Career Enhancement Program
Jean-Pierre Issa, MD
Peter Jones, PhD
The goal of the Career Enhancement Program (CEP) is to provide training and guidance for academic physician scientists, clinician-investigators, and laboratory-based scientists who wish to dedicate their career and research efforts to translational cancer epigenetics research. To achieve this goal, the CEP will pursue the following specific aims:
These objectives will be achieved through strong mentorship in which awardees will be instructed in the principles of clinical, basic, and translational cancer epigenetics research. Specific areas of education may include scientific and clinical methods, biomedical ethics, statistical design and analysis, bioinformatics, biology, biochemistry, genetics, epidemiology, and other areas relevant to individual projects. Mentorship will include laboratory-based investigators, clinical-translational investigators, biostatisticians, bioinformaticians and epidemiologists.
YEAR 2 - AWARDEES
Rachel Abbotts, MBChB, PhD
University of Maryland Baltimore
Translating in vitro studies inducing BRCAness in NSCLC using DNMT inhibitors to in vivo mouse models
The epigenetic drug 5-azacytidine, or AZA, produces gene expression changes across many different molecular pathways. Work from our lab has shown, in lung cancer cells, that AZA treatment downregulates mechanisms that are vital for repairing damage to DNA, and that this increases cancer cell sensitivity to a class of small molecule inhibitors (PARP inhibitors) that target a related DNA repair pathway. Our data shows that this effect may be dependent on the tumor suppressor protein p53, which is mutated in ~50% of lung cancers, and which plays a critical role in the cellular response to DNA damage. This project will test the AZA-PARP inhibitor combination in novel mouse models of p53 mutation as an important step to translating this treatment strategy into the clinic.
Shoghag Panjarian, PhD
Coriell Institute for Medical Research
Epigenetically Silenced Tumor Suppressor Genes in Breast Cancer
Aberrant DNA methylation is one of the most important events involved in breast cancer initiation and progression. Tumor suppressor genes (TSG) that gain DNA methylation at their promoters are inactivated and play significant roles in breast cancer. However, it remains elusive as to which of these epigenetically silenced genes play a driver role in tumorigenesis. Therefore, the goals of my research are as follows: 1) Decipher epigenetically modified driver genes from secondary passenger changes 2) Identify functionally enriched cancer circuitries in the presence of the epigenetically silenced TSGs 3) Target the cancer dependencies through synthetic essentiality approaches.
Timothy J. Triche, Jr., PhD
Van Andel Institute
Predictive Biomarkers for Epigenetic Priming in High-Risk Pediatric Leukemia
Leukemia is the most common cancer in children, and treatment depends on the type of cells affected. Outcomes are excellent for children diagnosed with B-cell leukemia; while, children and young adults whose disease emerges from other cell types have worse outcomes. Patients whose disease does not respond to therapy or quickly relapses fare worst of all, with a cure rate of less than 15%. However, in a Phase I pilot trial conducted by the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) consortium, we found that response rates for such patients more than doubled with the addition of epigenetic priming. We identified a highly specific biomarker for response that we validated in an independent phase II trial, and a high-risk subset of Children's Oncology Group Phase III trials. We have not yet identified the mechanism behind this marker, which may couple cholesterol biosynthesis and immune response. With data from COG/TARGET trials, where thousands of children have been comprehensively profiled in Phase III trials, and a new in vitro model to assess immune response, we can now determine a biological mechanism by which epigenetic therapies succeed or fail. In so doing, we seek to identify compounds that can reverse this resistant state, and further improve outcomes in high-risk pediatric leukemia.
