Phase 1B Trial With PTC-596 in High-Grade Serous Ovarian Cancer: a Targeted Approach Toward Chemoresistant Stem-Like Cancer Cells
Abstract
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 5 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. 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, reform tumors, and remain resistant to conventional drugs. Currently, there are no treatment options that specifically target these stem-like cells and prevent recurrence. 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 fewer chances of recurrence. Based on this information, we believe that reducing BMI1 levels might provide an effective roadmap to prevent resistance and conventional therapy failure in ovarian cancer. We have therefore proposed a Phase 1B clinical trial with PTC596, a small molecule inhibitor of BMI1 that will be combined with the standard-of-care carboplatin/paclitaxel therapy. The primary goals are to determine dose tolerance, related toxicities, response rate at the time of interval cytoreductive surgery, and overall survival in comparison with conventional chemotherapy. If this Phase 1 study demonstrates feasibility of combination dosing, a randomized evaluation of this strategy with a time-to-event endpoint would be planned to follow.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810073
Entities
People
- Resham Bhattacharya
Organizations
- United States Army
- University of Oklahoma Health Sciences Center