# Optimization of PI3K-inhibitors to augment the efficacy of microtubule-disrupting chemotherapy

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $124,999

## Abstract

This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-
CA-21-009. 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 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 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.
 Our Parent Proposal is slated to develop PI3K-inhibitor (PI3Ki) combinations for patients with PIK3CA-
mutant breast cancer. PI3Kinase is a nodal point of the intracellular signaling machinery that drives cell division
of breast cancer cells. PIK3CA-mutant breast cancer can be targeted with alpelisib, a recent FDA-approved
PI3K-a inhibitor now widely used in the metastatic setting in conjunction with estrogen receptor blockade. Our
Supplemental Proposal is an extension of Aim 2, To determine in vivo if the metabolic changes induced by PI3K-
inhibition are predictive of cancer treatment responses and of Aim 3, To determine in vivo if time-staggered PI3K-
inhibition can enhance the efficacy of antineoplastic treatments for endocrine-resistant PIK3CA-mutant BC of
our Parent Proposal. 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.

## Key facts

- **NIH application ID:** 10326434
- **Project number:** 3R01CA226776-04S1
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** GERBURG M WULF
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $124,999
- **Award type:** 3
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10326434

## Citation

> US National Institutes of Health, RePORTER application 10326434, Optimization of PI3K-inhibitors to augment the efficacy of microtubule-disrupting chemotherapy (3R01CA226776-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10326434. Licensed CC0.

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