Homologous Recombination Defects in the Etiology and Therapy of Malignant Mesothelioma
Abstract
Malignant mesothelioma (MM) is a cancer that develops in the tissue lining the lungs, heart, or abdominal organs. Asbestos exposure is the major risk factor with a latency from exposure to MM onset of 20-70 years. In the 20th century, asbestos products were widely used by all military branches, especially the Navy, contributing to the known increase in MM diagnoses among Veterans than in the general population. Unfortunately, ongoing exposures still occur due to unregulated asbestos production by many countries worldwide, putting our military personnel at risk for this cancer for the foreseeable future. Sadly, nearly all patients diagnosed will die from this disease with an expected average survival of 14-16 months. Chemotherapy modestly improves survival but only for the subset who respond. Because we lack tools that can identify which individual patients will respond, all patients healthy enough to tolerate the likely side effects are offered chemotherapy, knowing that only a subset will benefit and the rest only potentially harmed. Few subsequent line treatment options are available. Thus, clinical predictive tools to better identify patients likely to respond to available treatments and new, more effective therapies are urgently needed. The objective of this proposal is to use whole genome and RNA sequencing of both normal tissues and MM tumors from 200 patients with MM along with information on how they responded to chemotherapy to discover how one of the body’s major DNA repair pathways drives MM development and to create the first-ever model able to predict whether a patient is likely to respond to platinum chemotherapy or not for use in the clinic. This proposal specifically addresses the PRCRP Topic Area of mesothelioma and Military Health Focus Areas of exposure risk factors relevant to military personnel and gaps in cancer prevention, early detection, and treatment that impact mission readiness. This work has both near- and longer-term impact for patient care. First, this work will produce the largest whole genome datasets in MM to date that can not only be used for our study, but will become a resource for the community of MM researchers to make further discoveries. Second, we will have developed a clinical prediction model that can immediately be implemented into a clinical trial. Third, we have permission to return any immediately actionable results from our research to the individual patients who are part of this study and/or their designated family member to ensure rapid translation of our findings to improve patient care. Longer-term applications of this research are testing whether new pathways that we discover can be targeted by specific new drugs for treatment or can be found in the blood and used for early detection in those at risk, or allow us to better model how MM develops in the laboratory. Given that past and ongoing asbestos exposures in the line of duty disproportionately increase risk for MM, this work is highly relevant to Veterans, active-duty military personnel, and their beneficiaries. This proposal has the potential to discover how changes in genes that are inherited from birth may impact risk for MM and other cancers as well. This information can be used to offer already available early detection and prevention interventions (e.g., breast, ovarian, prostate, pancreatic cancer) for military personnel and their close relatives as well as guide development of new methods for MM prevention. The development of the first-ever clinical tool for predicting chemotherapy response in MM and gaining fundamental knowledge of how the inherited genome and exposures interact to cause MM are critical to improving patient care now as well as getting toward the ultimate goals of prevention and curative treatment options.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110817
Entities
People
- Jane Churpek
Organizations
- United States Army
- University of Wisconsin–Madison