Cancer Epigenetics & Genomics Program
Description of the Program
Mutations in genes involved in the epigenetic regulators of gene expression have now been found in a broad array of solid tumors and hematologic malignancies. These mutations affect not only DNA methylation and hydroxyl-methylation, but also the readers, writers and erasers of histone modifications. In fact, the discovery of mutations in sites of post-transcriptional modifications of histones in certain subtypes of cancer point to a key role for chromatin in oncogenesis. Additionally, the discovery of frequent mutations in DNMT3A in myeloid malignancies, and the finding that the TET2 and IDH mutations occur in similar cancers bring the role of these new mechanisms of transformation into focus.
The Cancer Epigenetics & Genomics Program aims to build on their mechanistic knowledge of the pathogenesis of these malignancies and translate the important insights that are gained into novel, potentially more effective epigenetic-focused therapies of cancer. The program is taking advantage of their unique strengths and resources to develop a collaborative and interactive program that will create, distribute, and utilize novel cell based assays and mouse models of cancer. Our efforts will generate important bioinformatics and biochemical resources for the cancer community at-large. Importantly, the program will leverage their genomic and epigenetic infrastructure capabilities to develop personalized cancer medicine approaches for patients.
Goals of the Program
- Define how signaling pathways affect chromatin modifications in order to identify potential enzymes and their targets affecting cancer (stem) cell behavior which will be utilized for the development of epigenetic targeted therapies.
- Determine how polycomb complexes including PRC2 function contributes to cancer biology (target EZH2, study the effects of ASXL1 and BAP1 mutations on stem cell behavior
- Examine how to restore TET protein function to cancer cells deficient in hydroxymethylation (e.g. leukemia, sarcoma, and brain tumors with IDH mutations)
- Discover how non-coding RNAs functions can be promoted or inhibited in order to turn on or off specific genes whose aberrant regulation contributes to cancer cell behavior
- Develop more potent differentiating therapies for cancer, based on inhibiting or promoting histone (and non-histone) protein modifications. These include efforts to target demethylases such as LSD1, alone or in combination with other forms of therapy.
- Target arginine methyltransferases (PRMT4 & PRMT5) in hematologic malignancies (including leukemia and lymphoma) and solid tumors (e.g. brain tumors and lung cancer)
- Define the epigenetic changes that accompany hypoxia and use that knowledge, plus knowledge on the role of the SETD2 H3K36 PKMT in GU cancers, to devise new treatment strategies for this and other solid tumors.
- Define the oncogenic and tumor suppressor properties of the histone acetyltransferases (e.g. p300) and develop inhibitor-based therapies for individual cancer types
- Utilize genomics and epigenetic profiling to individualize the understanding of each patient’s tumor (or malignancy) and develop specific therapies for cancer subsets