Sensitizing Ovarian Cancer to PARP Inhibition by Targeting Claudin-4 Activity
Abstract
Ovarian cancer is the deadliest gynecological disease and annually accounts for over 140,000 deaths worldwide. A critical problem of ovarian cancer is the lack of effective therapies. An emerging therapy for ovarian cancer is poly(ADP) ribose polymerase inhibitor (PARPi). PARPi targets cancer cells that have defects in DNA repair pathways. Almost half of all ovarian cancers have defects in DNA repair, such as tumors with BRCA1/2 mutations. Treatment with PARPi results in less severe complications than traditional chemotherapies, indicating expansion of PARPi use could improve outcomes and patient quality of life. Notably, clinical trials have demonstrated that patients with either an intact or a deficient DNA repair process respond to PARPi, which highlights the gap in our understanding and need for better tests to predict response. Upon examining ovarian cancer gene expression data, we determined that BRCA1/2 mutations and claudin-4 overexpression do not occur within the same tumor, indicating claudin-4 could potentially predict PARPi response. Claudin-4 (CLDN4) is found in approximately 70% of all ovarian tumors and associated with chemotherapy-resistant ovarian tumors. A therapy targeting claudin-4, CMP, was designed to disrupt claudin-4 activity. CMP causes tumor cell death when given in combination with chemotherapy. Also, CMP reduces overall tumor burden in a mouse model of ovarian cancer. The long-term goals of this proposal are to establish claudin-4 as a novel biomarker that better predicts PARPi response and to determine whether CMP treatment could be a strategy to sensitize ovarian tumors to PARPi. Several lines of data indicate that reducing the claudin-4 protein may lead to increased PARPi sensitivity: (1) In a panel of cancer cells the presence claudin-4 directly correlated to PARPi response. Several PARPi demonstrated this correlation. (2) In breast cancer, the "claudin-low" subtype is more responsive to PARP inhibition. Thus promotion of a "claudin-low like" ovarian cancer could increase the response to PARPi. (3) Ovarian cancer cells expressing claudin-4 are less responsive to chemotherapy, and that claudin-4 inhibition via CMP treatment significantly enhances anti-tumor response. (4) Also, in an ovarian cancer cell line artificially expressing claudin-4 expression decreased PARPi sensitivity. Thus, the data suggests that modulating claudin-4 could make the cells defective in DNA repair thereby sensitizing ovarian cancer tumors to PARPi. The central hypothesis is that targeting claudin-4 will sensitize ovarian tumors to PARPi. In line with DoD OCRP priorities, the ultimate goals of this proposal are (1) to evaluate whether claudin-4 expression could be utilized as a biomarker for therapeutic response and (2) to develop a novel ovarian cancer therapeutic strategy by targeting claudin-4 to increase PARPi clinical utility. Establishing claudin-4 as an additional predictor of PARPi response will provide a new paradigm to expand PARPi clinical use, which could improve patient outcomes and quality-of-life.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810326
Entities
People
- Benjamin G Bitler
Organizations
- United States Army
- University of Colorado Denver