Investigating Combinatorial Approaches to Enhance cGAS/STING Activation and Antitumor Immunity
Abstract
In the last 20 years, the fight against ovarian cancer has gained significant momentum, and there has been an improvement in patient care and quality of life! Much of this momentum is a direct result of the Department of Defense (DOD) Ovarian Cancer Research Program (OCRP) and the support it provides to researchers and clinicians. Further, the emergence of PARP inhibitors to treat patients with BRCA-mutations and DNA repair defects has changed the clinical course of battling ovarian cancer. However, given about 50% of patients with ovarian cancer do not have DNA repair defects and the propensity of therapy resistance, there is still a significant and urgent need to develop therapies that will be effective beyond chemotherapy and PARP inhibitors. The long-term vision of the proposed research is to characterize the cancer biology mediated through claudin-4, a targetable aspect of ovarian cancer biology, and to develop preclinical data for a novel combinatorial therapy that inhibits claudin-4 and activates anti-tumor immunity. Most cancers are defined by “uncontrolled” growth; while this definition is partially true, cancer cells maintain some regulatory mechanisms that allow cancer cells to undergo cell division. Cell division is a critical characteristic of cancers that allows for tumor growth. In normal cells, cell divisions are tightly regulated via numerous pathways, such as Golgi organization, to control for equal chromosomal distribution, to promote genetic stability, and to prevent damage to the cellular components, such as chromosomes. While total misregulation of cell division can result in cell death, a level of regulation can allow cells to divide and grow. Aberrant cell division often times results in DNA damage and abnormal chromosomal number. However, even though the chromosome numbers are often not equal, ovarian cancer cells remain viable, develop tumors, and progress to an aggressive disease. Through the support of a DOD OCRP Pilot Award, we have been able to elucidate and identify a unique regulator of cell division. Our Pilot Award focused on the contribution of a cancer-specific protein, claudin-4, in altering therapeutic response to PARP inhibitors. According to the Cancer Genome Atlas, claudin-4 is expressed in 80% of all ovarian cancer tumors. Our previous work found that claudin-4 expression promotes resistance to microtubule stabilizing taxane-based chemotherapies. Consistently, loss of claudin-4 promotes the destabilization of microtubules, which function during cell divisions to physically pull the chromosomes apart. Claudin-4 also is often expressed in tumors without BRCA1/2-mutations. Thus, targeting claudin-4 could potentially benefit a patient population that only has a mild response to PARP inhibitors. In our previous work, we discovered that, by inhibiting claudin-4, we are able to block DNA repair mechanisms and promote the accumulation of DNA damage. We further observed that claudin-4 inhibition significantly altered cell divisions and led to a genetically unstable cell. Our preliminary data highlight that claudin-4 is involved in a process (Golgi organization) that provides spatial cues to the cell to allow cell divisions to occur. Little is known on claudin-4 regulates cell division and Golgi organization, but uncovering claudin-4’s contribution to these pathways could lead to improved strategies to induce an anti-tumor immune response. Improving anti-tumor immunity in patients with ovarian cancer is a major area of research. For instance, activation of the cGAS/STING pathway promotes anti-tumor immunity in mouse models of ovarian cancer. We discovered that claudin-4 inhibition results in cGAS/STING activation potentially through aberrant cell division, Golgi fragmentation, and the accumulation of DNA damage. We hypothesize that claudin-4 functions to regulate cell division and Golgi organization through microtubule dynamics and providing spatial cues to the cel
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110382
Entities
People
- Benjamin G Bitler
Organizations
- United States Army
- University of Colorado Denver