Targeting Ovarian Cancer Immune Resistance
Abstract
One of the biggest challenges to extending patient survival from recurrent ovarian cancer is to understand how these tumors can “hide” from detection by the immune system. Immunotherapy encompasses treatments that use your body s own immune system to help fight cancer. Despite successes in other types of cancer, immunotherapy treatments for ovarian tumors have had limited success in promoting patient survival. Our proposal will build upon the idea that ovarian tumors can upregulate immune “protective” molecules and that these provide a “shield” against immune cell attack. We are studying a tumor-associated change that is very common to ovarian cancer. We are using mouse tumor models whereby changes in tumor and immune cell interactions can be evaluated in fine detail. The objective of our work is to provide “proof-of-principal” that either genetic or drug-mediated inhibition of a specific tumor signaling protein may weaken the immune defense shield and enable immunotherapy to work better. Because of its genetics, ovarian cancer is not a good candidate for the currently developed approaches to immunotherapy. This is unfortunate, because immunotherapy would be ideal for a tumor that has already spread and has the potential for a cure. We have found that a gene called PTK2 is highly amplified in ovarian cancer. The gene produces a protein called focal adhesion kinase, or simply FAK. In our mouse model systems, FAK is active within the tumor cells and sustains the expression of immuno-modulators – proteins that block immune (white blood cell) function. When FAK is active, the tumor cells are not recognized fully by the immune cells. Drugs have been developed to inhibit FAK and are being testing in ovarian cancer clinical trials to determine whether FAK inhibition may enhance the activity of carboplatin and paclitaxel (Re-sensitization of Carboplatin-resistant Ovarian Cancer with Kinase Inhibition of FAK [ROCK-IF] clinical trial) – two of the most common chemotherapies used to treat ovarian cancer. As we know that FAK inhibition can promote tumor shrinkage, we are pushing this combinatorial idea forward to test whether this is also connected to a role for FAK in promoting immune resistance. We have identified novel targets of FAK action that are known immuno-modulators. In our mouse models, the experiments proposed will test the cause-effect relationship between FAK inhibition and immune activation. Importantly, this will be extended to the analysis of ROCK-IF patient tumor biopsy samples to determine if FAK inhibition enhances immune cell infiltration into tumors. The results of this work may enable future clinical trials of combinatorial therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910134
Entities
People
- David Schlaepfer
Organizations
- United States Army
- University of California, San Diego