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 3 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
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in the United States. FDA approval for immune checkpoint therapy in metastatic disease represents a major therapeutic advance, but long-term survival remains limited in advanced disease and novel therapeutic approaches are essential. Low- dose DNA methyltransferase inhibitor (DNMTi) reprograms DNA double-strand break repair (DSBR), producing synergistic in vitro cytotoxicity with poly(ADP-ribose) polymerase inhibitor (PARPi) and ionizing radiation.
Basal levels of stimulator of interferon signaling (STING) are commonly suppressed in NSCLC, a state that has been correlated to immune checkpoint therapy resistance. STING expression is stimulated by low doses DNMTi, activating immune responses that prime tumors for immune checkpoint therapy response. Mechanics and sequelae of response to DNMTi may be dependent on mutation status of the tumor suppressor TP53, with missense mutations associated with a NFKB-mediated inflammasome response compared to the type 1 interferon response observed in TP53-wildtype NSCLC. In vitro 2D and 3D data indicates that DNMTi/PARPi combination cytotoxicity is limited in CRISPR-generated NSCLC TP53-mutant cells compared to wildtype.
We propose to determine the potential of DNMTi/PARPi combination therapy to sensitize NSCLC to immune checkpoint therapy in immune-competent murine models and in patient-derived organoids, and to utilize RNA-seq-based bioinformatics to evaluate pathways governing differential responses in TP53-wildtype and -mutant settings. Additionally, propose to establish the in vitro potential of a novel STING agonist to augment DNMTi-induced immune responses and further enhance treatment cytotoxicity. As TP53-mutant
status is correlated with low basal STING and poor response to standard therapy, this work has important future implications for treatment strategy in the ~50% of NSCLC harboring TP53 missense mutations.
Josh Jang, PhD
Van Andel Institute
Discovery of aberrantly spliced antigens in SETD2-mutant kidney cancer produced by epigenetic therapy
SETD2 protein encodes a critical histone methyltransferase (H3K36me3) and is commonly mutated in aggressive clear cell renal cell carcinoma (ccRCC). We recently discovered that SETD2-deficient ccRCC cells are especially sensitive to DNA methyltransferase inhibitor (DNMTi) treatment, which can be attributed to the increased levels of transposable element (TE) expression and RNA mis-splicing that trigger viral mimicry and interferon response. Recent works have shown that TE-chimeric and mis-spliced transcripts are translated into novel antigens with immunomodulatory consequence. DNMTi treatment in SETD2-deficient ccRCC cells also produces aberrantly spliced transcripts, and if translated, can become a valuable resource of tumor-specific antigens that can be targeted through cancer vaccine or antibody-based methods. Here, we will systematically address the hypothesis that DNMTi treatment in SETD2-deficient ccRCC cells can further boost tumor immunogenicity through the production and presentation of immunogenic antigens from aberrantly spliced RNA transcripts. This work will highlight the synergistic therapeutic potential of epigenetic therapies combined with antigen-targeting strategies, which is currently underexplored in current cancer immunotherapy approaches.
