BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)

Melanoma is the most aggressive of the common forms of skin cancer. Although melanoma represents only ~ 5% of the skin cancers that are diagnosed each year, it is responsible for more than 70% of skin cancer-related deaths. While the incidence of many cancers has declined over the last few decades, the number of new cases of melanoma diagnosed every year continues to rise. Overall, the annual incidence of melanoma has increased over 600% since 1950. Unfortunately, many of the patients who are diagnosed with melanoma, and who ultimately succumb to the disease, are young, particularly women. Thus, melanoma has one of the highest life-years lost per cancer-related death among all malignancies. For these many reasons, melanoma is a significant disease which is likely to become an increasingly important public health issue in the future if current trends are not reversed [1].

Multiple treatment modalities are utilized in the care of melanoma patients. Surgery is the mainstay of treatment for patients with both clinically localized (i.e. cutaneous primary tumor) and regionally metastatic (i.e. regional lymph nodes or in-transit disease) disease, and may also be utilized for palliation in patients with distant metastases. Radiation therapy has a clear role for palliation of painful metastases, but its benefits in earlier, potentially curable stages of disease are less clear [2]. Systemic therapies are used in some patients to reduce the risk of relapse after surgical treatment of regional metastases [3], and they are generally the primary treatment modality for patients with distant metastases or unresectable regional tumors.

Although cytotoxic chemotherapies represent the backbone of systemic therapy for most cancers, historically these agents have demonstrated minimal benefit in patients with metastatic melanoma [4]. For example, dacarbazine (DTIC) was approved for use in metastatic melanoma in the mid-1970s despite achieving clinical responses in = 10% of patients and having no demonstrated (or appreciable) impact on median progression-free (PFS) or overall survival (OS). Combining chemotherapy agents together in various regimens resulted in increased toxicity, but no proven impact on survival [1]. With these disappointing results, other therapeutic strategies have been investigated extensively in melanoma. Much of this effort has focused on the development of agents that stimulate the immune system to attack or control the cancer, which as a class have been termed immunotherapies. High-dose bolus interleukin-2 (HD IL-2) therapy was the first such agent to gain approval in patients with metastatic melanoma, in 1998. Non-randomized studies of metastatic melanoma patients treated with HD IL-2 demonstrated that this therapy was able to achieve durable (> 10 year) disease control in metastatic melanoma patients, leading to it regulatory approval [5, 6]. However, this was only achieved in the patients who had complete responses to treatment, which only occurred in ~ 5% of patients. Overall, only 15% of patients achieved even transient clinical responses. Further, HD IL-2 therapy is extremely toxic, requiring ICU-level care to manage the many side effects of the treatment, and resulting in treatment related deaths in ~ 1% of patients in early phase clinical trials. More recently, a number of new strategies and agents have been identified to stimulate anti-tumor immune responses. Most notably, ipilimumab, an antibody that blocks the inhibitory CTLA-4 receptor on the surface of T cells, was granted regulatory approval for patients with metastatic melanoma in 2011. While ipilimumab has a moderate clinical response rate of only ~ 10%, in randomized clinical trials treatment with this agent resulted in statistically significant improvements in PFS and OS compared to controls, and a three year survival rate of ~ 25% [7, 8]. In contrast to HD IL-2, ipilimumab has very few acute side effects and can be given in the outpatient setting. However, ipilimumab can produce significant autoimmune toxicities in some patients, including colitis, hepatitis, and endocrinopathies.

A relatively new systemic therapy modality to be explored in melanoma is targeted therapy. Conceptually, targeted therapies inhibit the molecules and/or pathways that are specifically dysregulated in cancer cells. Targeted therapies have demonstrated efficacy in a number of diseases, including those that are generally refractory to chemotherapy [9]. One of the earliest examples of the potential of targeted therapy was the development of imatinib for chronic myelogenous leukemia (CML). Almost all CML cells are characterized genetically by a translocation event between chromosomes 9 and 22, resulting in the characteristic Philadelphia chromosome that is the hallmark of this disease. This genetic event produces a novel fusion protein (BCR-ALB) that includes the kinase domain of the ABL gene. Imatinib, a small molecule inhibitor of ABL and other kinases, produced marked improvements in clinical outcomes even in very early phase clinical trials in CML, and rapidly became the standard of care of patients with this disease [10]. Targeted therapies have also become the standard of care for specific, molecularly-defined subpopulations of other cancers, including breast cancers with amplification of the HER2/neu gene (trastuzumab) and lung cancers with EGFR mutations (erlotinib) [11–14]. While targeted therapies have proven clinical benefit in these populations, efficacy is frequently limited by the rapid development of resistance. An improved understanding of the mechanisms of resistance is now leading to the development of new inhibitors and/or combinatorial strategies that aim to achieve a greater degree or duration of cancer control across multiple tumor types.

Perhaps more than any other cancer, the recent history of the development of targeted therapy for melanoma demonstrates both the promise and challenges of this therapeutic strategy. Specifically, the development of targeted therapies for melanomas with activating mutations in the BRAF gene has illustrated a number of key factors in this area of research. Further, both clinical and preclinical studies have now set in motion the development of various combinatorial strategies for this disease. The following is a summary of the foundation that had led to this new era of combinatorial therapies, and the rationale behind several of the leading combinations that are being pursued.

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