Subset of Preexisting, Poly-Resistant Cancer Stem Cells in High-Grade Serous Ovarian Cancer
Abstract
Rationale and Objective of the Proposed Work: Each year, 250,000 women are diagnosed with ovarian cancer, and most of these cases involve so-called high-grade serous ovarian cancer, or HGSOC, a particularly aggressive and lethal disease. Ironically, HGSOC in general responds extremely well to established, standard-of-care therapies, so much so that many advanced cases of HGSOC undergo a remission in which tumor cannot be detected in blood tests or by imaging. However, this state of remission is often temporary, and the cancer reappears in the next 6 to 24 months in approximately 80% of these women. This recurrent cancer often displays a newfound and sinister property of chemotherapy: resistance to the same therapy that caused the cancer to disappear in the first place is now ineffectual in handling the returning cancer. This emergent situation in patients who were in remission sets in motion the search for secondary chemotherapeutics, and many of these can be ineffective as well. This dire situation has made the study of chemotherapy resistance a central focus of the Ovarian Cancer Research Program and of cancer research in general. Two theories are emerging for chemotherapy resistance: one is that it is "acquired," a new property of cancer cells perhaps induced by genetic changes in the cancer cells induced by the chemotherapy itself. The second theory, based on new findings in other cancers, is that chemotherapy resistance is a pre-existing property of a small fraction of the tumor cells that only becomes apparent when all the sensitive tumor cells are eliminated by the chemotherapy. As such, the second theory readily explains the commonly observed remission-recurrent disease scenario following treatment of HGSOC: the minor fraction of pre-existing resistant clones survive treatment and eventually resume growth and lead the revival of the tumor in these patients. Our proposal leverages new technology we have developed to clone large numbers of tumor cells from an HGSOC patient before any chemotherapy. As expected, 99% of these tumor cell clones are killed in the laboratory by the chemotherapy drugs that will send this patient s disease into remission marked by undetectable tumor. Remarkably, however, all five patients analyzed to date have a minority of these clones that are unscathed by these drugs and almost certainly survive the multiple rounds of chemotherapy that HGSOC endure. Understanding how these pre-existing chemotherapy-resistant cells survive drug treatment will usher in new therapeutic strategies to prevent recurrent disease and ultimately render HGSOC a curable condition. Pre-Existing Resistant Clones: Enabling New Therapeutic Strategies: Our cloning technology now permits identification and isolation of pre-existing resistant tumor cells from all five HGSOC and this will be extended to 20 additional patients in the proposed study. The encouraging feature of these rare clones is that they are apparently all the same within a patient and share key features with those of other patients, raising the real possibility that we can find drugs that specifically eliminate them and the risk they bring for recurrent disease. We see two therapeutic strategies emerging from this work that could impact women newly diagnosed with HGSOC or those at risk for recurrent disease post-therapy. The first is to rapidly identify the minority contingent of resistant clones prior to standard therapy and identify compounds that could be included in the primary regimens that would eliminate them. The second strategy is to use the information gained from these pre-existing resistant clones to either predict the properties of recurrent disease and the optimal chemotherapeutics for subsequent, post-adjuvant treatment directed at these resistant cells or to knowledgeably address recurrent disease in these same patients. The potential clinical applications described above result in a significant decrease in recurr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010755
Entities
People
- Wa Xian
Organizations
- United States Army
- University of Houston