Year: 2014
Type: editorial
Abstract: Tremendous progress has been made in recent years in the treatment of melanoma and in the basic understanding of pigment cell and melanoma biology. In such a fast -moving field, it is critical to identify current unmet needs from both the basic science and clinical viewpoints. We have included our perspectives in this Editorial and anticipate that some of these topics will be addressed in the presentations and abstracts for the Society of Melanoma Research 2014 Congress in Zürich, Switzerland, which are included in this issue. The unprecedented response rates of MAPK pathway-targeted therapies in BRAF-mutant melanoma have increased survival in the majority of patients treated. However, responses are generally limited to 6–18 months. Combination therapy of BRAF and MEK inhibitors lengthens the time to progression; however, responses lasting greater than 2–3 years appear to be uncommon. Dedicated efforts by many laboratories have documented a variety of resistance mechanisms. The heterogenous nature of melanomas may contribute to the diversity of resistance mechanisms observed, suggesting that there is a need to better understand melanoma heterogeneity and associated cellular plasticity in more depth. Renewed efforts should delineate mechanisms by which selected subpopulations may potentiate survival signals and alter their metabolism to allow for therapeutic resistance to emerge. Ideally, these efforts would result in combination therapies that significantly increase 5-year survival rates, or better yet, are curative. Patients with melanomas that are not driven by BRAF activating mutations do not have the option of being treated with BRAF inhibitors. Fortunately, immunomodulatory agents, including anti-CTLA-4 and anti-PD-1 antibodies, appear to be equally effective on melanomas that do not contain BRAF activating mutations. Between 15% and ~ 50% of melanoma patients have responded to this class of therapies, depending on the agent, dose, and clinical trial. For ipilimumab, the first FDA-approved drug in this class, a small median survival benefit is observed, but a durable treatment-specific survival advantage appears to be present in 10–15% of patients. Combined treatment with anti-CTLA-4 and anti-PD-1 has resulted in unprecedented 2-year survival rates of 79%. While this is very promising, not all patients respond, raising the question of why some patients respond to immune therapies and others do not. Immune-related adverse effects are a significant issue for nearly all patients undergoing these therapies. Discovering a way to retain the efficacy of these therapies and decrease the side effects would be a major advance that would be greatly appreciated by patients. Collecting on-treatment biopsies for correlative translational science efforts as an integral part of clinical trials and the use of relevant immune-competent mouse models of melanoma may help to address some of these issues. As melanoma therapies are increasingly successful at treating systemic disease, an increasing proportion of patients die of brain metastasis. Patients with melanoma brain metastases are frequently excluded from eligibility for clinical trials and as a result, rational efforts to identify therapies that effectively treat melanoma brain metastases are lagging. While many efforts are currently ongoing to characterize factors associated with brain metastasis, further resource generation is required. Specific needs include the refinement of melanoma brain metastasis models, including both human-in-mouse and immune-competent mouse-in-mouse models, as well as collection of tissue resources for the identification of genetic and cellular factors that drive human melanoma brain metastasis. Melanoma is amongst the most metastatic of all human malignancies and rarely causes death in the absence of metastasis. Despite this, the biology of metastasis is poorly understood at a more basic level. Developing approaches to understand the various steps of metastasis, the crosstalk between tumor cells and the microenvironment in establishing pre-metastatic niche(s), and determining factors that regulate dormancy or progression are key processes that need to be addressed in more detail. Better imaging tools are needed, particularly for the non-invasive imaging of early metastatic foci. As metastasis is responsible for the overwhelming majority of cancer deaths, any progress in melanoma would likely have great impact in other cancer types. At Pigment Cell & Melanoma Research, we look forward to receiving your manuscripts that address these and other unmet needs.
Source: Pigment Cell & Melanoma Research
DOI: 10.1111/pcmr.12321
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W1994172386