MOLECULAR ONCOLOGY PROGRAM (Project-368) ABSTRACT Overview and Goals: The goal of the Molecular Oncology (MO) program is to harness the power of basic science approaches, from biochemistry to functional genomics, to elucidate molecular mechanisms of cancer evolution and progression, with the ultimate goal of enabling effective strategies for cancer prevention, diagnosis and treatment. The expertise of program members is broad and deep, with major strengths in the control of gene expression, epigenetic regulation, DNA repair and damage responses, telomeres, pathways controlling cell fate and elucidation of cancer-relevant molecular structures. Research Highlights: The transcription factor HIF1A is a key mediator of the cellular response to hypoxia. Despite the importance of HIF1A in homeostasis and various pathologies, little is known about how it regulates RNA polymerase II (RNAPII). A multidisciplinary team including members at UCB consortium site showed HIF1A employs Mediator-associated kinase CDK8 to stimulate RNAPII elongation. These results provide a mechanistic link between HIF1A and CDK8, two potent oncogenes, in the cellular response to hypoxia, and which may lead to novel therapeutic approaches (Cell, 2013). Program Activities: To accomplish this goal, the MO co-leaders employ resources provided by the UCCC to orchestrate intra- and inter-programmatic collaborations through organization of annual retreats and periodic technology forums, as well as routine chaperoning of transdisciplinary collaborations. Enabled by UCCC support, the co-leaders identify and evaluate novel technologies essential to catalyze new research by MO members through the creation and expansion of Shared Resources (SR), and by providing pilot funding to use these technologies, while leveraging resources and research strengths of consortium institutions across the state of Colorado. Through coordinated transdisciplinary relays from MO members to investigators in translational and clinical research programs, the discoveries made in this program move from bench to preclinical investigations and investigator-initiated trials (IITs), which will ultimately improve diagnosis, treatment and prevention of cancer. Members: The program has 43 Full and 20 Associate members with 89 grants encompassing $3.3M NCI and $7.5M of other cancer peer-reviewed research grant funding in 2015. Members are distributed across 20 basic science and clinical departments in the SOM and SOP at UCD as well as at UCB, CSU and at non-consortium institutions. MO members published 630 cancer-focused publications since 2011 of which 30% were inter- and 13% intra-programmatic. Future Directions: We plan to enhance current strengths in functional genomics and epigenetics, develop new capabilities in metabolomics, proteomics and cryo-electron microscopy, and promote interactions with programmatically relevant organizations at UCD such as the Linda Crnic Institute for Down Syndrome and the Division of Biomedical Informatics and Personalized Medicine (BIPM). These efforts will advance the discovery of basic cancer processes and their translation into improved cancer prevention and treatment.
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