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Oncogene-directed small molecule inhibitors for the treatment of cutaneous melanoma.

ABSTRACT: Achievements in cancer genetics and molecular biology have revolutionized the treatment options available for advanced melanoma. Patients with certain molecularly defined melanomas have been the most fortunate beneficiaries of recently US FDA-approved therapies that target aberrant MAPK pathway signaling, yet response rates and duration of response remain suboptimal. Furthermore, many patients harbor melanomas for which no approved targeted therapies currently exist. Since the approval of vemurafenib, a selective BRAF V600E inhibitor, in 2011, there has been a surge of preclinical and clinical studies aimed at developing novel targeted therapies for a wide range of molecularly defined melanomas. In this review, we will examine the present status and future potential of molecularly targeted therapies directed at the most significant oncogenic signaling pathways in melanoma.

SUBMITTER: Eliades P

PROVIDER: S-EPMC6094676 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Oncogene-directed small molecule inhibitors for the treatment of cutaneous melanoma.

Eliades Philip P Flaherty Keith T KT Tsao Hensin H

Melanoma management 20150518 2

Achievements in cancer genetics and molecular biology have revolutionized the treatment options available for advanced melanoma. Patients with certain molecularly defined melanomas have been the most fortunate beneficiaries of recently US FDA-approved therapies that target aberrant MAPK pathway signaling, yet response rates and duration of response remain suboptimal. Furthermore, many patients harbor melanomas for which no approved targeted therapies currently exist. Since the approval of vemura ...[more]

PMID: 30190843

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Project description:Therapeutic targeting of host cell factors required for virus replication rather than of pathogen components opens new perspectives to counteract virus infections. Anticipated advantages of this approach include a heightened barrier against the development of viral resistance and a broadened pathogen target spectrum. Myxoviruses are predominantly associated with acute disease and thus are particularly attractive for this approach since treatment time can be kept limited. To identify inhibitor candidates, we have analyzed hit compounds that emerged from a large-scale high-throughput screen for their ability to block replication of members of both the orthomyxovirus and paramyxovirus families. This has returned a compound class with broad anti-viral activity including potent inhibition of different influenza virus and paramyxovirus strains. After hit-to-lead chemistry, inhibitory concentrations are in the nanomolar range in the context of immortalized cell lines and human PBMCs. The compound shows high metabolic stability when exposed to human S-9 hepatocyte subcellular fractions. Antiviral activity is host-cell species specific and most pronounced in cells of higher mammalian origin, supporting a host-cell target. While the compound induces a temporary cell cycle arrest, host mRNA and protein biosynthesis are largely unaffected and treated cells maintain full metabolic activity. Viral replication is blocked at a post-entry step and resembles the inhibition profile of a known inhibitor of viral RNA-dependent RNA-polymerase (RdRp) activity. Direct assessment of RdRp activity in the presence of the reagent reveals strong inhibition both in the context of viral infection and in reporter-based minireplicon assays. In toto, we have identified a compound class with broad viral target range that blocks host factors required for viral RdRp activity. Viral adaptation attempts did not induce resistance after prolonged exposure, in contrast to rapid adaptation to a pathogen-directed inhibitor of RdRp activity.

Project description:BackgroundLack of biomarkers and in vitro models has contributed to inadequate understanding of the mechanisms underlying the inferior clinical response to immune checkpoint inhibitors (ICIs) in patients with oncogene-driven non-small cell lung cancer (NSCLC).MethodsThe effect of small molecule tyrosine kinase inhibitors (TKIs) on peripheral blood mononuclear cells (PBMCs) in 34 patients with oncogene-driven NSCLC (cohort A) was compared with those from 35 NSCLC patients without oncogene-driven mutations received ICI (cohort B) or from 22 treatment-naïve NSCLC patients (cohort C). Data for each blood biomarker were summarized by mean and standard deviation and compared by Wilcoxon rank sum tests or Kruskal-Wallis tests with significance at 2-sided p value < 0.05. Co-culture of PBMCs and pleural effusion-derived tumor cells from individual patients with oncogene-driven NSCLC was used to determine the in vitro cytotoxicity of TKI and ICI.ResultsExcept for low CD3% in cohort A, there were no significant differences in other 12 blood biomarkers among the 3 cohorts at baseline. TKI treatment in cohort A was associated with significant increase in CD3% and decrease in total and absolute neutrophils (p < 0.05). In cohort B, patients with good clinical response to ICI treatment (N = 18) had significant increases in absolute lymphocyte counts (ALCs), CD4 and/or CD8 cell counts. Conversely, those patients with poor clinical response to ICI (N = 17) had significant decreases in these cell counts. Of the 27 patients with pre- and post-treatment blood samples in cohort A, 11 had poor clinical response to TKIs and decreased lymphocyte counts. Of the remaining 16 patients who had good clinical response to TKI therapy, 10 (62.5%) patients had decreased, and 6 (37.5%) patients had increased lymphocyte counts. Multicolor immunophenotyping of PBMCs revealed ICI treatment activated additional immune cell types that need further validation. We confirmed that TKI treatment could either antagonize or enhance the effect of ICIs in the co-culture assay using patient's tumor cells and PBMCs.ConclusionsTo the best of our knowledge, this is the first study showing that TKIs can have various effects on blood immune cells, which may affect their response to ICIs. Further validation of the blood biomarker and in vitro assay is warranted.

Dataset Information

Oncogene-directed small molecule inhibitors for the treatment of cutaneous melanoma.

Publications

Oncogene-directed small molecule inhibitors for the treatment of cutaneous melanoma.

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