Specific Targeting of the TACE Protease as a Therapeutic Strategy in Lung Adenocarcinoma and Associated Cachexia
Abstract
Lung cancer is the most common and lethal cancer worldwide and has a poor overall 5-year survival rate of 15%. This poor survival rate is largely due both to late detection of the disease and the limited effectiveness of current surgery, chemotherapy, and radiotherapy treatments. In addition, many patients with advanced-stage lung cancer develop cachexia, a chronic muscle-wasting syndrome that leads to weight loss and fatigue and is a major contributing factor to the high death rate of this cancer. Lung cancer is among an increasing number of cancers that is caused by chronic (long-term) inflammation resulting from uncontrolled activation of the immune system; chronic inflammation is also linked to the onset of cachexia. However, the identity of specific genes of the immune system that promote inflammation-associated lung cancer and cachexia are poorly understood. Importantly, our novel preliminary findings reveal that a key gene of the body’s immune system, called TACE, which controls the activities of many other immune system regulators, can promote lung cancer in a well-defined mouse disease model that is representative of approximately one third of all types of lung cancer. Therefore, our objective is to determine the mechanism by which TACE drives lung cancer and cachexia and thus (1) discover TACE-controlled immune system regulators as candidate biomarkers (i.e., released into the blood) to assist with early disease detection and predict individuals who will develop the disease, and (2) reveal that the specific blockade of TACE activity via a new inhibitor has anti-cancer activity (in the lung) for future clinical use as a therapeutic in LAC and cachexia. Major risk factors for lung cancer are prolonged exposure to tobacco smoke and environmental chemical carcinogens, such as those found in diesel fuel exhaust. In the lung, these risk factors not only are the main causes of chronic inflammation, but also damage DNA, leading to mutations in certain genes that are known to drive the onset and progression of cancer. One such gene in particular is called KRAS, which is mutated in nearly one-third of all lung cancer cases. Unfortunately, drugs that target and block the cancer-causing effects of the mutated KRAS gene have been very difficult to develop for use on cancer patients. We note that, while cachexia is associated with the death of many advanced stage lung cancer patients, there are no effective treatments for this condition. Accordingly, the rationale of our proposal is driven by the urgent and unmet clinical need to identify more easily “druggable” genes (e.g., TACE) that cooperate with mutant KRAS to drive lung cancer and cachexia to enable development of an attractive alternative for new therapeutic strategies that indirectly block the cancer-causing activity of mutant KRAS and thus improve patient outcomes. Indeed, since a role for TACE in KRAS-induced LAC has not been studied, a powerful component of our proposal is testing of a new and highly specific TACE inhibitor in our KRAS mutant lung cancer mouse models as a next-generation anticancer drug for potential clinical application in personalized medicine trials on KRAS mutant lung cancer patients. The significance of this is evidenced by the failure of current TACE inhibitors to be effective on cancer patients because of their high toxicity due to non-specific targeting of other genes related to TACE. Importantly, the potential clinical utility of our study extends to TACE and its downstream regulators also serving as biomarkers for early detection of disease, as well as predicting individuals who are most likely to be at high risk of developing lung cancer and subsequent cachexia upon exposure to the above-mentioned risk factors. We envisage that these clinically relevant outcomes from our proposal can be achieved within 5 years. These discoveries will also open up a new paradigm on how key genes of the immune system, such as TACE, c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810335
Entities
People
- Brendan J. Jenkins
Organizations
- Monash University
- United States Army