The MAPK (ERK) Pathway: Investigational Combinations for the Treatment Of BRAF-Mutated Metastatic Melanoma.
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ABSTRACT:
SUBMITTER: McCain J
PROVIDER: S-EPMC3628180 | biostudies-literature | 2013 Feb
REPOSITORIES: biostudies-literature
Publications
The MAPK (ERK) Pathway: Investigational Combinations for the Treatment Of BRAF-Mutated Metastatic Melanoma.
P & T : a peer-reviewed journal for formulary management 20130201 2
The arrival of ipilimumab and vemurafenib has provided oncologists with new choices in a field in which options were slim and the prognosis was grim. Combination therapy may lead to an improved survival benefit. ...[more]
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Project description:Approximately half of metastatic cutaneous melanomas (CM) harbor a mutation in the BRAF protooncogene, upregulating the mitogen-activated protein kinase (MAPK)-pathway. The development of inhibitors targeting the MAPK pathway (MAPKi), i.e., BRAF- and MEK-inhibitors (BRAFi and MEKi), have substantially improved the survival in BRAFV600E/K-mutated stage IV metastatic CM. However, most patients develop resistance to treatment and no predictive biomarkers exist in practice. This study aimed at discovering plasma proteome changes during treatment MAPKi in patients with metastatic (stage IV) CM. Matched plasma samples before (pre) and during treatment (trm) from 23 patients with stage IV CM, treated with BRAF-inhibitors (BRAFi) alone or BRAF- and MEK- inhibitors combined (BRAFi and MEKi), were collected and analyzed with targeted proteomics by proximity extension assays. Additionally, plasma from 9 patients treated with BRAFi and MEKi was analyzed with in-depth high-resolution isoelectric focusing liquid-chromatography mass-spectrometry proteomics. Alterations of plasma proteins involved in granzyme and interferon gamma pathways were detected in patients treated with BRAFi, and cell adhesion-, neutrophil degranulation-, and proteolysis pathways in patients treated with BRAFi and MEKi. Several proteins were associated with progression-free survival after MAPKi treatment. We show that the majority of the altered plasma proteins were traceable to BRAFV600E-mutant metastatic CM tissue at mRNA level in 154 patients from the TCGA, further strengthening their involvement in tumoral response to treatment. This wide screen of plasma proteins unravels proteins that may serve as predictive and/or prognostic biomarkers of MAPKi treatment, opening a window of opportunity for plasma biomarker discovery in MAPKi-treatment of BRAFV600-mutant metastatic CM.
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Project description:Almost 50% of metastatic melanoma patients harbor a BRAF(V600) mutation and the introduction of BRAF inhibitors has improved their treatment options. BRAF inhibitors vemurafenib and dabrafenib achieved improved overall survival over chemotherapy and have been approved for the treatment of BRAF-mutated metastatic melanoma. However, most patients develop mechanisms of acquired resistance and about 15% of them do not achieve tumor regression at all, due to intrinsic resistance to therapy. Moreover, early adaptive responses limit the initial efficacy of BRAF inhibition, leading mostly to incomplete responses that may favor the selection of a sub-population of resistant clones and the acquisition of alterations that cause tumor regrowth and progressive disease. The purpose of this paper is to review the mechanisms of resistance to therapy with BRAF inhibitors and to discuss the strategies to overcome them based on pre-clinical and clinical evidences.
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Project description:BackgroundThe identification of somatic mutations in the gene encoding the serine-threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease.MethodsWe conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition.ResultsA total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months.ConclusionsTreatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.)
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Project description:The development of BRAF and MEK inhibitors (BRAFi/MEKi) has led to major advances in melanoma treatment. However, the emergence of resistance mechanisms limits the benefit duration and a complete response occurs in less than 20% of patients receiving BRAFi ± MEKi. In this study, we evaluated the impact of an intermittent versus continuous dosing schedule of BRAF/MEK inhibition in a melanoma model mildly sensitive to a BRAF inhibitor. The combination of a BRAFi with three different MEKi was studied with a continuous or intermittent dosing schedule in vivo, in a xenografted melanoma model and ex vivo using histoculture drug response assays (HDRAs) of patient-derived xenografts (PDX). To further understand the underlying molecular mechanisms of therapeutic efficacy, a biomarker pharmacodynamic readout was evaluated. An equal impact on tumor growth was observed in monotherapy or bitherapy regimens whether we used continuous and intermittent dosing schedules, with no significant differences in biomarkers expression between the treatments. The antitumoral effect was mostly due to modulations of expression of cell cycle and apoptotic mediators. Moreover, ex vivo studies did not show significant differences between the dosing schedules. In this context, our preclinical and pharmacodynamic results converged to show the similarity between intermittent and continuous treatments with either BRAFi or MEKi alone or with the combination of both.
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Project description:Purpose: Tumor radioresistance can be driven by ERK phosphorylation and its downstream targets. In this context, melanomas harboring constitutive MAPK/ERK activation have been considered for targeted radionuclide therapy (TRT) with a radiolabeled melanin tracer ([131I]ICF01012), alone or in combination with MEK inhibitors (MEKi). Experimental design: We used three dimensional (3D) melanoma spheroid models to evaluate the effects of TRT in combination with MEKi, in human BRAFV600E SK-MEL-3, NRASQ61K 1007 and WT B16F10 murine melanomas. TRT was assessed in vivo using the syngeneic model C57Bl5/NRAS 1007 for biodistribution, dosimetry, efficiency and molecular mechanisms. Results: In spheroids, TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant models that were resistant to TRT-induced apoptosis. However NRASQ61K spheroids were highly radiosensitive towards [131I]ICF01012-TRT. Actually, mice bearing NRAS1007 melanoma and receiving 18.5MBq of [131I]ICF01012 had a significant extended survival (median: 92 vs 44 days, p < 0.0001), associated with a 93 Gy tumor deposit, leading to a dramatic decrease of tumor growth. Furthermore, the number of lymph node metastases was reduced in mice receiving [131I]ICF01012. Comparative transcriptomic analyses confirm a decrease of mitosis, proliferation and metastasis signature in TRT-treated tumors vs control tumors. These analyses also suggest that in this NRAS-melanoma, TRT acts through an increase of oxidation and inflammation as well as P53 activation. Conclusions: Our data support the view that combining [131I]ICF01012-TRT with MEKi can be of benefit for the treatment of advanced pigmented BRAF-mutant melanoma. Likewise, [131I]ICF01012 alone can be considered as a new potential NRAS-mutant melanoma treatment.
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