Project 3 builds upon extensive basic, translational and ongoing clinical work within DF/HCC, and addresses a clinically pressing issue: the need for more effective treatment strategies for sporadic triple negative breast cancer.
It aims to shift current paradigms by the development of approaches that will sensitize BRCA-proficient triple negative breast cancer cells to PARP inhibition. Two highly innovative therapeutic strategies will be used, both involving newly appreciated aspects of homologous recombination.
In Aim 1, we will focus on the development of a CDK inhibitor/PARP inhibitor combination utilizing dinaciclib and veliparib. The drug combination will be studied in triple negative breast cancer cell lines and orthotopic primary tumor xenograft models. Ultimately, the combination will be translated to a Phase 2 clinical trial that will explore efficacy and pharmacodynamic endpoints.
Aim 2 takes advantage of another observation regarding previously unappreciated aspects of homologous recombination indicating that proteasome inhibition leads to a defect in homologous recombination, and thus sensitivity to PARP inhibition. We will proceed similarly through work in triple negative breast cancer cell lines, patient-derived orthotopic xenograft models and early phase clinical trial, focusing on the bortezomib/veliparib combination. For the clinical translation of the bortezomib/veliparib combination, the recommended phase 2 doses of the combination will be established in a UO1-supported phase 1 clinical trial. Following completion of the dose escalation, the SPORE will support enrollment of a triple negative breast cancer cohort in order to confirm safety in this population and to perform correlative studies.

Public Health Relevance

Our goals are to test novel therapeutic approaches directed against BRCA-proficient triple negative breast cancer, including targeted combinations that can induce sensitivity to DNA damaging agents. Altogether, the proposed project is well timed with respect to the current key challenges in breast cancer and we expect to make a significant impact in the future management of patients diagnosed with triple negative breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA168504-02
Application #
8753989
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
$314,266
Indirect Cost
$130,242
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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Schmit, Fabienne; Utermark, Tamara; Zhang, Sen et al. (2014) PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context. Proc Natl Acad Sci U S A 111:6395-400