There are several forms of kidney cancer. The most common form is referred to as clear cell renal carcinoma. The initiating event in most clear cell renal carcinomas is the inactivation of a protein called the VHL tumor suppressor protein. Loss of the VHL protein leads to increased activity of several proteins that belong to the HIF protein family. We showed before that increased activity of one of the HIFs, called HIF2, promotes the growth of clear cell renal carcinomas. HIF2 is a so-called transcription factor and controls the activity of over 100 genes in clear cell renal carcinomas, including the gene that governs the production of vascular endothelial growth factor (VEGF). It has been well established that drugs that block VEGF are helpful for treating clear cell renal carcinomas but they are not curative. We believe that targeting HIF2 itself will be far more effective than simply blocking one of the many genes it activates (such as VEGF). We are working closely with Peloton Therapeutics, which has developed a drug that blocks HIF2 function in laboratory models.
In aim 1 and 2 we will conduct a clinical trial to determine if this drug can, indeed, block HIF2 activity in man and, if so, whether this leads to clinical benefit for patients with clear cell renal carcinoma.
In aim 2 we will also develop new ways of monitoring HIF2 activity in clinical samples.
In aim 3 we will ask whether blocking HIF2 function can, as expected, enhance the antitumor effects of VEGF inhibitors against clear cell renal carcinomas in mouse models of this disease. We recently made the unanticipated discovery that thalidomide, which has become an important drug for the treatment of a cancer called multiple myeloma, works by earmarking two transcription factors (called IKZF1 and IKZF3) for destruction. This gives us hope that we could, in time, discover drugs that likewise mark the HIF2 transcription factor for destruction. We will attempt to identify such drugs in aim 4. If successful, such drugs should markedly enhance the actions of drugs, such as the Peloton drug, that block HIF2 function. In addition, combining two drugs that inhibit HIF2 in two different ways should decrease the emergence of clear cell renal carcinoma cells that are resistant to therapy (since they would now have to circumvent two forms of attack on the same target).

Public Health Relevance

The signature molecular abnormality in the most common form of kidney cancer (clear cell renal carcinoma) is loss of the VHL protein, leading to activation of the HIF transcription factor. We showed that deregulation of HIF, particularly HIF2, drives the growth of clear cell renal carcinomas. This project focuses on testing a firstin- class HIF2 antagonist in patients and in laboratory models. In addition, we will develop new ways of monitoring HIF2 activity in tumors and, based on our recent work on the mechanism of action of thalidomide, attempt to identify drug-like chemicals that can earmark HIF2 for destruction.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA101942-14
Application #
9554208
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Kuzmin, Igor A
Project Start
Project End
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
Scelo, Ghislaine; Muller, David C; Riboli, Elio et al. (2018) KIM-1 as a Blood-Based Marker for Early Detection of Kidney Cancer: A Prospective Nested Case-Control Study. Clin Cancer Res 24:5594-5601
Zhang, Jinfang; Bu, Xia; Wang, Haizhen et al. (2018) Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 553:91-95
Gao, Xin; Jegede, Opeyemi; Gray, Connor et al. (2018) Comprehensive Genomic Profiling of Metastatic Tumors in a Phase 2 Biomarker Study of Everolimus in Advanced Renal Cell Carcinoma. Clin Genitourin Cancer 16:341-348
Liu, Wenjing; Chen, Binbin; Wang, Yang et al. (2018) RGMb protects against acute kidney injury by inhibiting tubular cell necroptosis via an MLKL-dependent mechanism. Proc Natl Acad Sci U S A 115:E1475-E1484
Iorgulescu, J Bryan; Braun, David; Oliveira, Giacomo et al. (2018) Acquired mechanisms of immune escape in cancer following immunotherapy. Genome Med 10:87
Gopal, Raj K; Kübler, Kirsten; Calvo, Sarah E et al. (2018) Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hürthle Cell Carcinoma. Cancer Cell 34:242-255.e5
Nakashima, Hiroshi; Alayo, Quazim A; Penaloza-MacMaster, Pablo et al. (2018) Modeling tumor immunity of mouse glioblastoma by exhausted CD8+ T cells. Sci Rep 8:208
Signoretti, Sabina; Flaifel, Abdallah; Chen, Ying-Bei et al. (2018) Renal Cell Carcinoma in the Era of Precision Medicine: From Molecular Pathology to Tissue-Based Biomarkers. J Clin Oncol :JCO2018792259
Hamieh, Lana; Choueiri, Toni K; Ogórek, Barbara et al. (2018) Mechanisms of acquired resistance to rapalogs in metastatic renal cell carcinoma. PLoS Genet 14:e1007679
Gao, Xin; McDermott, David F (2018) Ipilimumab in combination with nivolumab for the treatment of renal cell carcinoma. Expert Opin Biol Ther 18:947-957

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