Tumor-Associated Macrophage Reprogramming to Improve Oral Cancer Therapeutic Efficacy
Abstract
Scientific Objective and Rationale: Each year, there are 400,000 new head and neck cancer case diagnoses, with an overall five-year survival rate of less than 50% for high-risk cases. Unfortunately, Veterans have twice the prevalence of head and neck cancer compared to non-Veterans. In fact, roughly half of all oral cancer patients die within 5 years, even with treatment. Most oral cancers occur in people over 40 years of age, but begin to develop when a person is younger. The bad news is that oral cancer is striking people at a younger age, and more women are developing oral cancer. Nearly 75% of oral cancers are caused by either alcohol or tobacco. In fact, those who both drink and smoke are 22 times more likely to develop oral cancer. Therefore, there is a great need for improved therapy in patients with advanced oral cancer as well as those with recurrent disease. Oral cancers are found on the tongue, the bottom or roof of the mouth, on the gums, on the lips, inside the cheek, in the tonsils, on the salivary glands, and in the back of the throat. Oral cancer can affect your speaking and eating ability, and can permanently disfigure your face. Certain types of white blood cells are often recruited at tumor sites and instructed by tumor cells or other cells within the tumor to acquire more aggressive behavior. Inflammation induced by these white blood cells often makes it more difficult for conventional and newer immunological-based therapies to work well. We have shown that a key controller of inflammation is silenced in oral cancer which was validated in large cancer data bases. After losing the ‘brakes’ in the system, there is more oral cancer growth due to a change in behavior in the white blood cells within the tumor itself. In this application, we are proposing to increase the expression of this key suppressor of tumor inflammation to regain control of the brakes. We will evaluate the effects of specific drugs that could be used together with conventional and immunological-based therapeutics to understand the impact of targeting this key negative regulator of inflammation in established preclinical models that use oral cancer tissues. Near-Term Impact: By using well-established Food and Drug Administration (FDA)-approved therapeutics, we have a sound and immediate opportunity to provide impactful new adjuvant platforms. By both increasing the sensitivity of tumors to traditional chemotherapeutics, as well as reprograming white blood cells to promote more tumoricidal activity, these agents could be used in both conventional and potentially as novel drugs for immunotherapeutic approaches to control oral cancer. If successful, these FDA-approved agents will shorten the time frame to get these agents into human clinical trials with minimal risks to patients since they are already deemed safe. Relevance to Military Health: The warfighting member, regardless of service affiliation, is the focus of any military force. As such, mission success depends on the service member’s well-being and fitness. Oral health, being one facet of overall health, is often misunderstood or relegated as another annual requirement prior to mission deployments. Because dental care is often taken for granted, dental health is a frequently neglected part of overall health. As an important aspect to the quality of life and general health of an individual, oral health can be thought of as a condition where an individual is free of oral disease, such as dental caries (tooth decay), periodontal disease (gum), dental pain, and oral cancer. Dental issues and emergencies can present monumental distractions to the mission and serve as a considerable downgrade in the quality of life.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110363
Entities
People
- Keith Kirkwood
Organizations
- United States Army
- University at Buffalo