TARGETING DNA DAMAGE RESPONSE IN BREAST CANCER The increased genome instability caused by DNA repair defects can be exploited using synthetic lethal approaches. For example, poly-ADP-ribose polymerase (PARP) inhibitors including olaparib have been approved to treat breast and ovarian cancer patients harboring mutations in BRCA1 or BRCA2. These drugs are thought to work by targeting defects in homology-directed repair (HR) of double-strand breaks (DSBs). However, HR proteins, including BRCA1 and BRCA2, ?moonlight? to regulate replication fork stability, and there is increasing evidence that these replication fork functions can be important determinants of PARP inhibitor outcomes independently of HR. Importantly, PARP inhibitor resistance is an increasing clinical problem. Thus, defining clinically relevant resistance mechanisms, biomarkers of resistance, and ways to overcome or prevent resistance are important research goals. This proposal addresses these issues both at the mechanistic and patient levels. Our overall goal is to improve patient outcomes by defining the mechanisms by which HR proteins regulate replication fork stability, understanding the contribution of replication fork dynamics to PARP inhibitor sensitivity, and identifying drug combinations that can be used to overcome resistance. We will use cell culture and patient-derived xenograft models to define mechanisms that influence PARP inhibitor sensitivity, utilize patient-derived 3D-ex vivo organoid cultures to examine mechanisms of PARP inhibitor resistance and explore rational drug combinations that can overcome resistance mechanisms in clinical trials. Completing these studies will test the hypothesis that fork protection is an important determinant of therapeutic efficacy of PARP inhibitors, identify therapeutic strategies to overcome resistance and potentially provide a rationale for expansion of PARP inhibitor use for clinical investigation and treatment.

Public Health Relevance

TARGETING DNA DAMAGE RESPONSES IN BREAST CANCER Poly-ADP-ribose polymerase (PARP) inhibitors are useful in the treatment of cancers with defects in select DNA repair mechanisms. This project will test the hypothesis that fork protection is an important determinant of therapeutic efficacy of PARP inhibitors, identify mechanisms of resistance, and test therapeutic strategies to overcome resistance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA098131-18
Application #
9984317
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2003-08-07
Project End
2024-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
18
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Santos Guasch, Gabriela L; Beeler, J Scott; Marshall, Clayton B et al. (2018) p73 Is Required for Ovarian Follicle Development and Regulates a Gene Network Involved in Cell-to-Cell Adhesion. iScience 8:236-249
Croessmann, Sarah; Sheehan, Jonathan H; Lee, Kyung-Min et al. (2018) PIK3CA C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3K? Inhibitors. Clin Cancer Res 24:1426-1435
Elion, David L; Cook, Rebecca S (2018) Harnessing RIG-I and intrinsic immunity in the tumor microenvironment for therapeutic cancer treatment. Oncotarget 9:29007-29017
Williams, Michelle M; Lee, Linus; Werfel, Thomas et al. (2018) Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers. Cell Death Dis 9:21
Hyman, David M; Piha-Paul, Sarina A; Won, Helen et al. (2018) HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature 554:189-194
Luo, Na; Nixon, Mellissa J; Gonzalez-Ericsson, Paula I et al. (2018) DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer. Nat Commun 9:248
Sudhan, Dhivya R; Schwarz, Luis J; Guerrero-Zotano, Angel et al. (2018) Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial. Clin Cancer Res :
Werfel, Thomas A; Wang, Shan; Jackson, Meredith A et al. (2018) Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival. Cancer Res 78:1845-1858
Zhao, Shilin; Li, Chung-I; Guo, Yan et al. (2018) RnaSeqSampleSize: real data based sample size estimation for RNA sequencing. BMC Bioinformatics 19:191
Williams, Michelle M; Vaught, David B; Joly, Meghan Morrison et al. (2017) ErbB3 drives mammary epithelial survival and differentiation during pregnancy and lactation. Breast Cancer Res 19:105

Showing the most recent 10 out of 341 publications