The Dietary Supplement Chondroitin-4-Sulfate Exhibits Oncogene-Specific Pro-tumor Effects on BRAF V600E Melanoma Cells.

Dietary supplements such as vitamins and minerals are widely used in the hope of improving health but may have unidentified risks and side effects. In particular, a pathogenic link between dietary supplements and specific oncogenes remains unknown. Here we report that chondroitin-4-sulfate (CHSA), a natural glycosaminoglycan approved as a dietary supplement used for osteoarthritis, selectively promotes the tumor growth potential of BRAF V600E-expressing human melanoma cells in patient- and cell line-derived xenograft mice and confers resistance to BRAF inhibitors. Mechanistically, chondroitin sulfate glucuronyltransferase (CSGlcA-T) signals through its product CHSA to enhance casein kinase 2 (CK2)-PTEN binding and consequent phosphorylation and inhibition of PTEN, which requires CHSA chains and is essential to sustain AKT activation in BRAF V600E-expressing melanoma cells. However, this CHSA-dependent PTEN inhibition is dispensable in cancer cells expressing mutant NRAS or PI3KCA, which directly activate the PI3K-AKT pathway. These results suggest that dietary supplements may exhibit oncogene-dependent pro-tumor effects.

The emerging role of radiotherapy for desmoplastic melanoma and implications for future research.

The National Comprehensive Cancer Network (NCCN) 2014 guidelines are unclear about the role of radiotherapy in the management of desmoplastic melanoma. The guidelines specify that radiotherapy can be 'considered' for select patients with desmoplastic melanoma with narrow surgical margins. Patient selection criteria, including margins, are not well defined, causing considerable differences in practice patterns across the country. There are also several conflicting reports about the role of radiotherapy in improving postsurgical outcomes when other adverse pathological risks factors, such as increased Clark level, head and neck involvement, perineural invasion, positive margins, or recurrent disease, are also present. Recent data provide further clarification and insights into the role of radiotherapy. Thus, in light of the NCCN guidelines and the recently published series, we critically review the role of radiotherapy for desmoplastic melanoma. In our review, we highlight the published risk factors that predict for increased risk of recurrence after surgery. We also provide a comparison of surgical and radiation outcomes data, and then address areas for further research.

Targeting mutant BRAF in melanoma: current status and future development of combination therapy strategies.

The discovery of activating BRAF mutations in ∼50% of all melanomas has proved to be a turning point in the therapeutic management of the disseminated disease. In this commentary, we review the latest research delineating the role of mutant BRAF in melanoma initiation and progression and discuss the remarkable 10-year journey leading up to the recent U.S. Food and Drug Administration approval of the small-molecule BRAF inhibitor vemurafenib. We further outline the most recent findings on the mechanisms that underlie intrinsic and acquired BRAF inhibitor resistance and describe ongoing preclinical and clinical studies designed to delay or abrogate the onset of therapeutic escape. It is hoped that our evolving understanding of melanoma genetics and intracellular signaling coupled with a growing armamentarium of signal transduction inhibitors will lead to significant improvements in the level and durability of therapeutic response in metastatic melanoma.

Novel targeted therapies for the treatment of metastatic melanoma.

The National Comprehensive Cancer Network guidelines for the treatment of stage IV metastatic melanoma state that clinical trials should be the preferred treatment option for these patients; therefore, clinical trials for these patients are the "standard of care." Our greater understanding of the molecular biology behind the development of melanoma has guided much of the translational research in this disease and has led to the development of novel targeted therapies. Specifically, advancement in our knowledge of alterations in signal transduction pathways in melanoma has led to the rapid development of a number of pharmacologic agents that inhibit these pathways. This review will discuss changes in signal transduction pathways involved in melanoma, specifically, activated mitogen-activated protein kinase, activated PI3 kinase, and inactivated p53/Rb pathways. This article will also review new targeted therapy in the context of the molecular biology of melanoma.