Developmental Research Program
Jean-Pierre Issa, MD
Peter Jones, PhD
The specific objectives of the Developmental Research Program are to:
To achieve our aims, we will establish 1) specific criteria for selection and funding through a peer review mechanism, and 2) mechanisms for close monitoring of, and collaboration between the SPORE leaders and program awardees to enhance the quality of the translational research goals.
Year 3 AWARDEES
Jozef Madzo, PhD
Coriell Institute for Medical Research
Pan-cancer analysis of epigenetically driven repetitive element deregulation
Around half of the human genome consists of various repetitive sequences. Divergent repetitive elements (RE) were incorporated into our genome when past viral infections affected germ cells during our evolution. Afterward, these pieces of DNA were integrated into our genome their expression is suppressed by epigenetic silencing and inactivating mutations. Despite their substantial contribution to the genome's overall size, the role of repetitive sequences in normal cell physiology, cancer onset, and their potential role in therapeutic response remains understudied. Recent research has demonstrated that repetitive elements can mimic viruses by triggering an immune response against tumor cells. Epigenetic drugs, such as DNA methyltransferase inhibitors, can reactivate silenced RE in cancer cells. These reactivated REs act as viral mimics and activate toll-like receptors (TLRs) and interferon (IFN) pathways in these cells. As a result, cancer cells with reactivated REs become more immunogenic by expressing viral mimicries5, which ultimately sensitizes them to immunotherapy, such as anti-PD1 and anti-CTLA-4. In this proposal, we will leverage publicly available pan-cancer datasets to examine the relationship between RE expression, underlying epigenetic regulation, and response to therapy. Our objective is to identify patients who would benefit the most from a combination of epigenetic therapy and immunotherapy.
Misty Dawn Shields, MD, PhD
Indiana University, School of Medicine
Defining Mechanisms of Acquired Chemoresistance for Novel Therapeutic Development in Extensive-Stage Small Cell Lung Cancer
Extensive-stage small cell lung cancer (ES-SCLC) is an aggressive recalcitrant form of lung cancer with a proclivity for early metastatic spread and relapse after initial treatment. Unfortunately, most patients who are diagnosed with ES-SCLC succumb to their disease within 12-15 months. Response to treatment with chemo-immunotherapy is minimal and is short-lived. Limitations to study ES-SCLC include models that were established in the 1970-1990s. These models do not reflect the evolving environment of drug resistance, and this is the area where novel drug development should be focused. Warm autopsy trials provide an outstanding resource of tissue for research post-mortem; however, it is a terminal representation of ES-SCLC and does not depict evolution of SCLC as represented by time. SCLC uniquely harbors large circulating tumor fractions of ctDNA and increased CTCs, compared to other malignancies. In fact, recent signatures from DNA methylation have demonstrated the ability to encode the unique blueprint of SCLC subtypes in cfDNA and have potential to unlock SCLC drug development for therapeutic vulnerabilities related to neuroendocrine subtypes. This project demonstrates advantage, compared to existing methodologies, by establishing a unique standardized pipeline for liquid biopsies and integrate longitudinal data in a minimally invasive fashion from patients with ES-SCLC.
Xiaodong Cheng, PhD
MD Anderson Cancer Center, Texas
Developing non-nucleoside DNMT3A/3B inhibitors
DNA cytosine methylation (5-methylcytosine, 5mC) is a major epigenetic modification involved in gene regulation. Mammalian DNA methylation, occurring mainly at CpG sites, is catalyzed by three DNA methyltransferases (DNMTs): DNMT3A and DNMT3B carry out de novo methylation to establish methylation patterns, whereas DNMT1 maintains the patterns during DNA replication. Cancer cells exhibit aberrant DNA methylation patterns, including global hypomethylation and regional hypermethylation, with the latter being linked to silencing of tumor suppressor genes. The demethylating agents 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine) have been approved by FDA for treating some hematological malignancies. However, these nucleoside analogs incorporate into DNA, leading to substantial DNA damage and cytotoxicity, and are ineffective in treating solid tumors. Recently, GlaxoSmithKline (GSK) reported the discovery of a new class of dicyanopyridine-containing DNMT1- selective inhibitors with therapeutic potential. Our preliminary studies of dicyanopyridine-containing or quinoline based derivatives identified several compounds that have DNMT3A/3B-inhibitory effect. The long-term goal of this research is to develop a highly potent and selective non-nucleoside DNMT3A/3B inhibitor for cancer treatment. The objective of this exploratory project is to further characterize the putative DNMT3A/3B inhibitors in order to identify one or more promising leads for further development.
