Endoplasmin: A Novel Therapeutic Target and Potential Marker of Chemoresistance
Abstract
Rationale and Objective: Ovarian cancer (OC) has the highest case-fatality ratio of any gynecologic cancer. It is associated with a very poor prognosis due to a high rate of resistance to standard platinum- and taxane-based chemotherapy regimens. First-line chemotherapy for the treatment of OC using platinum-based drugs (cisplatin, carboplatin) yields a response rate of 80%. Despite this initial response rate, over 50% of patients eventually suffer from a recurrence of the disease. The management of recurrent OC presents a clinical dilemma due to the development of chemoresistance with only 25-40% of these patients responding to platinum-based therapy. Therefore, the investigation and development of additional, new therapeutic targets is necessary to overcome the high rates of drug resistance in OC. The objective of this study is to evaluate a novel protein, Endoplasmin, as a potential therapeutic target in chemoresistant ovarian cancer. How the Proposed Research Is Unique: Endoplasmin is a novel protein that has been implicated to play a role in immune modulation and cancer. Studies have implicated that high expression in breast cancer is associated with metastatic disease and decreased survival. It has also been implicated to play a role in chemoresistance. While Endoplasmin has been identified as a unique biomarker for epithelial ovarian cancer, there are no studies to date that assess its expression in regards to chemosensitivity and chemoresistance. This study would not only validate endoplasmin as a biomarker for OC, but would also evaluate the clinical significance of endoplasmin expression and its potential contribution to OC chemoresistance. Additionally, we have developed a novel endoplasmin inhibitor that may have dual anticancer and antioxidant functions. This has the potential to greatly enhance the therapeutic effect of chemotherapy on tumor cells, specifically cells that have developed chemoresistance. Our laboratory has developed a microfluidic-based device for exosome isolation that has greater purity and specificity than conventional methods (ultracentrifugation and kits), which is a critical step toward translating our findings to the clinical setting. Thus, the proposed research is completely novel as we have identified a unique molecular target that has not yet been investigated. How This Proposed Research Is Relevant to OCRP and Addresses the Current Problems: The purpose of our proposed study is to identify endoplasmin protein expression as a predictive marker associated with OC chemoresistance using OC patients’ serum/tissue samples. Utilizing an endoplasmin small molecule inhibitor, we plan to assess carboplatin treatment using in vitro and in vivo studies with mice models as well as patient-derived xenografts (PDX). Our proposed research has the potential to provide fundamental insight into the mechanisms of endoplasmin-mediated chemoresistance and whether or not inhibition of this protein could decrease chemoresistance among this patient population. Who Will Benefit: We hope to contribute research that will lead to improved detection of chemoresistant subsets of patients as well as identification of targeted therapies for these patients. This research would benefit patients with ovarian cancer that is resistant to standard therapy, with its associated high mortality rate. Such discoveries could have significant impacts for female military Service members and their family members, as well as other military beneficiaries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010361
Entities
People
- Karuppaiyah Selvendiran
Organizations
- Ohio State University
- United States Army