Washington University PDX Development and Trial Center

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Project Summary This application is being submitted in response to the Funding Opportunity Announcement (FOA) PA- 20-272. This supplemental proposal seeks to uncover the mechanism of synergy and develop an optimized regimen of the combination of a microtubule-disrupting agent, eribulin, and a PI3K-inhibitor in patient-derived xenograft (PDX) models of breast cancer. The work will be conducted as a national collaboration between Washington University in St. Louis and BIDMC/Harvard Medical School in Boston. In her pre-clinical work, Dr. Ma at Washington University in St. Louis has shown that the combination of eribulin and the PI3K-inhibitor copanlisib greatly extends progression-free survival in eight PDX models of triple negative breast cancer (TNBC). This novel concept is now being carried forward into a clinical trial in patients with metastatic TNBC (NCT04345913). Her discovery was surprising as PI3K-inhibitor benefit so far had been restricted to ER+PIK3CAmt breast cancer. The exact mechanism and, based on the mechanism, best timing of eribulin and PI3K-inhibitor will be determined in the proposed work. This supplemental award will extend the work in Research Project 1 in testing PI3K inhibitor combinations in breast cancer PDX models and to uncover mechanisms of synergy for the combination of microtubule disrupting agent, eribulin, and the PI3K inhibitor, copanlisib. Dr. Wulf's Parent R01 Proposal entitled “Novel Uses for PI3K-inhibitors for the Treatment of Advanced PIK3CA-mutant Breast Cancer (1R01CA226776)” is slated to develop PI3K-inhibitor (PI3Ki) combinations for patients with PIK3CAmutant breast cancer. PIK3CA-mutant breast cancer can be targeted with alpelisib, a recent FDA-approved PI3K-an inhibitor now widely used in the metastatic setting in conjunction with estrogen receptor blockade. In this project, we hypothesize that PI3K-inhibition is a metabolic intervention that, if applied strategically following microtubule disruption, can deepen and prolong remissions obtained with microtubule disrupting drugs, which are widely used to treat metastatic breast cancer. We will employ in vitro imaging and metabolomic studies and in vivo imaging with 18FDG-glucose and 13C-pyruvate to deep-probe glycolysis in response to chemotherapy, PI3K-inhibition and their combination and test if these imaging modalities can predict responses. The team at WashU (Dr. Cynthia Ma, medical oncology and preclinical mouse work, Dr. Kooresh Shogi (quantitative PET-imaging), Dr. Cornelius von Morze (quantitative MRI imaging) and at BIDMC/Boston (Dr. Gerburg Wulf, pre-clinical mechanistic studies and Dr. Aaron Grant, pioneer in 13C- pyruvate imaging) have established a MTA for transfer of the PDX models and will conference bi-monthly to make this supplemental project happen within a year.