Lab Projects
Genomic approaches to identifying mechanisms of drug resistance in cancer
Although many cancers are initially susceptible to chemotherapy, over time they can develop resistance and stop responding to the treatment. This resistance is what leads to the progression of the disease and is the ultimate cause of death for many cancer patients. The development of multiple drug resistance (MDR) is one of the major challenges in cancer treatment and represents the leading cause of treatment failure.
Cooper’s lab is focused on identifying genes and mechanisms critical to the development of chemoresistance and establishing reliable methods for detecting them in clinical samples. One way in which the group is achieving this goal is using genome-wide CRISPR screening methods to identify genes associated with chemotherapy resistance in pancreatic and ovarian cancer. The CRISPR screen provides a promising new tool to predict a patient’s likelihood of developing resistance to common treatments, and help make informed treatment decisions. In addition, some of the new targets that are identified using the CRISPR screen are being used to identify and produce new therapeutics for cancer treatment.
The lab also works in collaboration with several clinicians and scientists at the University of Alabama at Birmingham. The ongoing collaborations explores a variety of applications for gene expression profiling in ovarian cancer including diagnosis, prognosis, and response to common therapies. The groups are particularly interested in using this method to predict response to immunotherapy and have applied methods for profiling RNA derived from the immune system to help assess this response in both animal models and human patients. The goal is to develop tests that can be used to help direct patient therapy and to propose novel targets that might be relevant for improving response to existing therapies.
Understanding the role of immune response in cancer
The Wnt/ß-catenin pathway is linked to tumorigenesis in a variety of tumors. It has been shown to promote T cell exclusion from tumors and resistance to checkpoint inhibitors and chemotherapies commonly used to treat some cancers. The Cooper lab and the lab of longtime UAB collaborator Rebecca Arend, MD, study Wnt/ß-catenin signaling in ovarian cancer in hopes of leveraging the pathway to reduce chemotherapy resistance in ovarian cancer.
In recent studies, the team has demonstrated that inhibition of Wnt signaling represents a potential therapeutic target. They tested a small molecule inhibitor of Wnt/ß-catenin signaling and show that the treatment with this inhibitor along with standard chemotherapy enhances the immune system and decreases tumor growth better than either agent alone. These data, generated using a mouse model of ovarian cancer, motivated further investigation of this pathway in human tumors. Genomic analysis of patient tumors pre- and post-chemotherapy treatment further indicates that this may be a fruitful treatment strategy.
Ongoing work in the labs focuses on understanding the importance of the immune response in the progression and treatment of cancer. We are working to develop in vitro models that will assist in understanding how Wnt signaling impacts immune-tumor cell interaction. The ultimate goal is to determine if inhibitors of Wnt/ß-catenin signaling could be used to treat ovarian cancer.
Cancer risk screening initiatives and gene discovery
Genetic predisposition to cancer has been recognized for hundreds of years, originally through observing familial clusters of cancer and later through identifying cancer-related genes in affected family members. Screening for cancer predisposition genes in individuals with a family history of cancer can inform earlier cancer screening and identify potential cancer earlier in its course.
Dr. Cooper leads the Institute’s genetic testing initiative called Information is Power. Over the past six years, the program has offered free or reduced-cost genetic tests to over 5000 residents of five North Alabama counties. The test looks at several dozen genes associated with increased risk for breast, ovarian, colon, and prostate cancers. The initiative recently expanded its reach beyond North Alabama to individuals throughout the state. Information is Power has forged collaborations with #NowIncluded and Montgomery area physicians to increase their reach to include medically underserved individuals throughout the state.
Some families with a high incidence of cancer do not carry changes in any known cancer predisposition genes. Cooper and her lab aim to find new genes that predispose individuals to cancer through a collaboration with the local Huntsville clinic Clearview Cancer Institute. During a pilot project, the team will collect DNA samples from 10 individuals with a strong family history of cancer at a young age. These individuals will have had cancer screening that did not return a cancer predisposition gene. By performing whole-genome sequencing on the samples, the team hopes to find new cancer predisposition genes. The pilot will serve as a proof of concept that the team can collect, sequence, and analyze the patient’s genomes.