Stalled Replication Fork Protection Defects as a Predictor of Therapeutic Response
Abstract
High-Grade Serous Ovarian Cancer (HGSC) is the most lethal type of ovarian cancer, with up to 70% of patients succumbing to their disease. This is due to the fact that most patients present with widely spread disease and also because there are limited therapeutic options. There are two newer therapeutic areas of interest for HGSC. The first are therapies that target defects in a tumor cell’s ability to effectively repair breaks or other types of damage to the tumor cell’s DNA, which include PARP, CHK1, and ATR inhibitors. The second are therapies that try to provoke the patient’s immune system into attacking the tumor, referred to as immuno-oncologic (IO) agents. We currently have no means of predicting which patients will respond to any of these agents, which is a major problem in the field. We hypothesized that a model system of each patient’s tumor that could be rapidly generated and quickly profiled for tumor cell defects in repairing DNA damage, anti-tumor immune activity, and tumor cell therapeutic sensitivity was needed. Thus, we have generated media and growth conditions for HGSC “organoids.” Organoids are generated when we take a sample of a patient’s tumor, digest the tissue to small groups of cells, and grow the tumor cells in culture in our special media. The tumor cells then grow as three-dimensional spherical structures that look like the tumor from which they were derived under the microscope and carry all of the functional defects of the tumor. Preliminarily, we have found that our organoid cultures contain the same types of immune cells as the parent tumors, and those immune cells are altered in ways that affect their anti-tumor ability when we treat our cultures with different types of chemotherapy. In addition, we have generated a platform of assays on the organoid cultures to try to understand whether the tumors have problems repairing damage to their DNA, which might make them sensitive to some of the DNA damage agents described above. Our analysis of the HGSC organoid cultures thus far has indicated that most of the tumors have problems repairing a specific type of DNA damage called “DNA replication-associated damage.” When a cell tries to divide, it has to replicate all of its DNA in a carefully managed process so that, after division, each new cell has a full copy of the DNA. If there are any problems in replicating the DNA, replication-associated DNA damage can occur, which requires specialized mechanisms of repair. We have found that most of the HGSC organoids have problems with repairing replication-associated DNA damage. These problems correlate with sensitivity of the organoid cultures to the commonly used carboplatin and also to the newer CHK1 and ATR inhibitors described above, suggesting that these agents might be beneficial to a wide number of patients. In addition, if we use the right type of DNA damage agent to exacerbate this repair defect, it is possible that we might also be able to enhance the immune response to the tumor, which we can test in our organoid cultures. Based on these data, we hypothesize that defects in repairing replication-associated DNA damage are more common in HGSC than other types of repair defects and that therapies targeting such a defect, which may include carboplatin and CHK1 and ATR inhibitors alone or in combination with appropriate IO agents, may offer benefit to a large patient population. There are three major goals of this work. The first goal will be to generate HGSC organoids from a large number of patients undergoing treatment with carboplatin or CHK1 or ATR inhibitors and assess how common replication-associated DNA damage repair defects are in these patients and how well the organoid functional assays can predict patient response to these agents. The second goal of the work will be to use HGSC organoids to understand the different types of replication-associated DNA damage repair defects and determine whether different defect
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910123
Entities
People
- Sarah Hill
Organizations
- Dana–Farber Cancer Institute
- United States Army