REPROGRAMMING CHROMATIN MODIFIERS IN KIDNEY CANCER

Project: Research project

Project Details

Description

Personnel: Dr. Thai H. Ho is an Assistant Professor and practicing Mayo Clinic oncologist with a clinical focus in renal cell carcinoma (RCC), 75% protected research time, a track record of significant publications in RCC, a track record of being awarded extramural grants, molecular biology training in a National Institutes of Health (NIH)-funded combined M.D./Ph.D. program, and a dedicated 600-foot lab. His career to date is focused on analyzing the role of chromatin modifiers in RCC, a Fiscal Year 2016 (FY16) Peer Reviewed Cancer Research Program (PRCRP) Topic Area. He developed biobank compatible chromatin immunoprecipitation (ChIP) and DNA methylation immunoprecipitation sequencing protocols with custom bioinformatics resources (ChIP-RNA-seqPRO) to generate genome-wide histone and DNA modification profiles in formalin-fixed, paraffin-embedded (FFPE) tissue and peripheral blood mononuclear cells. He is the first author on nine research articles in high-impact journals such as Oncogene, Modern Pathology, and the EMBO Journal. He is a co-author on an additional 30+ manuscripts in journals such as Cell, Science, and the New England Journal of Medicine, further supporting his research productivity. His extramural funding and awards include: (1) a Defense Advanced Research Projects Agency contract evaluating peripheral blood-based markers of treatment response in RCC, (2) an American Society of Clinical Oncology Young Investigator Award, and (3) The Cancer Genome Atlas.Dr. Alexander Parker is a Mayo Clinic Professor of Epidemiology with over 100 publications and expertise in RCC epidemiology. Of note, Dr. Parker has developed biomarkers in patient samples to address the FY16 PRCRP Topic Area of RCC. He has extramural funding (NIH R01, NIH R21, and CDRMP) to validate RCC biomarker-based prognosis scoring systems. He has mentored over 10 junior faculty. To supplement Dr. Parker’s expertise, the mentoring team includes Dr. Keith Robertson, a Mayo Clinic Professor of Pharmacology, who is an established expert in epigenetic profiling of DNA methylation. He holds two NIH R01 grants with over 9 years of continuous funding; he developed techniques to quantify DNA methylation and study the regulation of DNA methyltransferases. He has trained 10 post-doctoral mentees.Career Development: The mentorship experience designed by Drs. Parker and Robertson includes: (1) multidisciplinary mentorship, (2) structured didactic graduate school training in a certificate program, (3) career development workshop based education, and (4) develop research critique-writing skills. A PRCRP Career Development Award will provide support for salary and resources to further Dr. Ho’s goal of becoming an independently funded investigator with a focus in the epigenetics of RCC. With this support, he will translate basic science epigenetic assays into routine clinical practice by optimizing these assays in human biospecimens.Research: Our data reveal a novel crosstalk between DNA methylation and histone methylation, in which mutations in SETD2, a chromatin modifier, results in dramatic DNA hypermethylation coinciding with an increased risk of RCC recurrence.Objective of Grant: To improve upon treatments in metastatic RCC and identify patients with small renal tumors with an unexpected higher risk of recurrence by elucidating the role of chromatin modifications in RCC, and to test whether DNA hypermethylation represent a reversible, druggable mechanism.Aim 1: To determine the mechanism of how histone H3 lysine 36 trimethylation deregulation induces DNA hypermethylation and drives cancer metastasis.Aim 2: To determine if attenuation of de novo DNA methylation using epigenome targeting drugs reverses the SETD2 mutant-associated DNA hypermethylation.Aim 3: To validate a DNA hypermethylation prognostic signature in a nested case-control study (n=100) of FFPE RCCs matched for a validated “low-risk” clinicoprognostic algorithm (stage, size, grade, necrosis score), but with disparate clinical outcomes.Study Design: Dr. Ho and his team will utilize isogenic SETD2 cell lines, peripheral blood mononuclear cells from patients treated with DNA hypomethylating agents, and a case-control cohort of RCC tumors to interrogate DNA methylation and evaluate the functional outcomes of altered DNA methylation. Techniques to analyze these samples include established protocols for reduced representation bisulfite sequencing, PCR, proliferation/invasion assays.Impact: The intended outcome of these studies will be both an improved understanding, at the molecular level, of the functions of chromatin modifiers and, at the translational level, a unique opportunity to accelerate the drug development process by repurposing drugs with existing clinical data. Our proposal emphasizes the clinical potential of an epigenetic assay compatible with archival tissue to better identify nonmetastatic patients with small tumors and a higher risk of disease recurrence.Military Relevance: RCC is a FY16 Topic Area. RCC is relevant to the military as is it preferentially affects males, the predominant gender of the Armed Forces, and is associated with an average of 12 years of lost life.

StatusFinished
Effective start/end date8/15/178/14/19

Funding

  • Congressionally Directed Medical Research Programs: $597,600.00

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.