Future perspectives in melanoma research

Meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014

Paolo A. Ascierto, Michael Atkins, Carlo Bifulco, Gerardo Botti, Alistair Cochran, Michael Davies, Sandra Demaria, Reinhard Dummer, Soldano Ferrone, Silvia Formenti, Thomas F. Gajewski, Claus Garbe, Samir Khleif, Rolf Kiessling, Roger Lo, Paul Lorigan, Grant Mc Arthur, Giuseppe Masucci, Ignacio Melero, Martin Mihm & 17 others Giuseppe Palmieri, Giorgio Parmiani, Igor Puzanov, Pedro Romero, Bastian Schilling, Barbara Seliger, David Stroncek, Janis Taube, Sara Tomei, Hassane M. Zarour, Alessandro Testori, Ena Wang, Jérôme Galon, Gennaro Ciliberto, Nicola Mozzillo, Francesco M. Marincola, Magdalena Thurin

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Article number374
JournalJournal of Translational Medicine
Volume13
Issue number1
DOIs
Publication statusPublished - 30 Nov 2015

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Mitogen-Activated Protein Kinases
Melanoma
Biomarkers
Phosphatidylinositol 3-Kinase
Tumors
Mitogen-Activated Protein Kinase Kinases
CD274 Antigen
Immunology
Blocking Antibodies
Angiogenesis Inhibitors
Chemotherapy
Radiotherapy
Receptor Protein-Tyrosine Kinases
Cell death
Sirolimus
Therapeutics
Tumor Biomarkers
Surgery
Immunotherapy
Cells

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Future perspectives in melanoma research : Meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014. / Ascierto, Paolo A.; Atkins, Michael; Bifulco, Carlo; Botti, Gerardo; Cochran, Alistair; Davies, Michael; Demaria, Sandra; Dummer, Reinhard; Ferrone, Soldano; Formenti, Silvia; Gajewski, Thomas F.; Garbe, Claus; Khleif, Samir; Kiessling, Rolf; Lo, Roger; Lorigan, Paul; Arthur, Grant Mc; Masucci, Giuseppe; Melero, Ignacio; Mihm, Martin; Palmieri, Giuseppe; Parmiani, Giorgio; Puzanov, Igor; Romero, Pedro; Schilling, Bastian; Seliger, Barbara; Stroncek, David; Taube, Janis; Tomei, Sara; Zarour, Hassane M.; Testori, Alessandro; Wang, Ena; Galon, Jérôme; Ciliberto, Gennaro; Mozzillo, Nicola; Marincola, Francesco M.; Thurin, Magdalena.

In: Journal of Translational Medicine, Vol. 13, No. 1, 374, 30.11.2015.

Research output: Contribution to journalArticle

Ascierto, PA, Atkins, M, Bifulco, C, Botti, G, Cochran, A, Davies, M, Demaria, S, Dummer, R, Ferrone, S, Formenti, S, Gajewski, TF, Garbe, C, Khleif, S, Kiessling, R, Lo, R, Lorigan, P, Arthur, GM, Masucci, G, Melero, I, Mihm, M, Palmieri, G, Parmiani, G, Puzanov, I, Romero, P, Schilling, B, Seliger, B, Stroncek, D, Taube, J, Tomei, S, Zarour, HM, Testori, A, Wang, E, Galon, J, Ciliberto, G, Mozzillo, N, Marincola, FM & Thurin, M 2015, 'Future perspectives in melanoma research: Meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014', Journal of Translational Medicine, vol. 13, no. 1, 374. https://doi.org/10.1186/s12967-015-0736-1
Ascierto, Paolo A. ; Atkins, Michael ; Bifulco, Carlo ; Botti, Gerardo ; Cochran, Alistair ; Davies, Michael ; Demaria, Sandra ; Dummer, Reinhard ; Ferrone, Soldano ; Formenti, Silvia ; Gajewski, Thomas F. ; Garbe, Claus ; Khleif, Samir ; Kiessling, Rolf ; Lo, Roger ; Lorigan, Paul ; Arthur, Grant Mc ; Masucci, Giuseppe ; Melero, Ignacio ; Mihm, Martin ; Palmieri, Giuseppe ; Parmiani, Giorgio ; Puzanov, Igor ; Romero, Pedro ; Schilling, Bastian ; Seliger, Barbara ; Stroncek, David ; Taube, Janis ; Tomei, Sara ; Zarour, Hassane M. ; Testori, Alessandro ; Wang, Ena ; Galon, Jérôme ; Ciliberto, Gennaro ; Mozzillo, Nicola ; Marincola, Francesco M. ; Thurin, Magdalena. / Future perspectives in melanoma research : Meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014. In: Journal of Translational Medicine. 2015 ; Vol. 13, No. 1.
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AU - Botti, Gerardo

AU - Cochran, Alistair

AU - Davies, Michael

AU - Demaria, Sandra

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AU - Puzanov, Igor

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AU - Seliger, Barbara

AU - Stroncek, David

AU - Taube, Janis

AU - Tomei, Sara

AU - Zarour, Hassane M.

AU - Testori, Alessandro

AU - Wang, Ena

AU - Galon, Jérôme

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AU - Mozzillo, Nicola

AU - Marincola, Francesco M.

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AB - 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.

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