Targeting the Stem-Like Cells of Chemoresistant High-Grade Serous Ovarian Cancer: BMI1 in the Spotlight
Abstract
Many cancers prove deadly because they come back within a short period after treatment. The reason is because treatment with toxic drugs kills most but not all of the cancer cells. The cancer cells that survive gain special features and are called stem-like cells. These stem-like cells activate pumps that can drive drugs out of the cell. Also, the ovarian cancer stem-like cells depend on the mitochondria for energy production. We believe that these special features allow the stem-like cells to quickly expand back, re-form tumors, and remain resistant to conventional drugs. Currently, there are no treatment options that specifically target these stem-like cells and prevent recurrence. This is partly because there is poor understanding of how stem-like cells survive and behave within the tumors. We have recently found that the stem cell protein BMI1, by being present in the mitochondria and the nucleus, regulates energy production and drug efflux. We and others have shown that ovarian cancer patients with low BMI1 levels in the tumor live longer, with lesser chances of recurrence. Based on this information, we hypothesize that BMI1 supports the survival and expansion of stem-like cancer cells and that reducing BMI1 levels might provide an effective roadmap to preventing resistance and conventional therapy failure in ovarian cancer. Using patient-derived ovarian tumors as a model, we will dissect the role of BMI1 in maintaining stem-like cells and develop preclinical strategies to destroy these cells. This year, an estimated 22,440 women in the United States will be diagnosed with ovarian cancer and ~14,080 will die from this disease. Of the 850,000 female Service members, wives of active duty military, and adult daughters of active duty military, ~11,800 will be diagnosed with ovarian cancer over the course of their lifetimes (http://seer.cancer.gov/statfacts/html/ovary.html). Within the last five years alone, nearly 2,600 members of the military or their families have been hospitalized for ovarian cancer or suspected ovarian cancer. Therefore, it is clear that ovarian cancer poses a significant burden on the military not only in terms of troop readiness but also in healthcare costs. In this context, mechanistic studies proposed here are aimed at enhancing our understanding of how stem-like cells survive. Furthermore, testing of clinically relevant inhibitors of the survival pathway in patient-derived ovarian tumor models is expected to facilitate clinical translation potentially impacting patient survival in the near-term. Targeting BMI1 will hold the "holy grail" of the new age of cancer stem cell-based therapy for treating not only ovarian but also other cancers that are plagued by frequent recurrence and high BMI1 levels.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810054
Entities
People
- Resham Bhattacharya
Organizations
- United States Army
- University of Oklahoma Health Sciences Center