Melanoma genotypes and phenotypes get personal.

Traditionally, the diagnosis of metastatic melanoma was terminal to most patients. However, the advancements towards understanding the fundamental etiology, pathophysiology, and treatment have raised melanoma to the forefront of contemporary medicine. Indeed, the evidence of durable remissions are being heard ever more frequently in clinics around the globe. Despite having more gene mutations per cell than any other type of cancer, investigators are overcoming complex genomic landscapes, signaling pathways, and immune checkpoints by generating novel technological methods and clinical protocols with breath-taking speed. Significant progress in deciphering molecular genetics, epigenetics, kinase-driven networks, metabolomics, and immune-enhancing pathways to achieve personalized and positive outcomes has truly provided new hope for melanoma patients. However, obstacles requiring breakthroughs include understanding the influence of sunlight exposure on melanoma etiology, and overcoming all too frequently acquired drug resistance, complicating targeted therapy. Pathologists continue to have critically important roles in advancing the field, particularly in the area of transitioning from microscope-based diagnostic reports to pharmacogenomics through molecularly informed tumor boards. Although melanoma is no longer considered just 'one disease', pathologists will continue this rapidly progressing and exciting journey to identify tumor subtypes, to utilize tumorgraft or so-called patient-derived xenograft (PDX) models, and to develop companion diagnostics to keep pace with the bewildering breakthroughs occurring on a regular basis. Exactly which combination of drugs will ultimately be required to eradicate melanoma cells remains to be determined. However, it is clear that pathologists who are as dedicated to melanoma as the pioneering pathologist Dr Sidney Farber was committed to childhood cancers, will be required as the battle against melanoma continues. In this review, we describe what sets melanoma apart from other tumors, and demonstrate how lessons learned in the melanoma clinic are being transferred to many other types of aggressive neoplasms.

Why do women with melanoma do better than men?

Harnessing female sex hormones may improve how all patients with melanoma respond to treatment.

Making melanoma therapy personal: an interview with Dr Keiran Smalley for Melanoma Management.

Dr Smalley earned his PhD in Pharmacology from the University of Cambridge, UK, in 2001. He worked as a post-doctoral fellow in the Oncology Department of University College London, the Institute of Cancer Research, Fulham Road and the Wistar Institute, PA, USA. Currently, Dr Smalley is a Professor in the Departments of Tumor Biology and Cutaneous Oncology at the Moffitt Cancer Center, FL, USA. He is also currently the Donald A Adam Endowed Chair in Melanoma Research and is the Director of the Melanoma and Skin Cancers Center of Excellence. The lab of Dr Smalley focuses upon the development of targeted therapy strategies for melanoma and is currently funded by the NCI, the pharmaceutical industry and a number of philanthropic sources. Dr Smalley's work is highly translational in nature and work from his lab has led to the initiation of a number of clinical trials. To date, Dr Smalley has published over 120 papers in top peer-reviewed journals including Cancer Research, Cancer Discovery, Cancer Cell, New England Journal of Medicine, the Proceedings of the National Academy of Sciences, the Lancet, Gastroenterology and Clinical Cancer Research. He currently sits on the editorial boards of Clinical Cancer Research, Biochemical Pharmacology, Drugs, Melanoma Research and the American Journal of Clinical Dermatology and is the Associate Editor of Pharmacological Research. Dr Smalley is a charter member of the Basic Mechanisms of Cancer Therapeutics Study Section for the NCI/NIH and has served on many other peer review panels for the Department of Defense, the state of Texas and numerous melanoma research foundations. He has also fulfilled advisory roles with the University of Pennsylvania, the University of Pittsburgh and a number of pharmaceutical companies. Dr Smalley has been a visiting professor at the University of Sao Paulo, Brazil in 2011 and in 2014 received a Science Without Borders Scholarship from the Brazilian Government.

Inhibition of BRAF and BRAF+MEK drives a metastatic switch in melanoma.

Recent analyses by our group and others showed that the majority of melanoma patients who fail BRAF inhibitor therapy do so at new disease sites. Using phosphoproteomics we showed that BRAF inhibition mediates a switch to an aggressive/metastatic melanoma phenotype that is driven by ligand-independent erythropoietin-producing hepatocellular receptor A2 (EphA2) signaling.

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. OBJECTIVE: In the current review, we discuss how differences between the preclinical and clinical settings may influence the response of melanoma cells to BRAF/MEK inhibition. As the BRAF/MEK signaling pathway is not solely responsible for the growth and survival of melanoma cells, we further discuss the therapeutic utility of inhibiting the PI3K/AKT and mTOR pathways both alone and in combination with BRAF/MEK. CONCLUSION: In looking ahead to the future, it is likely that new advances in melanoma biology, such as the identification of melanoma stem cells and a greater understanding of intratumoral heterogeneity, may play a role in the design of any future melanoma targeted therapy.

In vitro three-dimensional tumor microenvironment models for anticancer drug discovery.

Anticancer drug discovery has long been hampered by the poor predictivity of the preclinical models. There is a growing realization that the tumor microenvironment is a critical determinant of the response of cancer cells to therapeutic agents. The past 5 years have seen a great deal of progress in our understanding of how the three-dimensional microenvironment modulates the signaling behavior of tumor cells. The present review discusses how three-dimensional in vitro cell culture models can benefit cancer drug discovery through an accurate modeling of the tumor microenvironment, leading to more physiologically relevant experimental outcomes.