The PALOMA-3 study is a multicenter, randomized Phase 3 study comparing the combination of fulvestrant-palbociclib vs. fulvestrant-placebo in hormone-receptor (HR) positive metastatic breast cancer (MBC). The study enrolled patients with ER+/HER2- disease that had progressed on prior endocrine therapy, primarily aromatase-inhibitors and up to one line of chemotherapy. CDK4/6 inhibition substantially improved progression-free survival, but predictive biomarkers of response are missing as evidenced by gene mutational analysis showing that patients with tumors harboring either ESR1 or PI3KCA mutations benefited equally from the combination regimen. Furthermore, gene expression analysis on MBC samples from the same study has more recently identified the genes whose expression levels were significantly associated with either reduced or increased clinical benefit from palbociclib treatment. One of the genes associated with an increased clinical benefit is SIRT3, encoding NAD-dependent deacetylase Sirtuin 3 that is thought to control mitochondrial integrity and metabolism. Our proposed research will: 1) determine if elevated SIRT3 expression levels are needed for ER+/HER2- breast tumors to be sensitized to palbociclib treatment in cell-based assays and animal models and, 2) identify the underlying mechanism connecting SIRT3 with enhanced palbociclib benefit. Thus, the overarching goals of our study are to reveal the SIRT3-dependent mechanisms of drug action for palbociclib that may provide the basis for new interventions to increase clinical benefits associated with CDK4/6 inhibition in otherwise palbociclib-resistant tumors (i.e., pathway/mechanism-based targeted combination therapies).
|Effective start/end date||10/14/19 → 10/14/20|
- Pfizer Inc. (Prot #WI245493)