Identifying Drivers of Therapy Resistance Within the Tumor Microenvironment of Esophageal Adenocarcinoma
Abstract
This proposal targets the Fiscal Year 2020 Peer Reviewed Cancer Research Program Esophageal Cancer Topic Area. Esophageal adenocarcinoma (EAC) includes cancers of the esophagus and the gastro-esophageal junction (the structure connecting the esophagus to the stomach) and is the fastest-rising cancer in the United States (U.S.). This is particularly true for U.S. military Veterans, who have experienced a 40% increase in the number of patients diagnosed with EAC in the U.S. Department of Veterans Affairs system from the periods of 1995-1999 to 2000-2005. Most patients are diagnosed with advanced disease (since there are no early symptoms or screening tools), driving a 5-year survival of less than 20%. Current clinical care includes chemo (-/+ radiation) therapy, but only approximately 60% of patients have cancers that respond to this treatment. In the ones that do respond, cancer recurs (usually at other body sites) in half of them. Therefore, our current treatments are only effective in 30% of patients. Selective therapies against new tumor targets have largely failed to improve outcome, partly due to the differences between individual tumors and between individual patients. Therefore, other avenues are urgently needed to complement traditional systemic chemotherapy for this cancer. Here, we propose an approach concentrating on not just the tumor, but also the structural and immune cells that surround the tumor (tumor environment) and influence response to treatment, in order to develop effective treatment for this devastating disease. Our team has access to many sets of cancer tissue from the same patient before and after treatment. This is a very valuable resource, because it allows for the study of changes caused by treatment in an individual. We will study these changes using existing tissue specimens from a large number (over 600) of consented patients to learn how treatment changes the tumor environment in each one. Linking our observations to the response of the patient to therapy allows for the identification of differences in the tumor and its environment that differentiate a responder from a non-responder. Genetic sequencing of samples, combined with analyzing their environment, will give insight into potential targets for therapy. In addition to existing patient samples, we will also collect future samples from patients before, during, and after their treatment, where the advantage is that we can isolate both cancer and surrounding cells. We will then test new drugs on systems where both of these cell types are grown together to find new treatments that help to make cancer cells sensitive to chemotherapy, based on the targets we identify. Combining gene analysis, identification of cell types surrounding the tumor, and linking it to patient response to therapy offers a unique and novel platform to study the changes that accompany chemotherapy for esophageal cancer. The proposed research will lead to mission readiness by finding ways to discover which patients would not benefit from chemotherapy before surgery, as well as treatments to make chemotherapy more effective. This will change the direction of the care of military members/Veterans and their families. An understanding of the tumor and how it interacts with its environment in esophageal cancer will lead to development of new tools to make treatment decisions, the introduction of novel therapy approaches, and, most importantly, improved survivorship.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110623
Entities
People
- Lorenzo Ferri
Organizations
- McGill University Health Centre
- United States Army