A Novel Epigenetic Mechanism Conferring Resistance to Treatment in Lung Cancer
Abstract
This application addresses the FY19 LCRP Area of Emphasis to Understand mechanisms of resistance to treatment. Lung cancer is a particularly devastating disease. It is one of the most common cancers caused by occupational exposures and the most prominent cause of cancer-related mortality. It has claimed the lives of animator/producer Walt Disney and retired Army Staff Sergeant and Medal of Honor recipient Ronald J. Shurer II, among many others. The majority of lung cancer patients are initially asymptomatic, and the disease usually presents at a later stage of progression where surgical resection alone does not cure the disease. Chemotherapies that include cisplatin or related drugs are extensively used to treat advanced lung cancers as first-line treatments. However, a frequent occurrence is that, after an initially favorable response, the cancer recurs, often in a more aggressive form. Hence, the prognoses and 5-year survival rates for lung cancers remain poor. Here we propose to use a novel approach to identify a non-genetic mechanism that confers resistance to the anticancer drug cisplatin. We have identified for the first time a pathway that dramatically increases sensitivity to cisplatin when blocked. We propose to investigate how circumventing resistance is achieved with the long-term aim of improving the survival of patients with lung cancer. Identifying novel targets to improve cancer drug efficiency that will prevent disease recurrence and even allow for lower drug dosing and side effects will have an immense impact on patient care, quality of life, and survival. This proposal is applicable to all patients with non-resectable lung cancers, and the information garnered could be implemented in a dual-use capacity to address a prominent military need that also benefits the civilian population. The research proposed is currently too basic for clinical applicability, but is aimed to identify a novel approach for targeted drug development to increase the effectiveness of current lung cancer treatments. It is anticipated that discoveries made in these studies will help inform drug combination approaches in other model systems and eventual clinical trials in the next 5 years. Furthermore, it is anticipated that identifying non-genetic mechanisms of drug resistance will significantly advance the field of lung cancer research into a new arena and opening the possibility of new avenues for the development of treatments. Lung cancer is a major health problem for both U.S. military members, citizens, and their beneficiaries, but with a high risk caused by military occupational exposure to irradiation and higher rates of smoking in Veterans. A serious illness such as lung cancer in either a military Service member or one of their family members will have serious consequences on a Warfighter’s ability to complete their mission, with a high financial and psychological cost of cancer care. Notably, lung cancer rates are documented to be higher in Veterans than the general civilian population. Lung cancer, in either a military Service member or one of their family members will have serious consequences on a Warfighter’s well-being. Identifying novel targets to improve standard-of-care, platinum-based, drug efficiency that will prevent resistance or allow lower drug dosing and side effects will have an immense impact on patient care for military Service members, Veterans, and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010796
Entities
People
- Patrick Grant
Organizations
- Florida Atlantic University
- United States Army