A Review of Novel Therapies for Melanoma

  title={A Review of Novel Therapies for Melanoma},
  author={C Karimkhani and R{\'e}n{\'e} Gonzalez and Robert Paul Dellavalle},
  journal={American Journal of Clinical Dermatology},
This review summarizes results from major recent trials regarding novel therapeutic agents in melanoma. The topics discussed include targeted therapy with BRAF (V-RAF murine sarcoma viral oncogene homolog B) inhibitors (vemurafenib and dabrafenib), MEK (mitogen-activated protein kinase kinase) inhibitors (trametinib), bcr-abl/c-kit/PDGF-R inhibitors (imatinib), and angiogenesis inhibitors (bevacizumab and aflibercept), as well as immunotherapy with anti-CTLA-4 (anti-cytotoxic T-lymphocyte… 
Immune-mediated Adverse Effects of Anti-CTLA-4 Antibody Therapy in Metastatic Melanoma
A critical evaluation of the underlying mechanisms of irAEs associated with anti-CTLA-4 therapy is presented and potentially beneficial effects of combinational therapies to alleviate ipilimumab-induced irAES in malignant melanoma are discussed.
Pembrolizumab: A Review in Advanced Melanoma
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New Mechanisms of Resistance to MEK Inhibitors in Melanoma Revealed by Intravital Imaging.
A longitudinal study tracks the course of MEKi treatment in an autochthonous imageable murine model of melanoma from initial response to therapeutic resistance, offering new insights into the basis for drug response, persistence, and resistance.
Inhibitor of vasculogenic mimicry restores sensitivity of resistant melanoma cells to DNA-damaging agents
Experimental evidence is provided that LCS1269 might be considered as a new potential anticancer agent capable of overcoming multidrug resistance for DNA-damaging agents in melanoma.
Immunovirotherapy with vesicular stomatitis virus and PD-L1 blockade enhances therapeutic outcome in murine acute myeloid leukemia.
Overall, the studies show that oncolytic virotherapy combined with immune checkpoint blockade is a promising approach to AML therapy.
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KRASi functions synergistically with BRAF inhibition to reduce melanoma proliferation and to induce apoptosis independently of BRAF mutational status, and acquired resistance to BRAF inhibitors in melanoma is dependent on dynamic regulation of KRAS expression with subsequent AKT and extracellular-signal regulated kinase activation and can be overcome by KRASi.
Abl Kinase Regulation by BRAF/ERK and Cooperation with Akt in Melanoma
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Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.
Dabrafenib and trametinib were safely combined at full monotherapy doses, and the rate of pyrexia was increased with combination therapy, whereas the rates of proliferative skin lesions was nonsignificantly reduced.
BRAF Inhibition Increases Tumor Infiltration by T cells and Enhances the Antitumor Activity of Adoptive Immunotherapy in Mice
Analysis of human melanoma patient tumor biopsies before and during BRAF inhibitor treatment showed downregulation of VEGF consistent with the preclinical murine model, providing a strong rationale to evaluate the potential clinical application of combining BRAF inhibition with T-cell–based immunotherapy for the treatment of patients with melanoma.
Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.
In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects.
Mechanisms of resistance to RAF inhibition in melanomas harboring a BRAF mutation.
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Understanding the various mechanisms of resistance will inform the attempts to prevent resistance to RAF inhibitors, and there is evidence that activation of parallel pathways, such as the PI3K/AKT pathway, may represent another mechanism of resistance.
Targeting angiogenesis in melanoma: prospects for the future
If these trials show meaningful clinical benefit, then careful consideration will need to be given when designing second-generation trials, in the light of novel gene-directed therapies currently showing promise in melanoma.
Improved survival with MEK Inhibition in BRAF-mutated melanoma for the METRIC Study Group
Tametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation.
The blockade of immune checkpoints in cancer immunotherapy
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    Nature Reviews Cancer
  • 2012
Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.
Improved survival with ipilimumab in patients with metastatic melanoma.
Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.