Patient-Specific Strategies for Targeting Therapy-Resistant Cells
Abstract
High-grade ovarian cancer (HCOG), the most common form of the disease, displays a heartbreakingly common response to surgery and chemotherapy marked by the onset of a "disease-free" state after therapy only to be followed, in most cases, with a return of the cancer in 6 to 24 months. In many cases, this so-called "recurrent disease" is resistant to the same drugs that previously proved effective against the tumor. Most believe that the small number of cells that survived the initial treatment ultimately begin to divide and reform tumors, but our inability to grow and examine cancer cells has limited our ability to both understand them and devise new ways of killing them. The present proposal is based on the unexpected finding that novel technologies we developed for cloning stem cells of normal regenerative tissues such as the intestine work exceedingly well for cloning a subpopulation of tumor cells. In fact, our recent findings have shown that the cancer cells we are growing from HCOG have all the theoretical properties of the so-called "cancer stem cell," including the ability to divide in an unlimited manner and to create tumors when injected into mice. Thus, the cancer cells we are growing with this new technology fit very well with those predicted by the cancer stem cell hypothesis, which itself was very radical in suggesting that most tumor cells are in fact "differentiated" and do not contribute to the future growth and evolution of a cancer. If true, chemotherapeutics of the future would only have to kill this very small population of cancer stem cells in a tumor to kill the whole tumor, and likely with less toxicity to the patient than in those in present use. Moreover, if cancer stem cells are the only cells we are cloning with this new technology, it potentially simplifies both the search for how some cells can evade standard-of-care chemotherapy as well as the search for drugs that selectively target the "resistant" cancer stem cells or the cancer stem cell population as a whole. This new-found ability to clone cancer stem cells from patients with HGOC is already yielding some surprising, if preliminary, results. The first is that in untreated tumors, we can find a small set of cancer stem cells that are already insensitive to the drugs typically used to treat HGOC, even though these cells have never seen these drugs before. This finding raises the intriguing possibility that these "pre-existing" resistant cells are the same ones responsible for the post-therapy return of HGOC. If so, as we propose to test in Aim 1, it would be possible to isolate these cells from patients about to undergo chemotherapy, find new drugs in screens of all drugs that best kill these cells, and use them to prevent or treat recurrent disease. Another benefit of actually cloning this subset of resistant cancer stem cells is an ability to determine what makes them distinct at a molecular level from the vast majority of cancer stem cells that the oncologists routinely eliminate using standard-of-care chemotherapy. In Aim 2, we will take advantage of these molecular differences to identify drugs focused on the same differences and thus provide the oncologist with new tools to prevent the onset of recurrent disease. Finally, in Aim 3, we want to take advantage of this technology for capturing the cancer stem cell to use them in so-called "high-throughput" assays to test enormous numbers of drugs to find the most efficient and least toxic to normal cells in an effort to fundamentally alter the therapeutic regimens of HGOC. My career goals are to continue to develop and constantly improve technology for the cloning of normal and cancer stem cells in close collaboration with physician-scientists working at the interface of patient care and therapy development. I am confident that the basic science that is my expertise will play a transformative role in improving the outcome of HGOC in a team and environment devoted to the cl
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710123
Entities
People
- Wa Xian
Organizations
- United States Army
- University of Texas Health Science Center at Houston