Targeting APOBEC3A-Induced Chromosomal Instability as a Driver of Metastasis in Bladder Cancer
Abstract
The most common type of bladder cancer is urothelial carcinoma (UC). Among Veterans, it is the fourth most common cancer. Each year there are 84,000 new diagnoses of urothelial carcinoma. Every year, it kills 18,000 people in the United States. Once UC spreads beyond the primary site of origin (e.g., becomes metastatic), it becomes incurable. Metastasis is the main barrier to cure. We recently discovered that no two metastatic tumors within the same patient are alike at the genetic level, and this divergence happens very early, sometimes at the time of diagnosis. We also identified a significant increase in the number and the clonality of C to T or C to G mutations (genetic typos) attributed to APOBEC3 enzymes in metastatic chemotherapy-resistant UC, indicating that the tumors continue to evolve. However, how APOBEC3-induced mutations drive metastatic spread and the early divergent evolution between primary and metastatic UC is unknown. Thus, there is a critical need for new methods to study and target this process to inhibit metastasis and therefore make cures within reach. The current proposal addresses this crucial area of clinical need in several ways. In Aim 1 of this application, we propose that the APOBEC3 enzymes introduce typos (mutations) into the DNA of the cancer cells to drive the development of metastasis. To test this hypothesis, we have developed a new clinically relevant mouse model in which patient-derived UC tumor cells are injected into the tail veins of immunodeficient mice, which develop lung metastases. We will expand this model by creating a library of patient-derived tumor organoids (tumor mini-avatars) from patients with metastatic UC. By deleting and overexpressing the APOBEC3 enzymes in these cells, we will be able to examine the function of each APOBEC3 enzyme in our animal model. In Aim 2, we will identify what proteins and pathways can be targeted to inhibit the process of UC metastasis. This will help us develop therapies that can be translated into clinics for the treatment of patients with advanced UC to prevent metastasis. The Department of Defense Idea Award will be critical for completing this research to improve outcomes for patients with bladder cancer. This research will have several critical clinical applications for most patients with metastatic bladder cancer in the near term. We expect this project to generate significant preliminary data identifying the mechanisms that drive the genetic evolution of metastasis. Our research will also lead to the development of new therapies that can prevent metastatic dissemination in patients with UC. It will enable clinicians to tailor treatments to the individual biology of each patient s cancer to deliver the proper treatment at the right time (precision medicine). Our proposal directly addresses two of the primary FY22 Military Health Focus Areas by providing knowledge on how environmental exposure to carcinogens and mutations drive cancer metastasis, and our data will fill gaps in cancer treatment that may impact mission readiness and the health and well-being of military members, Veterans, their beneficiaries, and the general public. We expect that the proposed research outcomes will advance fiscal year 2022 (FY22) Peer Reviewed Cancer Research Program (PRCRP) Overarching Challenges by focusing on transforming cancer treatment through the identification of new targets, especially for advanced disease and metastasis. Our research will provide an in-depth understanding of the roles of APOBEC3 enzymes in driving genetic heterogeneity of bladder cancer metastases and aid the development of novel therapies that prevent metastasis in UC; thereby simultaneously addressing two FY22 PRCRP Topic Areas: Bladder Cancer and Metastatic Cancers. By identifying mechanisms that drive cancer s spread and change, we hope to prevent or inhibit metastasis and curb the evolution of this lethal disease. Our team brings together a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310790
Entities
People
- Bishoy Faltas
Organizations
- United States Army
- Weill Cornell Medicine