Targeting BRAF in Advanced Melanoma: A First Step toward Manageable Disease

Program of Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Clinical Cancer Research (Impact Factor: 8.72). 03/2011; 17(7):1658-63. DOI: 10.1158/1078-0432.CCR-10-0174
Source: PubMed


Melanoma is the deadliest form of skin cancer and its incidence has been increasing worldwide. The disease manifests itself as clinically and genetically distinct subgroups, indicating the need for patient-specific diagnostic and treatment tools. The discovery of activating mutations (V600E) in the BRAF kinase in approximately 50% of patients spurred the development of compounds to inhibit aberrant BRAF activity, and the first drug candidate to show promising clinical activity is PLX4032 (also known as RG7204). Most recent clinical data from a phase II trial indicate that PLX4032 causes tumor regression and stabilized disease in >50% of advanced melanoma patients harboring BRAF V600E tumors. These data validate the effectiveness of oncogene-targeted therapy against advanced melanoma and offer hope that the disease can be overcome. However, as melanoma is dynamic and heterogeneous, careful treatment strategies and combination therapies are warranted to obtain long-term clinical effects.

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    • "Each of those three kinases may activate the next stage of the pathway, MEK1 or MEK2 kinases. The following stage of the pathway is kinases ERK1 and ERK2 that either phosphorylate cytoplasmic proteins or migrate into the cell nucleus influencing the transcription factors regulating proliferation, differentiation, and genes connected with these processes [7] [8] [9]. "
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    ABSTRACT: The incidence of malignant melanoma is increasing. The majority of patients are diagnosed in early stages when the disease is highly curable. However, the more advanced or metastatic cases have always been a challenge for clinicians. The poor prognosis for patients with melanoma is now changing as numerous of promising approaches have appeared recently. The discovery of aberrations of pathways responsible for intracellular signal transduction allowed us to introduce agents specifically targeting the mutated cascades. Numerous clinical studies have been conducted to improve effectiveness of melanoma treatment. From 2011 until now, the U.S. FDA has approved seven novel agents, such as BRAF-inhibitors (vemurafenib 2011, dabrafenib 2013), MEK-inhibitors (trametinib 2013), anti-PD1 antibodies (nivolumab 2014, pembrolizumab 2014), anti-CTLA-4 antibody (ipilimumab 2011), or peginterferon-alfa-2b (2011) intended to be used in most advanced cases of melanoma. Nevertheless, clinicians continue working on new possible methods of treatment as resistance to the novel drugs is a commonly observed problem. This paper is based on latest data published until the end of January 2015.
    07/2015; 2015:1-16. DOI:10.1155/2015/851387
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    • "Although melanoma metastases have been found to contain thousands of mutations, the V600E BRAF mutation is clearly a driver of the neoplastic phenotype and is present in approximately 50% of melanomas [5,18]. The discovery of activating mutations (V600E) in the BRAF kinase encouraged the development of compounds to inhibit aberrant BRAF activity [5]. "
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    ABSTRACT: Background BRAF inhibitors such as vemurafenib are a new family of biological drugs, recently available to treat metastatic malignant melanoma. Methods We present the case of a 38-year-old man affected by metastatic melanoma who had been under treatment with vemurafenib for a few days. The patient suffered from sudden onset of abdominal pain due to intra-abdominal hemorrhage with profuse hemoperitoneum. An emergency abdominal sonography confirmed the clinical suspicion of a splenic rupture. Results The intraoperative finding was hemoperitoneum due to splenic two-step rupture and splenectomy was therefore performed. Histopathology confirmed splenic hematoma and capsule laceration, in the absence of metastasis. Conclusions This report describes the occurrence of a previously unreported adverse event in a patient with stage IV melanoma receiving vemurafenib.
    World Journal of Surgical Oncology 07/2012; 10(1):155. DOI:10.1186/1477-7819-10-155 · 1.41 Impact Factor
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    • "For example, activating mutations in BRAF have been found to occur commonly in melanoma [31], and pimozide is more effective in tumors containing this mutation. Just as pimozide shows enhanced efficacy in CML when combined with BCR/ABL inhibitors, pimozide may be particularly useful in melanoma when combined with BRAF inhibitors [32, 33]. In addition, pimozide appears to be more effective in tumors that contain wildtype p53, which raises both mechanistic questions regarding STAT3 inhibitors in general and these drugs in particular. "
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    ABSTRACT: STAT transcription factors transduce signals from the cell surface to the nucleus, where they regulate the expression of genes that control proliferation, survival, self-renewal, and other critical cellular functions. Under normal physiological conditions, the activation of STATs is tightly regulated. In cancer, by contrast, STAT proteins, particularly STAT3 and STAT5, become activated constitutively, thereby driving the malignant phenotype of cancer cells. Since these proteins are largely dispensable in the function of normal adult cells, STATs represent a potentially important target for cancer therapy. Although transcription factors have traditionally been viewed as suboptimal targets for pharmacological inhibition, chemical biology approaches have been particularly fruitful in identifying compounds that can modulate this pathway through a variety of mechanisms. STAT inhibitors have notable anti-cancer effects in many tumor systems, show synergy with other therapeutic modalities, and have the potential to eradicate tumor stem cells. Furthermore, STAT inhibitors identified through the screening of chemical libraries can then be employed in large scale analyses such as gene expression profiling, RNA interference screens, or large-scale tumor cell line profiling. Data derived from these studies can then provide key insights into mechanisms of STAT signal transduction, as well as inform the rational design of targeted therapeutic strategies for cancer patients.
    Oncotarget 06/2011; 2(6):518-24. DOI:10.18632/oncotarget.296 · 6.36 Impact Factor
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