Understanding and Overcoming Treatment Resistance in MDM2-Amplified Esophageal Cancers
Abstract
Background on Esophageal Adenocarcinoma Esophageal adenocarcinoma (EAC) is an aggressive cancer – fewer than 20% of patients are still alive 5 years after their diagnosis. Moreover, the number of people diagnosed with the disease is rapidly rising in the United States. Most patients are diagnosed when the cancer has already spread beyond the esophagus. For these patients, the standard treatment is chemotherapy combined with radiation therapy (termed chemoradiotherapy), follow by surgery if feasible. However, around 70% of patients have little response to this chemoradiotherapy, and their subsequent risk of death is markedly higher than that of patients who have robust responses. Therefore, we believe the greatest opportunity to improve outcomes for patients with EAC lies in predicting which patients will respond poorly to therapy, understanding the reasons for the treatment resistance, and ultimately converting such patients to responders. Objectives and Rationale We have discovered several genes that, when mutated or otherwise altered in an EAC, predict that the cancer is likely to be resistant to chemoradiotherapy. Two of these genes, MDM2 and TP53, stood out because they are key players in a biological process, termed the p53 pathway, which helps maintain the integrity of DNA and chromosomes. Thus, the alterations in MDM2 or TP53 in EAC could lead to chromosome damage, which in turn could account for the poor responses to chemoradiotherapy. Our objectives are (1) to understand how MDM2 gene alterations in EAC contribute to treatment resistance and (2) to identify new approaches to therapy for these patients, for whom no effective options currently exist. For this second objective, we will assess an inhibitor of MDM2, testing its effect on models of EAC when administered alone, combined with conventional chemotherapy, and combined with immunotherapy. This work will lay the foundation for clinical trials for MDM2 inhibitors in advanced EAC. How the Research Will Help Patients We expect the proposed research to lead to new precision medicine strategies to greatly enhance patients’ chances of surgical cure and long-term survival. This will benefit patients with EAC with MDM2 alterations (approximately 10% of patients). Because MDM2 and TP53 alterations affect the same biological pathway, we expect that our research could also benefit many of the patients with TP53-mutant EAC (approximately 80% of patients). In addition, these findings may have relevance to other cancers that also have alterations in MDM2 or TP53, which include lung cancers and soft tissue sarcomas. In EAC, we have found that altered MDM2 and TP53 promote treatment resistance to a wide range of chemotherapies. Therefore, the knowledge we gain is likely to be broadly applicable to other cancers with MDM2 or TP53 alterations, even if the specific treatments differ from those used for EAC. Principal Investigator’s Career Goals Dr. Sihag is a surgeon specializing in esophageal and other thoracic cancers. Her time is evenly divided between clinical care of patients and translational research. Her central career goal is to build a productive research program in investigating the biology of esophageal cancers and devising new treatment strategies, with the ultimate goal of improving survival and quality of life for individuals affected by these diseases. She already has research expertise in two areas relevant to the proposed research: genomics and computational biology. The Career Development Award will provide training opportunities for her to acquire the additional skills and experience needed to fulfill her research goals. The award will also provide the time and resources that will enable her to launch her own independent research program. Relevance to Overarching Challenges and Military Health This proposal addresses two overarching challenges: transform cancer treatment through the identification of new targets and a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310250
Entities
People
- Smita Sihag
Organizations
- Sloan-Kettering Institute
- United States Army