Molecular targeted therapies in metastatic melanoma

Abstract

The advent of personalized medicine has ushered in a new era for cancer therapy with a significant impact on the management of advanced melanoma. Molecular targeted therapies have shown promise in the management of various malignancies, including melanoma, with lower toxicity profiles and better overall survival as compared with conventional therapy. The discovery of BRAF mutations in melanoma led to the development of BRAF inhibitors for the treatment of advanced melanoma. However, growing concerns over drug resistance to molecular targeted therapies including BRAF inhibitors, have spurred efforts to elucidate additional molecular targets for the treatment of advanced melanoma. In this review, we discuss the known molecular aberrations in melanoma, current and novel targeted approaches in its treatment, and drug resistance patterns.

The Antiproliferative Response of Indole-3-Carbinol in Human Melanoma Cells Is Triggered by an Interaction with NEDD4-1 and Disruption of Wild-Type PTEN Degradation

“…Disruption of PTEN causing PI3Kinase/AKT activation and NRAS/BRAF mutations leading to constitutive activation of signaling via the MAPK pathway are considered two of the key drivers of melanomagenesis (1, 2, 47). Therefore targeting components of these pathways with either single agents or combinations have been a developing therapeutic strategy in recent years.…”

“…Furthermore, given the significant degree of intratumoral heterogeneity in melanoma (1, 2), combinational therapies could conceivably be employed to simultaneously target multiple cell subpopulations within the tumor. In this regard, a combination of BRaf and MEK inhibitors (dabrafenib/trametinib) is now FDA approved for melanoma patients.…”

“…Human melanomas, which arise from melanocytes of neuro-ectodermal origin and can contain mutations in one or more tumor suppressors and/or oncogenes, are the most aggressive form of malignant skin cancers and can be remarkably resistant to conventional cancer therapies (1, 2). Natural dietary phytochemicals represent a promising but largely untapped source of chemotherapeutic agents that has the potential to control the formation, growth and metastasis of human cancers with minimal side effects, especially during prolonged treatments (3–6).…”

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

“…Despite the discovery of new cancer therapeutics (170,171,172,173,174,175,176,177), there are existing limitations to the targeted-and immune-therapy approaches (178,179) including the development of drug resistance (180). Data depicting an association of GH action and chemo-and radiotherapy refractoriness in human cancers have been scarce(141).…”

Identification of DRG-1 As a Melanoma-Associated Antigen Recognized by CD4+ Th1 Cells

“…Melanoma is the most aggressive form of skin cancer, with metastatic disease occurring in 10%–15% of patients at diagnosis [ 1 ], and is continuing to be a major health concern. The National Cancer Institute estimates that 76,100 Americans will be diagnosed with melanoma, and 9,710 will die from the disease in 2014.…”