Lectures and seminars Nobel Laureate Revisiting Lecture: William G. Kaelin Jr. Nobel Laureate in Physiology or Medicine 2019

Loss of the VHL tumor suppressor protein (pVHL) is the usual initiating event in hereditary (VHL Disease) and sporadic clear cell renal cell carcinoma (ccRCC), which is the most common form of kidney cancer. Tumor development in this setting requires additional cooperating mutations in genes such as PBRM1 or BAP1. pVHL is the substrate recognition subunit of an ubiquitin ligase that targets the alpha subunits of the HIF transcription factor for proteasomal degradation. Binding of pVHL to HIFα requires that HIFα be prolyl hydroxylated by the EglN (also called PHD) 2-oxoglutarate (2-OG)-dependent dioxygenases, which act as oxygen sensors. Several EglN inhibitors have now been approved around the world for the treatment of anemia. 

Of the HIF paralogs, HIF2α promotes ccRCC and HIF1α inhibits ccRCC in preclinical models. Drugs that inhibit the HIF-responsive gene product VEGF are mainstays of kidney cancer treatment. The allosteric HIF2α inhibitor Belzutifan was recently approved for the treatment of VHL Disease and sporadic ccRCC. We recently did a CRISPRa (gene activation) screen to identify genes that modify sensitivity of VHL-/- ccRCC cell lines to Belzutifan. One of the top scoring genes was Cyclin D1, which is known to be induced by HIF2 in ccRCC. This, and our earlier work showing that VHL-/- cells are hyperdependent on Cdk4/6, provides a rationale for testing Cdk4/6 inhibitors in ccRCC.

cRCC is an immunogenic tumor but does not have a particularly high mutational burden relative to other cancers. Earlier work by others suggested that this might be due, at least in part, to increased endogenous retrovirus expression (ERV) in ccRCC. We have discovered that multiple ERVs are regulated by HIF2, including some that can give rise to HLA-bound peptides.

Many genetically validated targets in cancer are deemed to be “undruggable”. Our group and Ben Ebert’s group showed that the thalidomide-like drugs (“IMiDs”) act as “molecular glues” that reprogram the cereblon ubiquitin ligase to target two undruggable transcription factors, IKZF1 and IKZF3, for proteasomal degradation and linked this to their antimyeloma activity. This has galvanized interest in small molecule protein degraders in the biotech and pharma community. We are developing new tools for identifying such degraders.

Host: Professor Randall Johnson, randall.johnson@ki.se. 

Contact: Ann-Mari Dumanski, Nobel Office, Nobel Forum, 08-524 878 00, ann-mari.dumanski@nobelprizemedicine.org.