporadic patients with type II papillary RCC the partial response rate is 30%.
Presented by W. Marston Linehan, MD at the 2015 Genitourinary Cancers Symposium - "Integrating Biology Into Patient-Centric Care" - February 26 - 28, 2015 - Rosen Shingle Creek - Orlando, Florida USA
Center for Cancer Research, National Cancer Institute, Bethesda, MD USA
Reported by Phillip Abbosh, MD, PhD, medical writer for UroToday.com