Development Awards are a subtype of a Pilot Award in which one year of funding is provided to test potentially transformative "high-risk, high-reward" ideas that do not have extensive preliminary data but would establish proof-of-concept. Investigators who are past the initial four years of their first academic faculty are eligible.
Regulatory Macrophages: A New Therapeutic Target in Melanoma
Susan M. Kaech, Ph.D. B.S., Yale University School of Medicine
With generous support from the David L. Klein Jr. Foundation
The immune system is capable of attacking melanoma, and recent therapies that promote anti-tumor immune responses have shown promise. It has become clear, however, that melanomas harbor cells that inhibit the immune response and interfere with immune-promoting drugs. Thus, an ideal therapeutic approach would deplete the cells that work against the anti-tumor immune response, while strengthening the cells that promote the anti-tumor response. We have characterized a melanoma-associated macrophage that appears to shut down effector T cells, which are a critical arm of the anti-tumor immune response. Shutting down these inhibitory cells may provide an important boost to the anti-melanoma immune response. We propose to study the way in which these macrophages inhibit T cells, and explore approaches to neutralizing their suppressive function. We expect that approaches that disarm these cells will synergize with approaches that improve immune function. Our studies could thus delineate a new therapeutic approach for advanced melanoma.
Mechanisms of synergy between vemurafenib and immunotherapy for melanoma
Mary Jo Turk, Ph.D., Dartmouth College
Melanoma therapy has recently been revolutionized by the discovery of a new drug that targets a mutation called BrafV600E in melanoma tumors. This drug inhibitor, called vemurafenib, selectively kills melanoma cells without harming normal cells, resulting in rapid and dramatic tumor regression in as many as 80% of melanoma patients that test positive for this mutation. Unfortunately, tumors generally become resistant to treatment and eventually re-grow, indicating that vemurafenib will need to be combined with other types of treatment to best benefit patients. Interestingly, studies show that vemurafenib may make melanoma cells more sensitive to killing by immune cells, suggesting that immunotherapy may boost the effectiveness of this treatment. The proposed studies will test how vemurafenib influences immune responses to melanoma, and determine whether treatment makes melanoma tumors more visible to the immune system. These studies will also test if combining vemurafenib with a potent immunotherapy strategy can extend the lifespan of mice with melanoma. These studies will enable medical researchers to determine which combination therapies will most benefit patients with melanoma.
Angiogenesis inhibitors modulate systemic immunity in metastatic melanoma
Svetomir N. Markovic, M.D., Ph.D., Mayo Clinic Rochester d/b/a Mayo Clinic College of Medicine
Markovic evaluated the mechanisms of immune regulation of angiogenesis inhibitors (bevacizumab) administered in patients with metastatic melanoma. A combination of chemotherapy and bevacizumab resulted in normalization of system-wide immunity in patients. He plans on investigating the addition of immune modulating agents to this combination of therapy in clinical trials supported by other sponsors.
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Transcriptome sequencing to detect gene fusions in melanoma
Nallasivam Palanisamy, University of Michigan
Recurrent chromosomal aberrations are the hallmark of hematological malignancies and soft tissue sarcomas and identification of such aberrations in solid tumors are difficult due to limitations in the conventional approaches. Palanisamy will apply the newly developed next generation sequencing technology (RNAseq) and high density oligo nucleotide comparative genomic hybridization (oligo array CGH) for the comprehensive assessment of melanoma cancer genome and transcriptome to identify the disease causing genetic aberrations.
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