Computational Drug Repositioning Identifies Statins as Modifiers of Prognostic Genetic Expression Signatures and Metastatic Behavior in Melanoma

Yu, Wesley Y.; Hill, Sheena T.; Chan, E. Ricky; Pink, John J.; Cooper, Kevin D.; Leachman, Sancy A.; Lund, Amanda W.; Kulkarni, Rajan P.; Bordeaux, Jeremy S.

doi:10.1016/j.jid.2020.12.015

Cited by 12 publications

(11 citation statements)

References 58 publications

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“…It was suggested that in fibroblast-led collective invasion of tumour cells, leading and following cells differ in activity and roles of RhoGTPases (Gaggioli et al 2007 ). The proposed employment of statins in the therapeutic manipulations of the tumour ecosystem harmonises with this observation (Emelyanova et al 2019 ; Ji et al 2020 ; Yu et al 2021 ).…”

Section: Discussionmentioning

confidence: 63%

Exosomes produced by melanoma cells significantly influence the biological properties of normal and cancer-associated fibroblasts

Strnadová

Pfeiferová

Přikryl

et al. 2021

Histochem Cell Biol

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The incidence of cutaneous malignant melanoma is increasing worldwide. While the treatment of initial stages of the disease is simple, the advanced disease frequently remains fatal despite novel therapeutic options . This requires identification of novel therapeutic targets in melanoma. Similarly to other types of tumours, the cancer microenvironment plays a prominent role and determines the biological properties of melanoma. Importantly, melanoma cell-produced exosomes represent an important tool of intercellular communication within this cancer ecosystem. We have focused on potential differences in the activity of exosomes produced by melanoma cells towards melanoma-associated fibroblasts and normal dermal fibroblasts. Cancer-associated fibroblasts were activated by the melanoma cell-produced exosomes significantly more than their normal counterparts, as assessed by increased transcription of genes for inflammation-supporting cytokines and chemokines, namely IL-6 or IL-8. We have observed that the response is dependent on the duration of the stimulus via exosomes and also on the quantity of exosomes. Our study demonstrates that melanoma-produced exosomes significantly stimulate the tumour-promoting proinflammatory activity of cancer-associated fibroblasts. This may represent a potential new target of oncologic therapy .

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Section: Discussionmentioning

confidence: 63%

Exosomes produced by melanoma cells significantly influence the biological properties of normal and cancer-associated fibroblasts

Strnadová

Pfeiferová

Přikryl

et al. 2021

Histochem Cell Biol

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“…Current literature on statins in melanoma has focused on melanoma initiation rather than progression [1]. In previously published work, we demonstrated that 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) influence tumor gene expression patterns and reduce metastasis in a retrospective patient cohort [2]. The effect of statins on survival in melanoma patients is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

Statin use is associated with improved overall survival in patients with melanoma

et al. 2022

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Melanoma remains a leading cause of cancer morbidity and mortality. Recent literature suggests that statin use may improve outcomes in patients with cancer. In order to determine whether statins may improve survival in melanoma patients, we analyzed data from the Veterans Health Administration Corporate Data Warehouse that contains individually identifiable clinical and demographic information from the 1990s to the present for over 19 million individual veterans. We found that melanoma patients who were taking a statin had better 5-year OS when compared with veterans not taking statins. This relationship remained significant in a multivariate model (hazard ratio, 0.38; 95% confidence interval, 0.34-0.43 for statin user vs. nonuser). Importantly, this effect was much larger than the effect of statins in the general population and was remained after controlling for the use of other medications (beta-blocker), implying that statins may have a direct effect on survival in melanoma patients. Melanoma

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“…[50][51][52] . Prognosis-related genes were used in 5 articles, employing the univariate Cox proportional hazards regression model [53][54][55] . Three articles combined DEG with other methods to build signatures, such as selecting genes satisfying both DEG and overall survival prognosis criteria [56,57] .…”

Section: Resultsmentioning

confidence: 99%

Tumor relapse-free survival prognosis related consistency between cancer tissue and adjacent normal tissue in drug repurposing for solid tumor via connectivity map

Hao,

Li,

Qiao

et al. 2024

Preprint

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Traditional drug discovery encounters challenges, including high costs, time-intensive processes, and inherent risks. Drug repurposing emerges as a compelling alternative strategy to identify new indications for investigational or approved drugs, circumventing these obstacles. Among the various drug repurposing methods, the Disease-specific Signature-based Connectivity Map (Cmap) approach is widely utilized. However, the commonly employed method for constructing disease-specific signatures, known as Differentially Expressed Genes (DEG), faces issues related to inconsistencies between dysregulated genes and the prognosis of genes in tumor tissue, as well as discrepancies in prognosis genes between tumor and normal tissues. In this study, we propose a novel approach, Prognosis Consistency Scoring (PCS), aimed at addressing these inconsistencies. PCS measures the consistency of gene prognosis between tumor and normal tissues by combining the Recurrence-Free Survival (RFS) prognosis power of genes in both contexts. Disease-specific signatures are then constructed based on PCS, and drug repurposing is performed using the Cmap and Lincs Unified Environment (CLUE). Validation of predicted drugs is conducted using data from DrugBank and ClinicalTrials databases. Our findings reveal that the aforementioned inconsistencies are pervasive. Compared to signatures based on DEGs, PCS-based signatures exhibit superior performance, identifying more drugs with higher prediction accuracy, as confirmed by DrugBank annotations. Notably, a significant proportion of predicted drugs without corresponding indications were subsequently validated in the ClinicalTrials database. Additionally, PCS-based signatures demonstrate elevated disease specificity and association with Drug Related Gene (DRG).

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Computational Drug Repositioning Identifies Statins as Modifiers of Prognostic Genetic Expression Signatures and Metastatic Behavior in Melanoma

Cited by 12 publications

References 58 publications

Exosomes produced by melanoma cells significantly influence the biological properties of normal and cancer-associated fibroblasts

Exosomes produced by melanoma cells significantly influence the biological properties of normal and cancer-associated fibroblasts

Statin use is associated with improved overall survival in patients with melanoma

Tumor relapse-free survival prognosis related consistency between cancer tissue and adjacent normal tissue in drug repurposing for solid tumor via connectivity map

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