Exploiting Synthetic Lethal Interactions for Esophageal Cancer Therapies
Abstract
Scientific Rationale and Objectives: Cancer of the esophagus (gullet or food pipe) is rare, but has extremely poor outcomes. It is estimated that cancer of the esophagus accounted for only 1 out of every 100 new cancer cases but around 3 out of every 100 cancer deaths in the United States in 2021. This poor statistic is largely because the efficacy of the few available treatment options for esophageal cancer has reached a plateau, particularly for patients with advanced stage cancers. Even in patients with potentially curable disease, remission is often short lived and all relapses are incurable at present time. Furthermore, the number of new cases of esophageal cancer have risen year on year over the past few decades, highlighting the urgency to address the unmet need for more effective treatments for this disease. Our goal is to identify potential new treatments by understanding the strengths and weaknesses of esophageal cancer at the genetic level. Esophageal cancer is caused by the accumulation of genetic mutations in cells of the esophagus, which provide the cancer cells with an advantage to grow uncontrollably and form a tumor and then spread to other parts of the body. However, these advantages or strengths can come at a cost to the cancer cells by increasing their reliance on other cell processes to survive the rigours of such rapid growth. Thus, by determining how different genetic mutations help esophageal cancer to grow and survive (its strengths) we can also identify the cancer’s potential Achilles’ heel (its weakness). Following this concept, in a previous study we found that mutation in a gene called SMAD4 (found in around a third of all esophageal cancers) causes esophageal cancer to form by providing a growth advantage and allowing the accumulation of additional mutations that help the tumour form. However, we also found that when SMAD4 is mutated, the tumor becomes reliant on a quality control process that operates inside the cell to ensure it is ready to grow and divide. This weakness can potentially be exploited by treating the tumor with new anti-cancer drugs that block this quality control process causing it to dysfunction and the tumor cells to die. Therefore, the specific objectives of this project are: (1) To establish the potential of these quality control blocking drugs to be used as new treatments for esophageal cancer. (2) To determine whether these drugs can also be used to treat esophageal cancers caused by mutations in other genes. To achieve these objectives, we will test and develop these new treatments in laboratory models of esophageal cancer. Importantly, we will use patient-derived models (also called patient avatars) in which tumor pieces donated by patients are grown directly in mice or embedded in a gel in a culture dish where they replicate that patient’s tumor. These are the gold standard for testing new treatments in the laboratory prior to testing in patients. FY21 RCRP Focus Areas: - Primary - Therapy; Secondary - Biology and Etiology; Research Model Ultimate Applicability of the Research and Anticipated Timeframe: The outcomes of the proposed research will lead to new treatment strategies that are potentially applicable to at least a third of all patients diagnosed with esophageal cancer esophageal adenocarcinoma (EAC). Chemotherapy is part of treatment for most EAC patients, but more than half will have their disease recur (relapse) soon after treatment, and there are few effective subsequent treatments available. The treatments we will test in this project have the potential to provide transformational outcomes for patients with EAC by improving cure rates for patients with early stage disease as well as prolong life and improve quality of life for patients with advanced stage disease. Our research will also identify signals or markers that we can test for in patients to identify those who are most likely to benefit from our treatments. Therefore, our research w
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210527
Entities
People
- Nicholas J Clemons
Organizations
- United States Army
- University of Melbourne