SIGNAL TRANSDUCTION & THERAPEUTICS RESEARCH PROGRAM (STT) ABSTRACT Director Richard Finn, MD and Co-Director Edward Garon, MD lead the highly translational UCLA Jonsson Comprehensive Cancer Center (JCCC) Signal Transduction and Therapeutics Research Program (STT). The Program brings together basic scientists and clinicians to achieve the main objective of enhancing the development of cancer therapies targeting growth signaling pathways, resulting from work focused on signal transduction, the cell cycle, and cellular metabolism. To accomplish this objective, the Program built a robust translational pipeline and clinical trials network that since the 1990s repeatedly delivers practice-changing, high- impact research and applications. STT investigators provided the first cyclin-dependent kinase inhibitor in cancer medicine, palbociclib, that then enabled two additional CDK 4/6 inhibitors, ribociclib and abemaciclib, for globally approved treatment of hormone-receptor positive breast cancer. Preclinical data from STT Translational Oncology Research Laboratory (TORL) identified genes that associate with responses to CDK 4/6 inhibitors for multiple tumor histologies, providing future targets for mining. Separately, STT investigator studies in melanoma showed the added benefit of dual MEK and BRAF inhibition in the 50% of melanoma patients that harbor V600 BRAF mutations. This pioneering research led to the approval of combinations of dual MEK and BRAF inhibitors for treating BRAF mutant melanoma, including dabrefinib/tremetinib and encorafenib/binimetinib therapeutic pairings. With these practice-changing translational successes using commercially available compounds, there is now an increased emphasis on targeting STT discovery and development towards in-house compounds for clinical translation. New collaborations with UCLA affiliate Caltech and 1200 Pharma provide pathways for moving in-house candidates towards clinical applications. Exceptional successes for enzalutamide, and more recently apalutamide, in prostate cancer treatment provides a flexible roadmap for commercializing JCCC- generated compounds for broad adoption and clinical impact that STT aims to continuously replicate. The STT Program has 36 members drawn from four UCLA schools that represent 17 academic departments. STT has support from $18,085,846 in direct cost funding, of which $2,649,209 (15%) is from the NCI and $4,887,029 (27%) is peer-reviewed. Program discoveries from 2013 ? 2018 resulted in 1,022 publications, of which 15% were from intra-programmatic and 31% were from inter-programmatic collaborations. In addition, 66% of Program publications were collaborative with investigators at other institutions, and 41% of publications were in high-impact (IF ?10, or field leading) journals. The STT Program leverages its broad scientific foundation and links laboratory scientists with clinical investigators to help translate early observations into clinical opportunities and investigator-initiated studies. These activities emphasize malignancies with a high mortality, prevalence, or population disparity in the JCCC Los Angeles County catchment area, informed by community interactions and input, and includes breast, lung, prostate, skin, and liver cancers.
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