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Objectives: • Gather a panel of Latin American experts in testing and treating BRAF -melanoma. • Describe the current landscape of BRAF -mutated melanoma in Latin America. • Outline the current gaps in testing and recommend improvements for testing and treating BRAF -mutated melanoma in the region., Introduction: Melanoma prevalence in Latin America is lower than in high- and middle-income countries. However, recent data indicate that the region's incidence and mortality are rising, with more stage IV patients being diagnosed. According to international clinical practice guidelines, conducting BRAF -mutation testing in patients with stage III or stage IV melanoma and high-risk resected disease is imperative. Still, BRAF -mutation testing and targeted therapies are inconsistently available in the region., Methods: Americas Health Foundation convened a meeting of Latin American experts on BRAF -mutated melanoma to develop guidelines and recommendations for diagnosis through treatment., Results and Conclusions: Some recommendations for improving diagnostics through improving access and reducing the cost of BRAF -mutation testing, enhancing efficiency in pathology laboratories, and creating country-specific local guidelines. The panel also gave treatment recommendations for neo-adjuvant therapy, adjuvant therapy, and therapy for patients with metastatic disease in Latin America., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Melanoma represents an increasing public health burden with extensive unmet needs in Latin America (LA). A mutation in the BRAF gene is present in approximately 50% of all melanomas in White populations and is a target of precision medicine, with the potential to dramatically improve patient outcomes. Thus, increased access to BRAF testing and therapy is LA must be explored. At a multi-day conference, a panel of Latin American experts in oncology and dermatology were provided with questions to address the barriers limiting access to testing for BRAF mutation in patients with melanoma in LA, who may be eligible for targeted therapy to improve their prognosis. During the conference, responses were discussed and edited until a consensus on addressing the barriers was achieved. Identified challenges included ignorance of BRAF -status implications, limited human and infrastructural resources, affordability and reimbursement, fragmented care delivery, pitfalls in the sample journey, and lack of local data. Despite the clear benefits of targeted therapies for BRAF -mutated melanoma in other regions, there is no clear path to prepare LA for a sustainable personalized medicine approach to this disease. Due to melanoma's time-sensitive nature, LA must aim to provide early access to BRAF testing and consider mutational status within treatment decision making. To this end, recommendations are provided and include establishing multidisciplinary teams and melanoma referral centers and improving access to diagnosis and treatment., Competing Interests: GC received: grants or had contracts from Novartis, Merck Sharp & Dohme, Pfizer, Roche/Genentech, Bristol Myers Squibb, Array, Springer, Grupo Español de Melanoma; consulting fees from Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, Roche/Genentech; honoraria for presentations from Novartis, Merck Sharp & Dohme, Pfizer, Roche, Bristol Myers Squibb, Array, Springer, and Grupo Español de Melanoma; support for attending meetings from Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Roche; payment for board participation from Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Roche/Genentech. AM’s institution received grants from Clovis Oncology, Regeneron, Merck Sharp & Dohme, Bristol Myers Squibb, GlaxoSmithKline, AstraZeneca, Novartis, Amgen, and Roche for clinical trials. AM received payment for lectures from Merck Sharp & Dohme, Bristol Myers Squibb, GlaxoSmithKline, AstraZeneca, Novartis, Roche, Sanofi. Advisory Board participation from Merck Sharp & Dohme, Bristol Myers Squibb, GlaxoSmithKline, AstraZeneca, Novartis, Roche. RS received: consulting fees from Merck Sharp & Dohme and L’Oreal; payment for presentations from Merck Sharp & Dohme, Bristol Myers Squibb, Sanofi Genzyme, Pfizer, Merck Serono, Novartis; support from Bristol Myers Squibb for expert testimony; support for attending meetings from Sanofi Genzyme and Merck Sharp & Dohme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Salman, de Melo, Rico-Restrepo, Rodriguez, Russi, Schmerling, Zambrano and Cinat.)

The overexpression of chondroitin sulfate proteoglycan 4 (CSPG4) is associated with several tumor types, including malignant melanoma, squamous cell carcinoma, triple‑negative breast carcinoma, oligodendrocytomas or gliomas. Due to its restricted distribution in normal tissues, CSPG4 has been considered a potential target for several antitumor approaches, including monoclonal antibody (mAb) therapies. The aim of the present study was to characterize the impact of the CSPG4‑specific mAb clone 9.2.27 on its own or in combination with the commonly used BRAF‑selective inhibitor, PLX4032, on different functions of melanoma cells to assess the potential synergistic effects. The BRAF V600‑mutant human melanoma cell lines, M14 (CSPG4‑negative) and WM164 (CSPG4‑positive), were exposed to the CSPG4‑specific 9.2.27 mAb and/or PLX4032. Cell viability and colony formation capacity were evaluated. A 3D‑cell culture spheroid model was used to assess the invasive properties of the treated cells. In addition, flow cytometric analysis of apoptosis and cell cycle analyses were performed. Incubation of the WM164 cell line with CSPG4‑specific 9.2.27 mAb decreased viability, colony formation ability and the invasive capacity of CSPG4‑positive tumor cells, which was not the case for the CSPG4‑negative M14 cell line. Combined treatment of the WM164 cells with 9.2.27 mAb plus PLX4032 did not exert any significant additional effect in comparison to treatment with PLX4032 alone in the clonogenic and invasion assays. M14 cell cycle distribution was not influenced by the CSPG4‑specific 9.2.27 mAb. By contrast, the exposure of WM164 cells to the mAb resulted in an arrest of the cells in the S phase. Moreover, combined treatment of the WM164 cells led to a significantly increased accumulation of cells in the subG1 phase, combined with a decrease of cells in the G2/M phase. On the whole, findings of the present study indicate that the CSPG4‑specific 9.2.27 mAb exerts an anti‑invasive effect on CSPG4‑positive melanoma spheroids, which is not enhanced by BRAF inhibition. These findings provide the basis for further investigations on the effects of anti‑CSPG4‑based treatments of CSPG4‑positive tumors.

Leptomeningeal metastases (LM) from solid tumors represent an unmet need of increasing importance due to an early use of MRI for diagnosis and improvement of outcome of some molecular subgroups following targeted agents and immunotherapy. In this review, we first discussed factors limiting the efficacy of targeted agents in LM, such as the molecular divergence between primary tumors and CNS lesions and CNS barriers at the level of the normal brain, brain tumors and CSF. Further, we reviewed pathogenesis and experimental models and modalities, such as MRI (with RANO and ESO/ESMO criteria), CSF cytology and liquid biopsy, to improve diagnosis and monitoring following therapy. Efficacy and limitations of targeted therapies for LM from EGFR-mutant and ALK-rearranged NSCLC, HER2-positive breast cancer and BRAF-mutated melanomas are reported, including the use of intrathecal administration or modification of traditional cytotoxic compounds. The efficacy of checkpoint inhibitors in LM from non-druggable tumors, in particular triple-negative breast cancer, is discussed. Last, we focused on some recent techniques to improve drug delivery.

Chondroitin sulfate proteoglycan 4 (CSPG4) is a multifunctional transmembrane proteoglycan involved in spreading, migration and invasion of melanoma. In addition to the activating BRAF V600E mutation, CSPG4 was shown to promote MAPK signaling by mediating the growth‑factor induced activation of receptor tyrosine kinases. However, it remains elusive which factors regulate CSPG4 expression. Therefore, the aim of the present study was to examine whether BRAF and MEK inhibitors have an effect on the expression of CSPG4. We exposed a panel of BRAF‑mutant CSPG4‑positive or ‑negative melanoma cell lines to BRAF and MEK inhibitors. Protein levels of CSPG4 were analyzed by flow cytometry (FACS), immunofluorescence microscopy (IF), and western blotting. CSPG4 mRNA levels were determined by quantitative PCR (qPCR). The prolonged exposure of cells to BRAF and MEK inhibitors resulted in markedly reduced levels of the CSPG4 protein in permanent resistant melanoma cells as well as decreased levels of its mRNA. We did not observe increasing levels of CSPG4 shedding into the culture supernatants. In addition, patient‑derived matched tumor samples following therapy with kinase inhibitors showed decreased numbers of CSPG4‑positive cells as compared to pre‑therapy tumor samples. Our results indicate that BRAF and MEK inhibition downregulates CSPG4 expression until the cells have developed permanent resistance. Our findings provide the basis for further investigation of the role of CSPG4 in the development of drug‑resistance in melanoma cells.

Background: The spectrum of treatment options for patients with metastatic BRAF-mutated melanoma is broad, spanning multiple treatment classes. However, there is a lack of head-to-head evidence comparing targeted and immunotherapies. The purpose of this study is to conduct a network meta-analysis (NMA) in previously untreated, BRAF-mutated melanoma patients and estimate the relative efficacy of systemic therapies for this patient population at the treatment level., Methods: The literature review included searches of MEDLINE, EMBASE, and the Cochrane Central Registry of Controlled Trials (CENTRAL) to November 2018. Randomized controlled trials of previously untreated patients with advanced melanoma were eligible if at least one intervention was either a targeted or immune therapy. Relative treatment effects were estimated by fixed effect Bayesian NMAs on progression-free survival (PFS) and overall survival (OS), based on the hazard ratio., Results: Combination dabrafenib with trametinib (HR 0.22 [95% CrI 0.17, 0.28] vs dacarbazine) and combination vemurafenib with cobimetinib (HR 0.22 [95% CrI 0.17, 0.29] vs dacarbazine) were likely to rank as the most favorable treatment options for PFS, while combination nivolumab with ipilimumab was likely to be the most efficacious in terms of OS (HR 0.33 [0.24, 0.47] vs dacarbazine)., Conclusions and Relevance: The findings highlight the efficacy of combination PD-1 with CTLA-4 inhibitors and combination BRAF with MEK inhibitors in the treatment of advanced melanoma. However, as few trials informed each treatment comparison, research is needed to further refine our understanding of this complex and rapidly evolving treatment landscape., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Although significant progress has been made in the treatment of unresectable or metastatic melanoma, at least half of all advanced melanoma patients eventually progress and pass away due to their disease. In particular, patients with NRAS-mutated melanoma still face limited therapeutic options, with immunotherapy being the current treatment type of choice. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. The results of a recent Phase III trial rendered binimetinib the first targeted therapy agent to significantly improve progression-free survival in NRAS-mutated melanoma. This review will summarize the development and clinical data of binimetinib in melanoma in general and also explore the potential future role of this substance as single agent or combination therapy.

The RAS-ERK pathway plays a major regulatory role in various cellular processes. This pathway is hyperactivated and takes an active part in the malignant transformation of more than 85% of cancers. The hyperactivation is mainly due to oncogenic activating mutations in the pathway's components RAS, RAF and MEK, but also due to indirect mechanisms in cells transformed by other oncogenes. Various inhibitors targeting the different tiers of the cascade have been successfully developed and clinically approved, while some are still undergoing preclinical and clinical evaluation. Treatments with the clinically approved RAF and MEK inhibitors have substantially improved the clinical outcome of metastatic mutated-BRAF melanoma. However, the rapid emergence of drug resistance of initially responsive cancers and limited efficacy towards other cancers has led to only marginal patient benefit. Deciphering the molecular mechanisms underlying intrinsic or acquired resistance is a necessity in order to enhance the treatment efficacy of ERK-addicted cancers. Therefore, many studies in the past 5 years embarked on this campaign, revealing several resistance mechanisms. These include, expression of drug-resistant RAF isoforms, molecular or genetic alterations of active downstream components, overexpression of upstream components of the cascade that can reactivate ERK and other survival-related pathways. The understanding of these molecular resistance mechanisms led to further development of drugs that can overcome drug resistance, including our own effort aiming to prevent the nuclear translocation of ERK without affecting its activation. In this review we will focus on the mechanisms underlying drug resistance and efforts to develop activity-independent, more efficacious, antitumor drugs., (Copyright © 2016 Elsevier Ltd. All rights reserved.)