The objectives of the MOO program are to identify and understand cellular pathways deregulated during neoplastic transformation and progression, decipher how these changes promote cancer phenotypes, and develop methodologies to target cancer-specific events. MOO members are studying the priority cancers in our CA as identified by COE using innovative in vitro and in vivo models. Members also established a strong program to study how human DNA tumor viruses deregulate epigenetic control and noncoding RNAs to drive tumorigenesis. The aims of the MOO program are:
- Aim 1. Elucidate the Role of Genetic and Epigenetic Alterations in Cancer.
Examples range from discovering the critical mechanisms underlying the oncogenes (EML4-ALK fusion, CRTC1-MAML2 fusion), tumor suppressor genes (LKB1, p16), oncohistones (H2B mutations), chromatin regulators (NSD2, DNMTs), and RNA modifying regulators (ALKBH5, YTHDC1) to validate therapeutic targets in solid and hematologic malignancies. Moreover, MOO members study DNA tumor viruses (KSHV, EBV) and have established viral oncogenesis models that led to the discovery of novel mechanisms on host-viral interactions affecting immunity and epigenetics.
- Aim 2. Define the Role of Regulatory microRNAs and long noncoding RNAs in Oncogenesis.
MOO members are studying how aberrantly expressed ncRNAs drive oncogenesis. Examples range from basic discovery of novel miRNA maturation pathways and control of miRNAs/mRNA interactions to the discovery of human lncRNA in lung cancer with the potential for therapeutic and biomarker development. Novel ribonomics methods allow rigorous identification of miRNA targetomes of EBV and KSHV-associated tumors, as well as melanoma, and breast and colorectal cancers. These discoveries are poised to inform the development of RNA-based therapeutics. MOO members investigating RNA cancer biology also study virology and epigenetics and engage in productive collaborations leading to joint publications and MPI grants.
- Aim 3. Translate MOO Discoveries into Novel Therapeutic Approaches.
MOO investigators discover and validate cancer drivers that represent potential therapeutic targets for precision medicine approaches. Examples include efforts to translate MOO findings on the susceptibilities of tumors harboring mutations of epigenetic regulators such as NSD2, KDM6A, DNMT3A. MOO research validated RNA modifying enzymes as molecular targets and showed how to target the BCL-XL anti-apoptotic protein with PROTACs in a spectrum of tumors. Translation of MOO discoveries is facilitated by collaboration among members across all 3 programs. Candidates for clinical development are evaluated in close collaboration between the investigator and the ADs for Basic Sciences, Translation and Innovation, and Clinical Research, and further advanced in the monthly IIT Think Tank (see CTHR Aim 4). Trials based on MOO discoveries are performed collaboratively by clinical researchers within CTHR or CCPS, with all necessary infrastructure provided by the UFHCC CRO.
Cutting-edge discoveries in the role of microbiota and treatment responses (CTHR). This led to a lung cancer mini retreat as a first step to stimulate transdisciplinary P01 and U01 proposals to address this CA need. In alignment with the UFHCC strategic plan, Momentum 2027, UFHCC leadership will support this effort by establishing a lung cancer Pilot RFA. This initiative will serve as a model for additional CA-relevant translation of MOO discoveries.