Identifying and Targeting Epigenetic Vulnerabilities in the Histone H3 Lysine 36 Methylation Axis in Renal Cell Cancer

Area of Emphasis: Our proposal, 'Identifying and targeting epigenetic vulnerabilities in the histone H3 lysine 36 methylation axis in renal cell cancer,' directly addresses the FY20 KCRP Area of Emphasis Chromatin and Gene Regulation (Basic/Translational Science), as our proposal is focused on elucidating how chromatin and gene dysregulation drive RCC and can be therapeutically targeted.

Rationale/Objective: Clear cell renal cell carcinoma (ccRCC), the predominant form of renal cancer, is currently the 8th leading cause of cancer death in the United States and has an incidence rate that has increased nearly 40% over the last decade. The frequency of ccRCC in the Veterans population treated within the VA healthcare network is even higher. Kidney cancer disproportionately affects military professionals and families, with patients averaging 12 years of lost life. Unlike breast or colon cancer, there are no screening tests, and once patients develop metastatic disease, they succumb to their disease within 3 years despite immunotherapy. As such, there is an urgent need to develop new drug targets outside established immunotherapy or targeting the blood vessels that take advantage of known mutations inside the cancer.

Unlike many tumor types, multiple chromatin modifiers are mutated in ccRCC, resulting in a highly disrupted epigenome that fuels tumor progression and, eventually, metastasis. The epigenome is an information coding system that sits atop the genetic information and regulates how, when, and to what level that genetic information is used to specify gene expression patterns, including those that control cell growth and metastasis. SETD2, a writer of the epigenome, is one such epigenetic regulator that is mutated in upwards of 30% of all ccRCC cases, yet there are no approved therapies that target this mutation. Importantly, SETD2 mutations in ccRCC are associated with reduced survival and shorter time to relapse, highlighting the need to target this mutation.

Ultimate applicability: Pharmaceutical companies have largely focused their efforts on targeting the immune system or blood vessels in RCC, leaving a vacuum of knowledge about the epigenome. Identification of genes that act as a redundant backup to known cancer mutations is a proven approach to identifying new therapeutic drug targets. This functional redundancy in RCC is akin to brakes on the front and rear wheels of a runaway car. Losing one set of brakes is not enough to impair the car, but knocking out both the front and rear brake would lead to a 'lethal' event. We took advantage of this concept, called 'synthetic lethality' to identify NSD1, an epigenome writer, and PCL2, an epigenome reader, that act as functional backups for SETD2 mutated RCC. Knocking out only SETD2 in RCC is not sufficient to kill a tumor, but our data suggests if we knock out either NSD1 or PCL2 in the setting of a SETD2 mutation it leads to cell death, suggesting SETD2 mutant RCC is very sensitive to these other newly discovered targets. That is, while mutations in SETD2 provide a growth advantage and drive cancer development, they may also create a novel vulnerability or sensitivity that does not exist in SETD2 normal cells and can be exploited as a therapy that should be completely specific for the tumor cells. Significantly, both of these factors are targetable with existing drugs. Our synergistic scientific team is comprised of several PhDs with 20 years of experience in studying the epigenome and a practicing oncologist with 10 years of experience treating patients in RCC clinical trials. Here we propose to translate the findings of our synthetic lethal screen to RCC models, to determine how alterations of the epigenome drives ccRCC, to obtain a completely unbiased view of potential new druggable pathways, and to exploit currently available drugs to determine whether they can specifically target SETD2 mutant cancer cells and the molecular mechanisms by which they induce tumor cell death.

The expected long-term outcome of this research project is to fill an area unexplored by pharmaceutical companies and the generation of new therapeutics that target mutations in the cancer cell, rather than the tumor microenvironment. These epigenome therapies may complement existing therapies and lead to more effective treatment of Veterans and the general population suffering from ccRCC, to ultimately reverse the terrible statistic of 12 years of lost life per patient.