Role of C-Terminal Binding Protein as Oncogene and Therapeutic Target in Epithelial Ovarian Cancer
Abstract
Ovarian cancer is among the most lethal of women s cancers, as it often presents at a later, more advanced stage due to a lack of symptoms associated with early-stage curable ovarian cancer. Of the various subtypes of ovarian cancer, the most aggressive, difficult to treat, and lethal form is termed "High-Grade Serous Ovarian Cancer" or HGSOC. HGSOCs grow rapidly, can rapidly develop resistance to our standard therapies, which include the chemotherapeutic cis-platinum, and also do not generally harbor DNA mutations that lend themselves to our modern "targeted therapies" that can kill cancer cells harboring specific gene mutations. As such, we desperately need new therapies for HGSOC that do not depend on gene mutations for efficacy, and that offer better side effect profiles than platinum-based therapies, which negatively impact quality of life, even while not affording high cure rates. Our research into an exciting "target" for developing a new type of cancer drug began in colon cancer, where we identified a protein called C-terminal binding protein, that is frequently produced at higher than normal quantities but never mutated. This work sparked many other groups to explore CtBP across human cancer types, and ovarian cancer was specifically found to have the highest rate of CtBP overproduction of all cancers, at 85% of tumors screened. In addition, our work in colon cancer has shown the following: (1) CtBP is required for the development of the precursor to colon cancer, the intestinal adenoma; (2) Removing the CtBP gene from mice that are predisposed to polyps of the intestine nearly eradicated the polyps, and doubled the life span of the mice; (3) A novel anti-CtBP drug that we developed also reduced intestinal polyps in these mice, and can kill breast, colon, pancreatic, and ovarian cancer cells in cell culture. With these exciting findings as a backdrop, we now propose to intensively study CtBP s role in ovarian cancer, and also test its validity as a target for therapy in ovarian cancer models in the mouse. Moreover, we will build a mouse model that closely resembles human HGSOC that express an abundance of CtBP. Our proposal closely aligns with the goals of the OCRP, which include patient-centered research to prevent, detect, treat, and cure ovarian cancer. More specifically, our project addresses one of the FY17 Areas of Encouragement, "Novel therapies and associated predictive biomarkers." If we succeed in completing the proposed experiments, and our hypotheses are correct, development of models to examine CtBP function and targeting in ovarian cancer will be of help both to women with advanced HGSOC and other forms of ovarian cancer where the treatment options remain very limited and toxic, as well as, potentially, women with early-stage ovarian cancer, where therapies are directed at reducing the rate of post-surgical recurrence. From a speculative standpoint, our work in colon cancer polyps even suggests that anti-CtBP therapy could be envisioned as a preventive therapy in women with a high risk for development of cancer due to genetic or other predisposition. The potential impact of this research on the health and welfare of our women in uniform, as well as their families and other beneficiaries, is highly significant though not specific to military personnel and families, as the development of anti-CtBP therapy and CtBP as a predictive biomarker in ovarian cancer will reduce the burden of sickness and mortality caused by HGSOC and other forms of ovarian cancer in women in service or who are part of military families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810093
Entities
People
- Steven Grossman
Organizations
- United States Army
- Virginia Commonwealth University