Understanding melanoma signaling networks as the basis for molecular targeted therapy.

Despite years of research, there has been little improvement in survival for patients with disseminated melanoma. Recent work has identified mutations in BRAF and NRAS, leading to constitutive mitogen-activated protein kinase (MAPK) pathway as well as constitutive activity in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, as being critical events in melanoma growth and progression. In the current review, we discuss how these complex mutational and signaling profiles can be understood using a network biology approach, and suggest how an understanding of the key signaling nodes involved in progression and survival will lead to improvements in melanoma therapy.

The future of targeted therapy approaches in melanoma.

Background: The past 30 years have seen little improvement in the survival of patients with stage IV melanoma. Following the discovery of activating BRAF mutations in most melanomas, a wealth of preclinical experimentation has validated the BRAF/MAPK pathway as an excellent therapeutic target in melanoma. Despite these encouraging results, early clinical trials on BRAF/MAPK inhibition have been disappointing.

c-KIT signaling as the driving oncogenic event in sub-groups of melanomas.

As we enter the era of targeted therapy for melanoma, attempts are being made to sub-group tumors on the basis of their driving oncogenic mutations, with the hope of developing truly personalized therapeutic regimens. c-KIT is a receptor tyrosine kinase whose aberrant activation is implicated in the progression of gastrointestinal stromal tumors and some acute myeloid leukemias. The role of c-KIT signaling in melanoma has been controversial; although c-KIT activity is critical to melanocyte development, its expression tends to be lost in most melanomas.

Ipilimumab: controversies in its development, utility and autoimmune adverse events.

A promising new class of anti-cancer drugs includes antibodies that mediate immune regulatory effects. It has become very clear over the last decade that different types of immune cells and different pathways serve to suppress anti-cancer immunity, particularly in the microenvironment of the tumor. The first examples of immune modulating antibodies are those directed against cytotoxic T lymphocyte antigen-4 (CTLA-4), a molecule present on activated T cells.

Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events.

The immune system is a powerful natural agent against cancer. Cytotoxic T lymphocyte antigen 4 (CTLA-4), a key negative regulator of T-cell responses, can restrict the antitumor immune response. Ipilimumab (MDX-010) is a fully human, monoclonal antibody that overcomes CTLA-4-mediated T-cell suppression to enhance the immune response against tumors.

A phase III trial evaluating the combination of cisplatin, etoposide, and radiation therapy with or without tamoxifen in patients with limited-stage small cell lung cancer: Cancer and Leukemia Group B Study (9235).

Based on both clinical and laboratory data that suggested that tamoxifen (TAM) enhanced the effectiveness of cisplatin (DDP)-based chemotherapy regimens, the Cancer and Leukemia Group B (CALGB) designed and initiated a prospective, randomized phase III trial to test the efficacy of the addition of high-dose TAM to a standard chemoradiation regimen of DDP and etoposide (VP-16) in patients with limited-stage small cell lung cancer (LS-SCLC). Between August 6, 1993, and January 15, 1999, 319 patients with LSSCLC were accrued to CALGB 9235. Patients were randomized to receive chemotherapy with or without high-dose TAM.