Molecular and Genetic Determinants of Response to Carboplatin with or without an ATR Inhibitor (M6620) in mCRPC
Abstract
Prostate cancer is the most common non-skin cancer and the second most common cause of cancer death in men. Over the past decade, we have learned a great deal about genes that are commonly mutated in prostate cancers, but we are only starting to learn about how particular gene mutations in a patient’s cancer might allow his physician to select the most appropriate treatment for him (so-called “personalized medicine” or “precision medicine”). It turns out that many genes that are commonly mutated in prostate cancer are involved in repairing damage to their DNA, and we have discovered recently that these mutations can lead some patients’ cancers to be sensitive to certain treatments that can then lead their cancer to shrink and their symptoms to improve. I am leading a multi-center clinical trial to test whether an experimental approach of a treatment regimen combining a new drug called M6620 with a chemotherapy drug called carboplatin is better at shrinking prostate cancer than a standard chemotherapy combination of carboplatin with a drug called docetaxel. M6620 is a type of targeted cancer therapy that targets an enzyme in cancer cells called ATR. ATR plays an important role in repairing damage to DNA caused by various forms of stress to the cells, thus allowing cancer cells to repair the DNA in an effort to fix themselves. M6620 stops cancer cells with high levels of stress from fixing themselves (by blocking their ability to repair damaged DNA) so that they are unable to survive. Carboplatin is a chemotherapy drug that is commonly used in many cancer types, including ovarian and other gynecologic cancers, lung cancers, and bladder cancers and in combination with docetaxel in metastatic castration-resistant prostate cancer. Carboplatin is known to lead to stress in cancer cells, causing DNA damage. In the presence of M6620, cancer cells are unable to repair this DNA damage and undergo cell death. Therefore, we expect that M6620 in combination with carboplatin will be more toxic to cancer cells than either drug alone. The clinical trial requires the participants to have a biopsy of their tumor prior to starting and to have blood collected for research before, during, and at completion of the trial. This proposal is to perform genetic sequencing and molecular tests from the biopsy and blood specimens collected during this trial to understand which patients are most likely to respond to the study medications. Genetic profiling from cancer cell DNA found in the blood of these patients after the study drugs stop working will demonstrate how cancers can evolve to become resistant to the medications so that we can investigate ways to kill the resistant cells in the future. In addition, we will test in genetically engineered prostate cancer cells in a laboratory setting how alterations in different genes involved in the DNA damage response in prostate cancer can impact the sensitivity of these cells to M6620, carboplatin, and the combination. This application addresses FY19 PCRP Overarching Challenges to (1) develop treatments that improve outcomes for men with lethal prostate cancer and (2) define the biology of lethal prostate cancer to reduce death. We hope to learn whether M6620+carboplatin is an effective treatment option for men with advanced prostate cancer and to develop diagnostic tests to figure out which men are most likely to respond to this treatment within the next few years. Understanding which patients are unlikely to respond can spare them side effects from ineffective therapy, but new approaches to treatment in patients who do respond will improve symptoms related to their cancer and quality of life.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010057
Entities
People
- Atish D. Choudhury
Organizations
- Dana–Farber Cancer Institute
- United States Army