title: Future perspectives in melanoma research: meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014.
abstract: The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma.
authors.affiliation: Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. paolo.ascierto@gmail.com.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.affiliation: Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA. mba41@georgetown.edu.
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authors.affiliation: Translational Molecular Pathology, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA. carlo.bifulco@providence.org.
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authors.affiliation: Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. gbotti1@alice.it.
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authors.affiliation: Departments of Pathology and Laboratory Medicine and Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), John Wayne Cancer Institute, Santa Monica, CA, USA. ACochran@mednet.ucla.edu.
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authors.affiliation: Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. mdavies@mdanderson.org.
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authors.affiliation: Departments of Radiation Oncology and Pathology, Weill Cornell Medical College, New York, NY, USA. szd3005@med.cornell.edu.
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authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. sferrone@mgh.harvard.edu.
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authors.affiliation: Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. formenti@med.cornell.edu.
authors.forename: Silvia
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authors.affiliation: Departments of Medicine and of Pathology, Immunology and Cancer Program, The University of Chicago Medicine, Chicago, IL, USA. tgajewsk@medicine.bsd.uchicago.edu.
authors.forename: Thomas F
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authors.affiliation: Department of Dermatology, Center for Dermato Oncology, University of Tübingen, Tübingen, Germany. claus.garbe@med.uni-tuebingen.de.
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authors.affiliation: Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden. rolf.kiessling@ki.se.
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authors.affiliation: University of Manchester/Christie NHS Foundation Trust, Manchester, UK. paul.lorigan@christie.nhs.uk.
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authors.affiliation: Peter MacCallum Cancer Centre and University of Melbourne, Victoria, Australia. grant.mcarthur@petermac.org.
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authors.affiliation: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen, Germany. bastian.schilling@uk-essen.de.|German Cancer Consortium (DKTK), Essen, Germany. bastian.schilling@uk-essen.de.
authors.forename: Bastian
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authors.affiliation: Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany. barbara.seliger@uk-halle.de.
authors.forename: Barbara
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authors.lastname: Seliger
authors.affiliation: Cell Processing Section, Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, MD, USA. dstroncek@cc.nih.gov.
authors.forename: David
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authors.affiliation: Department of Dermatology, Johns Hopkins University SOM, Baltimore, MD, USA. jtaube1@jhmi.edu.
authors.forename: Janis
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authors.affiliation: Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar. stomei@sidra.org.
authors.forename: Sara
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authors.affiliation: Departments of Medicine, Immunology and Dermatology, University of Pittsburgh, Pittsburgh, PA, USA. zarourhm@upmc.edu.
authors.forename: Hassane M
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authors.forename: Alessandro
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authors.affiliation: Division of Translational Medicine, Sidra Medical and Research Centre, Doha, Qatar. ewang@sidra.org.
authors.forename: Ena
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authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, Université Paris Descartes, Sorbonne Paris Cité, Centre de Recherche des Cordeliers, Paris, France. jerome.galon@crc.jussieu.fr.
authors.forename: Jérôme
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authors.affiliation: Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. gennaro54.ciliberto@gmail.com.
authors.forename: Gennaro
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authors.forename: Nicola
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authors.affiliation: Sidra Medical and Research Centre, Doha, Qatar. fmarincola@sidra.org.
authors.forename: Francesco M
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authors.affiliation: Cancer Diagnosis Program, National Cancer Institute, NIH, Bethesda, MD, USA. thurinm@mail.nih.gov.
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mesh_terms: D014408:Biomarkers, Tumor; D006801:Humans; D007167:Immunotherapy; D007558:Italy; D008545:Melanoma / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor