Nuclear Dynamics and Cancer Program

PROJECT SUMMARY/ABSTRACT – NUCLEAR DYNAMICS AND CANCER PROGRAM The Nuclear Dynamics and Cancer (NDC) program was created in 2022 following a series of Center-wide retreats and strategic planning sessions. The Program brings together several thematic elements that had been housed in three previous Programs: Cancer Signaling and Epigenetics, Molecular Therapeutics, and Blood Cell Development and Function. The NDC Program was intentionally crafted to promote potential synergies among these themes, such as the role of cancer-related epigenetic changes in modulating the specification of immune cell function, the effect of nuclear 3D architecture on gene expression and on genome stability (and vice-versa), and the mechanisms by which epigenetic plasticity contributes resistance to chemotherapies and to targeted therapies. The Program is led by Tomasz Skorski and Johnathan Whetstine. Together they bring highly complementary expertise to support the NDC mission: Skorski focuses on DNA damage and repair, particularly with regard to myeloid malignancies. Whetstine focuses on histone methylases and demethylases and their role in regulating oncogene amplification. The themes of the Program are 1) Genome Integrity: mechanisms impacting cancer and non-cancer cell genome and epigenome; 2) Gene Regulation: processes that control gene expression related to tumorigenesis; 3) Mechanistic relationships between Epigenetics and Drug Response. NDC comprises 33 members who are supported by $6.7M (DC) in total peer-reviewed grant funding, of which $3.1M is from NCI. The new NDC Program is complementary to, but distinct from, the new Cancer Signaling and Microenvironment (CSM) Program. The NDC Program addresses several primary goals as enunciated in FCCC’s strategic plan. First, it is designed as a “full-spectrum” Program; that is, it spans fundamental bench science all the way to clinical trials. Second, it is intentionally constructed to address the needs of our Catchment Area, focusing attention on cancers that have elevated incidence and/or mortality among this population. The Program also has developed deep, bidirectional ties to our community through formal mechanisms that include Program Liaisons, Community Ambassadors, and various public educational events. Third, the Program is responsive to new scientific developments that point to profound links between epigenetic changes to histones and DNA, gene expression, and genome stability/nuclear architecture. By combining these themes in one program, we hope to stimulate synergistic interactions and uncover new therapeutic strategies. While the Program is relatively new, it has already shown great progress. Since its inception in 2022, five new laboratory-based Assistant Professors have been hired to join the NDC Program. An impressive one-third of all publications from members of this Program were published in journals with >10 impact factor. Twenty-eight interventional clinical trials were open during the period of 10/1/2022-9/30/2023 based on science from this Program, including those that test inhibitors of DNA methylases and demethylases, DNA repair enzymes, and combinations of epigenetic therapies with immune checkpoint inhibitors and conventional chemotherapy.