University of California, Riverside (UCR) has never implemented a therapeutic trial. Building therapeutic trial capacity at UCR was our biggest challenge – and the biggest failure - of our P20 planning grant. City of Hope Comprehensive Cancer Center (CoHCCC) runs hundreds of therapeutic trials (Phase 0 to 4) ranging from chemoprevention to Phase 1 CAR-Tcell therapy. In our P20 planning grant, we leveraged an on-going CoHCCC outreach trial testing, in women with insulin-resistance, testing the ability of metformin to reduce 1) production of inflammatory cytokines and 2) circulating senescent inflammatory cells. While CoHCCC has implemented this trial in community centers, the trial rapidly ran into problems at UCR. Key issues were 1) lack of experience of the UCR Institutional Review Board (IRB) and 2) a need for greater mentorship of UCR investigators. In this U54 grant, we are determined to help UCR open therapeutic trials; however, first we need to build capacity. U54 Pilot Project 1 uses state-of-the-art single cell-transcriptomics and -ATACseq in the context of a simple therapeutic trial. This trial tests the ability of standard-of-care metformin to reduce inflammation in insulin-resistant breast cancer survivors. Under the oversight of David Lo, M.D. Dean of Research at UCR Medical School, the trial will be conducted at CoH using CoH patients, personnel, and IRB. CoH will provide hands-on training in 1) therapeutic trials and 2) rigor and reproducibility of clinical biomarkers. CoH’s IRB will use this opportunity to mentor UCR’s IRB. In Year 3, the trial will be opened for accrual at UCR. Metformin is known to reverse insulin- resistance and remove senescent cells. In this capacity building trial – we aim to test in insulin-resistant Latina and African American/Black breast cancer survivors, the hypothesis that metformin can 1) restore metabolic health (reverse insulin-resistance), 2) reduce H3K9ac-chromatin opening of genes coding for IL6/TNFα/INFβ, and 3) reduce inflammation and circulating SASP cells. Aim 1 will build UCR clinical-trials capacity by conducting a UCR-CoH partnered trial at CoH in a diverse cohort. Aim 2 will provide capacity building in biospecimen collection, biomarker analysis, and rigor and reproducibility. In Aim 3 CoH IRB continues its mentorship (started during P20) of UCR IRB in regulations for therapeutic trials.