Computational repurposing of therapeutic small molecules from cancer to pulmonary hypertension

Negi, Vinny; Yang, Jeyul; Speyer, Gil; Pulgarin, Andres; Handen, Adam; Zhao, Jingsi; Tai, Yi Yin; Tang, Ying; Culley, Miranda K.; Yu, Qingzhen; Forsythe, P.; Gorelova, Anastasia; Watson, Annie; Aaraj, Yassmin Al; Satoh, Taijyu; Sharifi‐Sanjani, Maryam; Rajaratnam, Arun; Sembrat, John; Provencher, Steeve; Yin, Xianglin; Vargas, Sara O.; Rojas, Mauricio; Bonnet, Sébastien; Torrino, Stéphanie; Wagner, Bridget K.; Schreiber, Stuart L.; Dai, Mingji; Bertero, Thomas; Ghouleh, Imad Al; S, Kim; Chan, Stephen Y.

doi:10.1126/sciadv.abh3794

Cited by 21 publications

(20 citation statements)

References 83 publications

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“…Immunohistochemical staining showed that Mxi1 was expressed abundantly in the medial layer mainly composed of PASMCs, which was further validated by immunofluorescence indicating that Mxi1 overlapped with α-SMA, a specific biomarker of smooth muscle cells. Although Mxi1 has been extensively studied in the context of carcinogenesis and well documented as a tumor suppressor ( Zervos et al, 1993 ; Huang et al, 2018 ), this is probably the first study to determine that it is also an important player in HPH, reminiscent of multiple shared pathomechanisms between pulmonary hypertension and cancer ( Negi et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Mxi1-0 Promotes Hypoxic Pulmonary Hypertension Via ERK/c-Myc-dependent Proliferation of Arterial Smooth Muscle Cells

Dong

Liu

et al. 2022

Front. Genet.

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Background: Hypoxic pulmonary hypertension (HPH) is a challenging lung arterial disorder with remarkably high incidence and mortality, and so far patients have failed to benefit from therapeutics clinically available. Max interacting protein 1–0 (Mxi1-0) is one of the functional isoforms of Mxi1. Although it also binds to Max, Mxi1-0, unlike other Mxi1 isoforms, cannot antagonize the oncoprotein c-Myc because of its unique proline rich domain (PRD). While Mxi1-0 was reported to promote cell proliferation via largely uncharacterized mechanisms, it is unknown whether and how it plays a role in the pathogenesis of HPH.Methods: GEO database was used to screen for genes involved in HPH development, and the candidate players were validated through examination of gene expression in clinical HPH specimens. The effect of candidate gene knockdown or overexpression on cultured pulmonary arterial cells, e.g., pulmonary arterial smooth muscle cells (PASMCs), was then investigated. The signal pathway(s) underlying the regulatory role of the candidate gene in HPH pathogenesis was probed, and the outcome of targeting the aforementioned signaling was evaluated using an HPH rat model.Results: Mxi1 was significantly upregulated in the PASMCs of HPH patients. As the main effector isoform responding to hypoxia, Mxi1-0 functions in HPH to promote PASMCs proliferation. Mechanistically, Mxi1-0 improved the expression of the proto-oncogene c-Myc via activation of the MEK/ERK pathway. Consistently, both a MEK inhibitor, PD98059, and a c-Myc inhibitor, 10058F4, could counteract Mxi1-0-induced PASMCs proliferation. In addition, targeting the MEK/ERK signaling significantly suppressed the development of HPH in rats.Conclusion: Mxi1-0 potentiates HPH pathogenesis through MEK/ERK/c-Myc-mediated proliferation of PASMCs, suggesting its applicability in targeted treatment and prognostic assessment of clinical HPH.

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Section: Discussionmentioning

confidence: 99%

Mxi1-0 Promotes Hypoxic Pulmonary Hypertension Via ERK/c-Myc-dependent Proliferation of Arterial Smooth Muscle Cells

Dong

Liu

et al. 2022

Front. Genet.

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“…The mRNA expression profile datasets GSE11341 [ 13 ] and GSE160255 [ 14 ] were downloaded from the GEO database ( https://www.ncbi.nlm.nih.gov/geo/ ), which are located on the GPL96 [HG-U133A] Affymetrix Human Genome U133A Array and GPL23159 [Clariom_S_Human] Affymetrix Clariom S Assay, Human (includes Pico Assay), respectively. Human cardiac microvascular endothelial cells from GSE11341 were included to screening DEGs and hub genes, containing nine hypoxia samples (three for 3 h, 24 h, and 48 h, respectively) and three normoxia samples.…”

Section: Methodsmentioning

confidence: 99%

Bioinformatic Exploration of Hub Genes and Potential Therapeutic Drugs for Endothelial Dysfunction in Hypoxic Pulmonary Hypertension

Chen

Lin

et al. 2022

Computational and Mathematical Methods in Medicine

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Hypoxic pulmonary hypertension (HPH) is a fatal chronic pulmonary circulatory disease, characterized by hypoxic pulmonary vascular constriction and remodeling. Studies performed to date have confirmed that endothelial dysfunction plays crucial roles in HPH, while the underlying mechanisms have not been fully revealed. The microarray dataset GSE11341 was downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) between hypoxic and normoxic microvascular endothelial cell, followed by Gene Ontology (GO) annotation/Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis, and protein-protein interaction (PPI) network construction. Next, GSE160255 and RT-qPCR were used to validate hub genes. Meanwhile, GO/KEGG and GSEA were performed for each hub gene to uncover the potential mechanism. A nomogram based on hub genes was established. Furthermore, mRNA-miRNA network was predicted by miRNet, and the Connectivity Map (CMAP) database was in use to identify similarly acting therapeutic candidates. A total of 148 DEGs were screened in GSE11341, and three hub genes (VEGFA, CDC25A, and LOX) were determined and validated via GSE160255 and RT-qPCR. Abnormalities in the pathway of vascular smooth muscle contraction, lysosome, and glycolysis might play important roles in HPH pathogenesis. The hub gene-miRNA network showed that hsa-mir-24-3p, hsa-mir-124-3p, hsa-mir-195-5p, hsa-mir-146a-5p, hsa-mir-155-5p, and hsa-mir-23b-3p were associated with HPH. And on the basis of the identified hub genes, a practical nomogram is developed. To repurpose known and therapeutic drugs, three candidate compounds (procaterol, avanafil, and lestaurtinib) with a high level of confidence were obtained from the CMAP database. Taken together, the identification of these three hub genes, enrichment pathways, and potential therapeutic drugs might have important clinical implications for HPH diagnosis and treatment.

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Section: How To Harness Big Data Sets In Ph?mentioning

confidence: 99%

“…Alternative approaches to drug repurposing include utilization of differential dependency networks to predict potential chemotherapeutics for PH based on shared molecular reprogramming patterns, illustrated through networks, observed in response to drug treatment in cancer and as well as under conditions of hypoxia and inflammation. 83 Defining Pathogenic Pathways: Reticulotypes Recently, a method for individualizing PPI networks was applied it to a cohort of patients with heart failure from obstructive hypertrophic cardiomyopathy, which predisposes to group 2 PH. 84 Individualized PPI network data could be used to predict pathobiological and histopathophenotypic profiles that were unique to specific patients.…”

Section: Drug Repurposing and Network Medicine In Phmentioning

confidence: 99%

Harnessing Big Data to Advance Treatment and Understanding of Pulmonary Hypertension

Rhodes

Sweatt

Maron

2022

Circulation Research

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Pulmonary hypertension is a complex disease with multiple causes, corresponding to phenotypic heterogeneity and variable therapeutic responses. Advancing understanding of pulmonary hypertension pathogenesis is likely to hinge on integrated methods that leverage data from health records, imaging, novel molecular -omics profiling, and other modalities. In this review, we summarize key data sets generated thus far in the field and describe analytical methods that hold promise for deciphering the molecular mechanisms that underpin pulmonary vascular remodeling, including machine learning, network medicine, and functional genetics. We also detail how genetic and subphenotyping approaches enable earlier diagnosis, refined prognostication, and optimized treatment prediction. We propose strategies that identify functionally important molecular pathways, bolstered by findings across multi-omics platforms, which are well-positioned to individualize drug therapy selection and advance precision medicine in this highly morbid disease.

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Computational repurposing of therapeutic small molecules from cancer to pulmonary hypertension

Abstract: A network dependency platform was generated to define a landscape of cancer drug mechanisms in pulmonary hypertension.

Cited by 21 publications

References 83 publications

Mxi1-0 Promotes Hypoxic Pulmonary Hypertension Via ERK/c-Myc-dependent Proliferation of Arterial Smooth Muscle Cells

Mxi1-0 Promotes Hypoxic Pulmonary Hypertension Via ERK/c-Myc-dependent Proliferation of Arterial Smooth Muscle Cells

Bioinformatic Exploration of Hub Genes and Potential Therapeutic Drugs for Endothelial Dysfunction in Hypoxic Pulmonary Hypertension

Harnessing Big Data to Advance Treatment and Understanding of Pulmonary Hypertension

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