Novel Drugs and Combination Therapies for the Treatment of Metastatic Melanoma

Vennepureddy, Adarsh; Thumallapally, Nishitha; Nehru, Vijeyaluxmy Motilal; Atallah, Jean-Paul; Terjanian, Terenig

doi:10.14740/jocmr2424w

Cited by 54 publications

(42 citation statements)

References 74 publications

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“…The BREAK trials demonstrated tumor regression and improved progression free survival in patients treated with dabrafenib 60 . The efficacy of different compounds targeting BRAF V600 demonstrated the importance of this underlying mutation in tumorigenesis.…”

Section: Expert Opinionmentioning

confidence: 99%

The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma

Kim

Cohen

2016

Expert Opinion on Drug Discovery

141

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Introduction In the era of precision medicine and sophisticated modern genetics, the discovery of the BRAFV600 inhibitor, vemurafenib, quickly became the model for targeted therapy in melanomas. As early as 2002, the majority of metastatic melanomas were described to harbor the BRAFV600 mutation, setting the stage for an explosion of interest for targeting this protein as a novel therapeutic strategy. The highly selective BRAFV600 inhibitor, vemurafenib, was identified initially through a large-scale drug screen. Areas Covered Here we examine vemurafenib's journey from discovery to clinical use in metastatic melanoma. Topics covered include preclinical data, single agent Phase 1,2 and 3 clinical trials, resistance issues and mechanisms, adverse effects including the development of squamous cell cancers, and combination trials. Expert Opinion Due to its tolerance, low toxicity profile, rapid tumor response, and improved outcomes in melanoma patients with BRAFV600 mutations, vemurafenib was advanced rapidly through clinical trials to receive FDA approval in 2011. While its efficacy is well documented, durability has become an issue for most patients who experience therapeutic resistance in approximately 6-8 months. In addition, a concerning toxicity observed in patients taking the drug include development of localized cutaneous squamous cell carcinomas (SCCs). It is hypothesized that drug resistance and SCC development result from a similar paradoxical activation of protein signaling pathways, specifically MAPK. Identification of these mechanisms has led to additional treatment strategies involving new combination therapies.

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Section: Expert Opinionmentioning

confidence: 99%

The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma

Kim

Cohen

2016

Expert Opinion on Drug Discovery

141

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“…However, targeted molecular therapies relying on blockage of altered MAPK pathway, such as BRAFV600E (e.g., vemurafenib) and MAPK/ERK kinase (MEK) (e.g., trametinib) inhibitors (23), have demonstrated only partial antitumor responses in patients (24, 25). This is largely due to the rapid emergence of drug-resistant (6) and more aggressive melanoma clones (26), reflecting the high degree of cellular plasticity of melanoma cells and possibly pre-existing heterogeneity, which is one of the major hallmarks of this aggressive disease.…”

Section: Melanomamentioning

confidence: 99%

Adapt, Recycle, and Move on: Proteostasis and Trafficking Mechanisms in Melanoma

et al. 2016

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Melanoma has emerged as a paradigm of a highly aggressive and plastic cancer, capable to co-opt the tumor stroma in order to adapt to the hostile microenvironment, suppress immunosurveillance mechanisms, and disseminate. In particular, oncogene- and aneuploidy-driven dysregulations of proteostasis in melanoma cells impose a rewiring of central proteostatic processes, such as the heat shock and unfolded protein responses, autophagy, and the endo-lysosomal system, to avoid proteotoxicity. Research over the past decade has indicated that alterations in key nodes of these proteostasis pathways act in conjunction with crucial oncogenic drivers to increase intrinsic adaptations of melanoma cells against proteotoxic stress, modulate the high metabolic demand of these cancer cells and the interface with other stromal cells, through the heightened release of soluble factors or exosomes. Here, we overview and discuss how key proteostasis pathways and vesicular trafficking mechanisms are turned into vital conduits of melanoma progression, by supporting cancer cell’s adaptation to the microenvironment, limiting or modulating the ability to respond to therapy and fueling melanoma dissemination.

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“…In comparison with standard treatment, using chemo- and/or radiotherapy, immunotherapy is relatively safe, effective, and has low-grade side effects. Consecutively, this treatment modality gained high interest in CRC, too [27, 28]. …”

Section: Discussionmentioning

confidence: 99%

Programmed death-ligand 1 expression in rectal cancer

et al. 2016

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SummaryBackgroundColorectal cancer (CRC) is the fourth most common cause of death worldwide. Approximately 30 % of all CRC occurs in the rectum. Improvements in survival rates were achieved thanks to multimodal therapy, combining surgery and chemoradiation. Nevertheless, the prognosis of patients suffering from rectal cancer (RC) remains poor. Programmed cell death protein 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1) regulate tumor immune response. The aim of this study was to analyze the expression of PD-L1 in RC pre- and post-neoadjuvant therapy and evaluate PD-L1 as a biomarker and potential target for therapy.MethodsIn all, 29 patients with RC treated at the Medical University Vienna who received preoperative chemoradiation were retrospectively enrolled in this study. Expression of PD-L1 was investigated by immunohistochemistry with two different anti-PD-L1 antibodies.ResultsNo PD-L1 expression on cancer cells could be observed in all 29 cases in the specimens before chemoradiation as well as in the surgical specimens after neoadjuvant therapy. In one of the two staining methods performed, five (17.24 %) post-chemoradiation cases showed faint lymphohistiocytic staining.ConclusionNo expression of PD-L1 in RC cells before and after chemoradiation was found in our collective of 29 patients. Further investigations to evaluate the role of PD-L1 as a potential therapeutic target in RC are urgently needed.

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Novel Drugs and Combination Therapies for the Treatment of Metastatic Melanoma

Cited by 54 publications

References 74 publications

The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma

The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma

Adapt, Recycle, and Move on: Proteostasis and Trafficking Mechanisms in Melanoma

Programmed death-ligand 1 expression in rectal cancer

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