Development of New Therapeutic Strategies of Chemobrain for Ovarian Cancer Survivors
Abstract
Ovarian cancer is the sixth most common cancer in women with more than 20,000 individuals diagnosed in the United States each year. Taxane and platinum-based chemotherapies are standard treatment for ovarian cancer and these treatments help avoid death from this disease. Nearly 70% of ovarian cancer survivors suffer from chemotherapy-induced cognitive impairment (CICI or chemobrain) and, unfortunately, the cognitive (memory and mood-anxiety) dysfunction continues well after chemotherapy has ended. Since the median survival for patients with ovarian cancer exceeds 5 years and about one third of patients are cured, CICI is of significant medical concern, as it negatively affects quality of life. Therefore, our research hopes to establish an understanding of the pathological mechanisms that drive CICI and, consequently, find effective therapies to help cancer survivors cope with these negative side effects. Given the critical importance that military Service Members, their families, as well as Veterans, provide to the security and overall well-being of the United States general population, it is imperative to find ways to improve quality of life for past (Veterans) and presently active U.S. Service Members or their families who are cancer survivors. Overall, by improving survivorship, our proposal will improve defense readiness for active members of the military so that they can perform their duties in service of our country. In our recent studies, we revealed that cisplatin significantly increases the levels of the adenosine A2A receptor (A2AR) protein in the adult mouse hippocampus, a brain region known for its control of learning and memory. In addition, our preliminary results show that this phenotype is shared by paclitaxel and methotrexate chemotherapies, indicating that A2AR induction may be a common pathological mechanism mediating CICI. Most importantly, istradefylline, a drug that targets the A2AR and prevents it from increasing in function, significantly prevents cisplatin-induced cognitive deficits without promoting tumor growth or interfering with cisplatin’s anti-tumor activity. Based on our observations, we will investigate whether chemotherapy causes cognitive impairment due to robust A2AR induction and that, conversely, by inhibiting A2AR, we can show that this is a safe and effective therapeutic strategy against CICI. To test this novel hypothesis, we will elucidate whether the FDA-approved A2AR inhibitor istradefylline has a prolonged preventative effect against CICI and/or rescues symptoms after onset of CICI in aged mice. Furthermore, given the importance of A2AR inhibition in preventing tumor growth as observed in multiple tumor bearing mouse models, we will further evaluate the impact of istradefylline-mediated A2AR inhibition on tumor growth and istradefylline’s ability to avoid interfering with chemotherapy’s anti-neoplastic activity using ovarian cancer tumor-bearing mouse models. Subsequently, by using mice which have had genetic deletion of the A2AR in specific cell types (e.g., cell type-specific conditional A2AR knockout mice), we will determine which neural cell type increases A2AR expression due to chemotherapy treatment. Additionally, using these mouse models, we will determine whether increased A2AR abundance in these cell types is responsible for CICI. Last, to achieve long-lasting A2AR inhibition in a cell type-specific manner, we will develop an innovative delivery system where we genetically modify an inert, non-pathogenic viral sequence that silences the A2AR (siRNA-A2AR) and package this payload in nanoparticles which we will deliver directly in the brain of our mouse models to determine whether this treatment can maximize therapeutic efficacy in preventing CICI. Taken together, the short-term impact of our proposed work is to provide critical pathological mechanisms mediating CICI. Our long-term impact is to pave the way for transformative clinical interventions to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310365
Entities
People
- Ki Bum Lee
Organizations
- Rutgers University
- United States Army