The Role of Adenosine A2BR in Metastatic Melanoma
Abstract
Career Goals: Dr. Barkauskas has always had an ambition to develop new clinical technologies and therapies that improve patient outcomes and quality of life. Her doctoral research has produced key findings on multiple sclerosis, and through collaboration, pediatric and young adult cancers. The experience has inspired her to deepen her commitment to the nascent discipline of immunotherapy for halting metastasis of cancer. The Horizon Award was specifically crafted for researchers like Dr. Barkauskas, who have recently obtained their PhD and will become a leading candidate for future funding mechanisms, where this award will be crucial in launching her career in melanoma research. Melanoma is one of the most deadly and immunogenic tumors. It is the fifth most common cancer among Department of Veterans Affairs cancer patients, with Airmen having the highest incidence, and it has shown a beneficial response to emerging immunotherapies. Dr. Barkauskas will be mentored by one of the leading researchers of adenosine in the tumor microenvironment, which not only comes with sound guidance on research plans and contextual interpretation of results but also all the relevant tumor and mouse models needed to reach a clinically relevant conclusion within the 12-month award time. Scientific Objective/Rationale: Dr. Barkauskas will be investigating the role of adenosine in the metastatic dissemination of melanoma. Due to the high mutation rate and disease heterogeneity, a large proportion of advanced stage disease patients either do not respond to conventional strategies or relapse with metastases. The ultimate goal is to induce the patient s own immune system to recognize a melanoma tumor and possible metastasis and clear it from the body without the use surgery or ionizing radiation -- both of which carry well-known risks that are widely understood. In the context of the tumor microenvironment, adenosine is upregulated and subsets of cells differentially upregulate two of four adenosine receptor types. This allows novel melanoma immunotherapies under development to be evaluated. This promising therapy has a high probability of success based on: (1) evidence from preclinical trials of other adenosine-related molecules; (2) adenosine signaling inhibitors are currently used by Parkinson s patients with little to no side effects; and (3) MedImmune has a clinical efficacy trial on anti-CD73, an adenosine signaling antagonist, for the treatment of solid tumors. With the proposed research plan, there is a possibility this project will be able to predict the clinical relevance of targeted receptor inhibition in metastatic melanoma in 12-18 months. Our rationale for targeting adenosine 2B receptor in adenosine signaling is to specifically inhibit metastasis of melanoma. In the same way, checkpoint inhibitors are shaping the landscape of immunotherapy, we anticipate affecting adenosine signaling in the tumor microenvironment in combination with immune modulating therapies. In total, the treatment regime would rid the patient of primary and metastatic melanoma and could lead to enhanced outcomes with fewer side effects. With U.S. combat operations concentrated in Iraq and Afghanistan, exposure to ultraviolet radiation by active duty Service members increases their risk of melanoma and metastatic cancer -- both now and as Veterans in the future. Note that the incidence of melanoma exceeded that of prostate cancer in the male U.S. Air Force population. Thus, melanoma is a significant risk for the active duty population as well as for Veterans. Finding novel therapies to treat metastatic melanoma will save Service people s lives.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610224
Entities
People
- Deborah Barkauskas
Organizations
- QIMR Berghofer Medical Research Institute
- United States Army