The incidence of melanoma has risen dramatically in recent years, but no therapy has improved overall survival for the majority of patients with unresectable metastatic disease. The University of Pittsburgh Cancer Institute (UPCI) Melanoma and Skin Cancer Program (MSCP) will continue to conduct a Specialized Program of Research Excellence (SPORE) to improve our understanding of molecular and immunologic mechanisms of cancer progression and to validate prognostic and predictive biomarkers for personalized treatment of advanced melanoma and cutaneous T cell lymphoma (CTCL). Of our 4 Projects, 1 is continued from the prior funding period, and 3 new projects have been derived from developmental research conducted in the last period;1 of the prior SPORE projects will be continued with independent ROI funding. Our highly integrated approach leverages complementary expertise in melanoma, oncology, dermatology, immunology, biostatistics, bioinformatics, machine learning, genomics, proteomics, and biomarker discovery to test hypotheses central to the improvement of therapeutic outcome in skin cancers. Regardless of clinical outcomes, these Projects will also generate urgently needed mechanistic data to inform development of new therapeutic strategies and pathways through which to monitor relapse and progression. Our 4 Projects will evaluate: (1) the prognostic and predictive value of the pro-inflammatory response and markers of immune suppression in relation to ipilimumab and interferon (IFN)? adjuvant therapy (leveraging an Eastern Cooperative Oncology Group-led adjuvant trial);(2) an engineered, 3-antigen dendritic cell vaccine and IFN? boost in patients with metastatic melanoma;(3) the safety and efficacy of vemurafenib modulation of immunotherapy with IFN?2b in patients with metastatic melanoma;and (4) an entirely new personalized microneedle vaccination technology in patients with melanoma and CTCL. The Administrative Core (A) coordinates the clinical research and provides scientific and fiscal oversight of the entire SPORE. The Biospecimen Core (B) is housed in the UPCI Immunologic Monitoring and Cellular Products Laboratory, where all tissue banking, biospecimen processing, and immune assays are conducted. The Biostatistics Core (C) and Informatics Core (D) support all projects with data analysis and management, respectively. We will continue to solicit, review, and fund applications for the career development and developmental research programs, which in the prior funding period led to the design of a new full project in this application (Project 3) and the promotion of career development recipients to co-investigators and a project leader.
The goal of this application is to use a multi-disciplinary approach to improve outcomes in skin cancer and in particular, metastatic melanoma, a disease with a 15% 5-year survival rate. We will improve treatment and outcomes for skin cancer patients by identifying new ways to treat the disease based on the biology of the individual patient's tumor and new biomarkers that predict risk and response to therapy to prevent recurrence based on an individual patient's genetics and the tumor impact upon the microenvironment.
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|Sabbatino, Francesco; Wang, Yangyang; Wang, Xinhui et al. (2014) PDGFR? up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation. Oncotarget 5:1926-41|
|Tarhini, Ahmad A; Edington, Howard; Butterfield, Lisa H et al. (2014) Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS One 9:e87705|
|Ng, Yuen-Keng; Lee, Jia-Ying; Supko, Kathryn M et al. (2014) Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment. Melanoma Res 24:207-18|
|Tarhini, Ahmad A; Shin, Donghoon; Lee, Sandra J et al. (2014) Serologic evidence of autoimmunity in E2696 and E1694 patients with high-risk melanoma treated with adjuvant interferon alfa. Melanoma Res 24:150-7|
|Pancoska, Petr; Kirkwood, John M; Bouros, Spyros et al. (2014) A new mathematical model for the interpretation of translational research evaluating six CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon. PLoS One 9:e86375|
|Tarhini, Ahmad A; Lin, Yan; Yeku, Oladapo et al. (2014) A four-marker signature of TNF-RII, TGF-?, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma. J Transl Med 12:19|
|Geskin, Larisa J; Akilov, Oleg E; Lin, Yan et al. (2014) Distinct age-matched serum biomarker profiles in patients with cutaneous T-cell lymphoma. Exp Dermatol 23:598-600|
|Schowalter, Michael K; Dulmage, Brittany O; Ho, Jonhan et al. (2014) Comparative proteomic analysis reveals unique tumor protein composition among the melanoma subtypes pure desmoplastic and superficial spreading. Melanoma Res 24:397-400|
|McArthur, Grant A; Chapman, Paul B; Robert, Caroline et al. (2014) Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 15:323-32|
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