Targeting Stress Pathways in Esophagus Cancer to Boost Antitumor Immunity, Promote Response to Therapy, and Prolong Survival
Abstract
Scientific Objective: Cancer patients are under a lot of stress. Our animal studies show that chronic stress promotes cancer by suppressing the immune system and making cancer cells hard to kill. The scientific objective of the proposed research is to find out whether blocking the effects of stress in patients with esophageal cancer, a Fiscal Year 2021 (FY21) Peer Reviewed Cancer Research Program (PRCRP) Topic Area, will improve response to therapies (chemoradiation and immunotherapy), improve quality of life, and increase survival. To accomplish this, our team has initiated two new clinical trials for patients with esophagus cancer which will test, for the first time, the impact of reducing the biological effects of stress as part of their therapy. Using patient samples from these trials, we will also identify the specific mechanisms to see how stress influences cancer progression and the immune response against esophageal cancer cells. Scientific Rationale: Our previous studies in mice have shown that chronic stress reduces the efficacy of cancer therapies and promotes tumor growth and metastasis. We found chronic stress increases the stress hormone norepinephrine, which binds to adrenergic receptors on tumor and immune cells. This turns on survival and growth pathways making tumor cells hard to kill. This type of adrenergic stress signaling activates suppressive types of immune cells and inhibits the types of immune cells that can kill a tumor. We discovered that a common beta-adrenergic receptor blocker used to treat high blood pressure, propranolol, reverses this stress-induced immune suppression and increases tumor cell killing by both chemoradiation and immunotherapy in mouse models of melanoma, breast, and pancreatic cancer. More excitingly, we have translated these results into an ongoing phase 1/2 clinical trial in melanoma patients. Results show that adding propranolol improves tumor responses to an immunotherapy drug, showing that our mouse strategy seems to work in people. Propranolol is safe, cheap, and effective. To support trying this approach in esophageal cancer, we have recently looked back at patients with esophageal cancer who have been taking beta-blockers, like propranolol, before and during their cancer treatment, and found that they had significantly longer survival and less tumor spread to other distant sites. Altogether, our published and preliminary data has led to this application and the initiation of two new phase 1/2 clinical trials testing the combination of propranolol with standard of care (including combination with checkpoint inhibitor immunotherapy) in patients with esophageal cancer. Thus, we are now well positioned to examine for the first time patient tumor samples taken before and after chemoradiation therapies (and immunotherapy), to explore new ways by which blockade of stress signaling can reduce resistance to chemoradiation and immunotherapies. The results of these studies address the FY21 PRCRP Military Health Focus: Mission Readiness and will support the development of strategies and biomarkers that can help predict and lessen treatment resistance and recurrence, major goals of the FY21 PRCRP Overarching Challenges, aiding our military to return to service faster. In this proposal, clinicians, and scientists from two premier research institutions, in The University of Michigan (which includes the Ann Arbor VA) and Roswell Park Comprehensive Cancer Center in Buffalo, New York, have joined forces and organized an impressive team of experts in cancer biology, immune-oncology, tumor genomics, tumor models, and functional imaging to developing new treatments for patients with esophageal cancers. Thus, our team brings a significant degree of interaction between basic research skills and clinical expertise of the collaborating groups at two sites, which is a distinguishing feature of this proposal. Military Relevance: Esophageal cancer, the seventh leadi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210914
Entities
People
- Elizabeth Repasky
Organizations
- United States Army