scholarly journals EGFR and PI3K Pathway Activities Might Guide Drug Repurposing in HPV-Negative Head and Neck Cancers

2021 ◽  
Vol 11 ◽  
Author(s):  
Andreas Mock ◽  
Michaela Plath ◽  
Julius Moratin ◽  
Maria Johanna Tapken ◽  
Dirk Jäger ◽  
...  
Keyword(s):  
Head And Neck ◽  
Hdac Inhibitors ◽  
Drug Repurposing ◽  
B Cell Lymphoma ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
The Cancer Genome Atlas ◽  
Cancer Drug ◽  
Oncogenic Signaling

While genetic alterations in Epidermal growth factor receptor (EGFR) and PI3K are common in head and neck squamous cell carcinomas (HNSCC), their impact on oncogenic signaling and cancer drug sensitivities remains elusive. To determine their consequences on the transcriptional network, pathway activities of EGFR, PI3K, and 12 additional oncogenic pathways were inferred in 498 HNSCC samples of The Cancer Genome Atlas using PROGENy. More than half of HPV-negative HNSCC showed a pathway activation in EGFR or PI3K. An amplification in EGFR and a mutation in PI3KCA resulted in a significantly higher activity of the respective pathway (p = 0.017 and p = 0.007). Interestingly, both pathway activations could only be explained by genetic alterations in less than 25% of cases indicating additional molecular events involved in the downstream signaling. Suitable in vitro pathway models could be identified in a published drug screen of 45 HPV-negative HNSCC cell lines. An active EGFR pathway was predictive for the response to the PI3K inhibitor buparlisib (p = 6.36E-03) and an inactive EGFR and PI3K pathway was associated with efficacy of the B-cell lymphoma (BCL) inhibitor navitoclax (p = 9.26E-03). In addition, an inactive PI3K pathway correlated with a response to multiple Histone deacetylase inhibitor (HDAC) inhibitors. These findings require validation in preclinical models and clinical studies.

scholarly journals High-resolution AP-SMALDI MSI as a tool for drug imaging in Schistosoma mansoni

2021 ◽  
Author(s):  
Annika S. Mokosch ◽  
Stefanie Gerbig ◽  
Christoph G. Grevelding ◽  
Simone Haeberlein ◽  
Bernhard Spengler
Keyword(s):  
Schistosoma Mansoni ◽  
Egg Production ◽  
Drug Repurposing ◽  
Cancer Drug ◽  
Ionization Mass ◽  
Parasitic Flatworm ◽  
Paired Female ◽  
First Time ◽  
Organ Tropism

AbstractSchistosoma mansoni is a parasitic flatworm causing schistosomiasis, an infectious disease affecting several hundred million people worldwide. Schistosomes live dioeciously, and upon pairing with the male, the female starts massive egg production, which causes pathology. Praziquantel (PZQ) is the only drug used, but it has an inherent risk of resistance development. Therefore, alternatives are needed. In the context of drug repurposing, the cancer drug imatinib was tested, showing high efficacy against S. mansoni in vitro. Besides the gonads, imatinib mainly affected the integrity of the intestine in males and females. In this study, we investigated the potential uptake and distribution of imatinib in adult schistosomes including its distribution kinetics. To this end, we applied for the first time atmospheric-pressure scanning microprobe matrix-assisted laser desorption/ionization mass spectrometry imaging (AP-SMALDI MSI) for drug imaging in paired S. mansoni. Our results indicate that imatinib was present in the esophagus and intestine of the male as early as 20 min after in vitro exposure, suggesting an oral uptake route. After one hour, the drug was also found inside the paired female. The detection of the main metabolite, N-desmethyl imatinib, indicated metabolization of the drug. Additionally, a marker signal for the female ovary was successfully applied to facilitate further conclusions regarding organ tropism of imatinib. Our results demonstrate that AP-SMALDI MSI is a useful method to study the uptake, tissue distribution, and metabolization of imatinib in S. mansoni. The results suggest using AP-SMALDI MSI also for investigating other antiparasitic compounds and their metabolites in schistosomes and other parasites. Graphical abstract

scholarly journals JOSD1 promotes proliferation and chemoresistance of head and neck squamous cell carcinoma under the epigenetic regulation of BRD4

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chao Jing ◽  
Dandan Liu ◽  
Qingchuan Lai ◽  
Linqi Li ◽  
Mengqian Zhou ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Gene Expression Omnibus ◽  
Neck Squamous Cell Carcinoma ◽  
The Cancer Genome Atlas ◽  
In Vivo Experiments

Abstract Background Deubiquitinating enzymes (DUBs) play critical roles in various cancers by modulating functional proteins post-translationally. Previous studies have demonstrated that DUB Josephin Domain Containing 1 (JOSD1) is implicated in tumor progression, however, the role and mechanism of JOSD1 in head and neck squamous cell carcinoma (HNSCC) remain to be explored. In this study, we aimed to identify the clinical significance and function of JOSD1 in HNSCC. Methods The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed to find novel DUBs in HNSCC. Immunohistochemistry assay was performed to determine the expression of JOSD1 in our cohort of 42 patients suffered with HNSCC. Kaplan–Meier analysis was used to identify the correlation between JOSD1 and the prognosis of HNSCC patients. The regulation of BRD4 on JOSD1 was determined by using pharmacological inhibition and gene depletion. The in vitro and in vivo experiments were conducted to elucidate the role of JOSD1 in HNSCC. Results The results of IHC showed that JOSD1 was aberrantly expressed in HNSCC specimens, especially in the chemoresistant ones. The overexpression of JOSD1 indicated poor clinical outcome of HNSCC patients. Moreover, JOSD1 depletion dramatically impaired cell proliferation and colony formation, and promoted cisplatin-induced apoptosis of HNSCC cells in vitro. Additionally, JOSD1 suppression inhibited the tumor growth and improved chemosensitivity in vivo. The epigenetic regulator BRD4 contributed to the upregulation of JOSD1 in HNSCC. Conclusions These results demonstrate that JOSD1 functions as an oncogene in HNSCC progression, and provide a promising target for clinical diagnosis and therapy of HNSCC.

scholarly journals HER2 missense mutations have distinct effects on oncogenic signaling and migration

2015 ◽  
Vol 112 (45) ◽  
pp. E6205-E6214 ◽  
Author(s):  
Daniel J. Zabransky ◽  
Christopher L. Yankaskas ◽  
Rory L. Cochran ◽  
Hong Yuen Wong ◽  
Sarah Croessmann ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Breast Cancers ◽  
Oncogenic Signaling ◽  
Pathway Activation ◽  
And Migration ◽  
Endogenous Loci

Recurrent human epidermal growth factor receptor 2 (HER2) missense mutations have been reported in human cancers. These mutations occur primarily in the absence of HER2 gene amplification such that most HER2-mutant tumors are classified as “negative” by FISH or immunohistochemistry assays. It remains unclear whether nonamplified HER2 missense mutations are oncogenic and whether they are targets for HER2-directed therapies that are currently approved for the treatment of HER2 gene-amplified breast cancers. Here we functionally characterize HER2 kinase and extracellular domain mutations through gene editing of the endogenous loci in HER2 nonamplified human breast epithelial cells. In in vitro and in vivo assays, the majority of HER2 missense mutations do not impart detectable oncogenic changes. However, the HER2 V777L mutation increased biochemical pathway activation and, in the context of a PIK3CA mutation, enhanced migratory features in vitro. However, the V777L mutation did not alter in vivo tumorigenicity or sensitivity to HER2-directed therapies in proliferation assays. Our results suggest the oncogenicity and potential targeting of HER2 missense mutations should be considered in the context of cooperating genetic alterations and provide previously unidentified insights into functional analysis of HER2 mutations and strategies to target them.

scholarly journals Synthetic Evaluation of MicroRNA-1-3p Expression in Head and Neck Squamous Cell Carcinoma Based on Microarray Chips and MicroRNA Sequencing

2021 ◽  
Vol 2021 ◽  
pp. 1-24
Author(s):  
Yubing Chen ◽  
Mingjiang Liu ◽  
Hu Jin ◽  
Bo Peng ◽  
Luo Dai ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Molecular Mechanisms ◽  
Gene Expression Omnibus ◽  
Neck Squamous Cell Carcinoma ◽  
The Cancer Genome Atlas ◽  
Regulatory Pathways

Background. MicroRNA-1-3p (miR-1-3p) exerts significant regulation in various tumor cells, but its molecular mechanisms in head and neck squamous cell carcinoma (HNSCC) are still ill defined. This study is aimed at detecting the expression of miR-1-3p in HNSCC and at determining its significant regulatory pathways. Methods. Data were obtained from the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Oncomine, ArrayExpress, Sequence Read Archive (SRA) databases, and additional literature. Expression values of miR-1-3p in HNSCC were analyzed comprehensively. The R language software was employed to screen differentially expressed genes, and bioinformatics assessment was performed. One sequence dataset (HNSCC: n = 484 ; noncancer: n = 44 ) and 18 chip datasets (HNSCC: n = 656 ; noncancer: n = 199 ) were obtained. Results. The expression of miR-1-3p in HNSCC was visibly decreased in compare with noncancerous tissues. There were distinct differences in tumor state ( P = 0.0417 ), pathological stage ( P = 0.0058 ), and T stage ( P = 0.0044 ). Comprehensive analysis of sequence and chip data also indicated that miR-1-3p was lowly expressed in HNSCC. The diagnostic performance of miR-1-3p in HNSCC is reflected in the sensitivity and specificity of the collection, etc. Bioinformatics analysis showed the possible biological process, cellular component, molecular function, and KEGG pathways of miR-1-3p in HNSCC. And ITGB4 was a possible target of miR-1-3p.Conclusions. miR-1-3p’s low expression may facilitate tumorigenesis and evolution in HNSCC through signaling pathways. ITGB4 may be a key gene in targeting pathways but still needs verification through in vitro experiments.

scholarly journals Identification of MALT1 feedback mechanisms enables rational design of potent antilymphoma regimens for ABC-DLBCL

Blood ◽  
2021 ◽  
Vol 137 (6) ◽  
pp. 788-800 ◽  
Author(s):  
Lorena Fontan ◽  
Rebecca Goldstein ◽  
Gabriella Casalena ◽  
Matthew Durant ◽  
Matthew R. Teater ◽  
...  
Keyword(s):  
B Cell ◽  
Rational Design ◽  
Tumor Regression ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Pi3k Pathway ◽  
Irreversible Inhibitor ◽  
Feedback Mechanisms

Abstract MALT1 inhibitors are promising therapeutic agents for B-cell lymphomas that are dependent on constitutive or aberrant signaling pathways. However, a potential limitation for signal transduction–targeted therapies is the occurrence of feedback mechanisms that enable escape from the full impact of such drugs. Here, we used a functional genomics screen in activated B-cell–like (ABC) diffuse large B-cell lymphoma (DLBCL) cells treated with a small molecule irreversible inhibitor of MALT1 to identify genes that might confer resistance or enhance the activity of MALT1 inhibition (MALT1i). We find that loss of B-cell receptor (BCR)- and phosphatidylinositol 3-kinase (PI3K)-activating proteins enhanced sensitivity, whereas loss of negative regulators of these pathways (eg, TRAF2, TNFAIP3) promoted resistance. These findings were validated by knockdown of individual genes and a combinatorial drug screen focused on BCR and PI3K pathway–targeting drugs. Among these, the most potent combinatorial effect was observed with PI3Kδ inhibitors against ABC-DLBCLs in vitro and in vivo, but that led to an adaptive increase in phosphorylated S6 and eventual disease progression. Along these lines, MALT1i promoted increased MTORC1 activity and phosphorylation of S6K1-T389 and S6-S235/6, an effect that was only partially blocked by PI3Kδ inhibition in vitro and in vivo. In contrast, simultaneous inhibition of MALT1 and MTORC1 prevented S6 phosphorylation, yielded potent activity against DLBCL cell lines and primary patient specimens, and resulted in more profound tumor regression and significantly improved survival of ABC-DLBCLs in vivo compared with PI3K inhibitors. These findings provide a basis for maximal therapeutic impact of MALT1 inhibitors in the clinic, by disrupting feedback mechanisms that might otherwise limit their efficacy.

scholarly journals FGF18–FGFR2 signaling triggers the activation of c-Jun–YAP1 axis to promote carcinogenesis in a subgroup of gastric cancer patients and indicates translational potential

Oncogene ◽  
2020 ◽  
Vol 39 (43) ◽  
pp. 6647-6663
Author(s):  
Jinglin Zhang ◽  
Chi Chun Wong ◽  
Kam Tong Leung ◽  
Feng Wu ◽  
Yuhang Zhou ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Molecular Mechanisms ◽  
Mapk Signaling ◽  
Nuclear Accumulation ◽  
Cancer Drug ◽  
Oncogenic Signaling ◽  
Antitumor Effects ◽  
Primary Tumors

Abstract Fibroblast growth factor receptor type 2 (FGFR2) has emerged as a key oncogenic factor that regulates gastric cancer (GC) progression, but the underlying mechanism of FGF–FGFR2 signaling pathway remains largely unknown. To identify the potential molecular mechanisms of the oncogenic FGFR2 in gastric carcinogenesis and convey a novel therapeutic strategy, we profiled the FGFR alterations and analyzed their clinical associations in TCGA and Hong Kong GC cohorts. We found that FGFR2 overexpression in GC cell lines and primary tumors predicted poor survival and was associated with advanced stages of GC. Functionally, growth abilities and cell cycle progression of GC were inhibited by inactivation of ERK–MAPK signal transduction after FGFR2 knockdown, while apoptosis was promoted. Meanwhile, the first-line anti-cancer drug sensitivity was enhanced. RNA-seq analysis further revealed that YAP1 signaling serves as a significant downstream modulator and mediates the oncogenic signaling of FGFR2. When stimulating FGFR2 by rhFGF18, we observed intensified F-actin, nuclear accumulation of YAP1, and overexpression of YAP1 targets, but these effects were attenuated by either FGFR2 depletion or AZD4547 administration. Additionally, the FGF18–FGFR2 signaling upregulated YAP1 expression through activating c-Jun, an effector of MAPK signaling. In our cohort, 28.94% of GC cases were characterized as FGFR2, c-Jun, and YAP1 co-positive and demonstrated worse clinical outcomes. Remarkably, we also found that co-targeting FGFR2 and YAP1 by AZD4547 and Verteporfin synergistically enhanced the antitumor effects in vitro and in vivo. In conclusion, we have identified the oncogenic FGF–FGFR2 regulates YAP1 signaling in GC. The findings also highlight the translational potential of FGFR2–c-Jun–YAP1 axis, which may serve as a prognostic biomarker and therapeutic target for GC.

scholarly journals The Significance of Natural Product Derivatives and Traditional Medicine for COVID-19

Processes ◽  
2020 ◽  
Vol 8 (8) ◽  
pp. 937 ◽  
Author(s):  
Dongdong Wang ◽  
Jiansheng Huang ◽  
Andy Wai Kan Yeung ◽  
Nikolay T. Tzvetkov ◽  
Jarosław O. Horbańczuk ◽  
...  
Keyword(s):  
Natural Products ◽  
Traditional Medicine ◽  
Effective Treatment ◽  
Drug Repurposing ◽  
Nucleoside Analogs ◽  
Cancer Drug ◽  
Double Blind ◽  
Promising Source

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, there have been more than 10 million reported cases, more than 517,000 deaths in 215 countries, areas or territories. There is no effective antiviral medicine to prevent or treat COVID-19. Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads. There is increasing number of publications reporting the effect of natural products and traditional medicine products on COVID-19. In our review, we provide an overview of natural products and their derivatives or mimics, as well as traditional medicine products, which were reported to exhibit potential to inhibit SARS-CoV-2 infection in vitro, and to manage COVID-19 in vivo, or in clinical reports or trials. These natural products and traditional medicine products are categorized in several classes: (1) anti-malaria drugs including chloroquine and hydroxychloroquine, (2) antivirals including nucleoside analogs (remdesivir, favipiravir, β-D-N4-hydroxycytidine, ribavirin and among others), lopinavir/ritonavir and arbidol, (3) antibiotics including azithromycin, ivermectin and teicoplanin, (4) anti-protozoal drug, emetine, anti-cancer drug, homoharringtonine, and others, as well as (5) traditional medicine (Lian Hua Qing Wen Capsule, Shuang Huang Lian Oral Liquid, Qingfei Paidu Decoction and Scutellariae Radix). Randomized, double-blind and placebo-controlled large clinical trials are needed to provide solid evidence for the potential effective treatment. Currently, drug repurposing is a promising strategy to quickly find an effective treatment for COVID-19. In addition, carefully combined cocktails need to be examined for preventing a COVID-19 pandemic and the resulting global health concerns.

scholarly journals Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance

2021 ◽  
Vol 14 (5) ◽  
pp. 470
Author(s):  
Nirmala Tilija Pun ◽  
Chul-Ho Jeong
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Drug Repurposing ◽  
Synergistic Action ◽  
Cancer Drug ◽  
Cancer Cell Proliferation ◽  
Cancer Drug Resistance ◽  
Anti Cancer

Cancer is incurable because progressive phenotypic and genotypic changes in cancer cells lead to resistance and recurrence. This indicates the need for the development of new drugs or alternative therapeutic strategies. The impediments associated with new drug discovery have necessitated drug repurposing (i.e., the use of old drugs for new therapeutic indications), which is an economical, safe, and efficacious approach as it is emerged from clinical drug development or may even be marketed with a well-established safety profile and optimal dosing. Statins are inhibitors of HMG-CoA reductase in cholesterol biosynthesis and are used in the treatment of hypercholesterolemia, atherosclerosis, and obesity. As cholesterol is linked to the initiation and progression of cancer, statins have been extensively used in cancer therapy with a concept of drug repurposing. Many studies including in vitro and in vivo have shown that statin has been used as monotherapy to inhibit cancer cell proliferation and induce apoptosis. Moreover, it has been used as a combination therapy to mediate synergistic action to overcome anti-cancer drug resistance as well. In this review, the recent explorations are done in vitro, in vivo, and clinical trials to address the action of statin either single or in combination with anti-cancer drugs to improve the chemotherapy of the cancers were discussed. Here, we discussed the emergence of statin as a lipid-lowering drug; its use to inhibit cancer cell proliferation and induction of apoptosis as a monotherapy; and its use in combination with anti-cancer drugs for its synergistic action to overcome anti-cancer drug resistance. Furthermore, we discuss the clinical trials of statins and the current possibilities and limitations of preclinical and clinical investigations.

scholarly journals A Multiparametric Pharmacogenomic Strategy for Drug Repositioning predicts Therapeutic Efficacy for Glioblastoma Cell Lines

2021 ◽  
Author(s):  
Ashish H Shah ◽  
Robert Suter ◽  
Pavan Gudoor ◽  
Tara T Doucet-O’Hare ◽  
Vasileios Stathias ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Drug Repositioning ◽  
Hdac Inhibitors ◽  
Drug Repurposing ◽  
The Cancer Genome Atlas ◽  
Treatment Modalities ◽  
Activity Data ◽  
Integrated Network ◽  
Disease Signature

Abstract Background Poor prognosis of glioblastoma patients and the extensive heterogeneity of glioblastoma at both the molecular and cellular level necessitates developing novel individualized treatment modalities via genomics-driven approaches. Methods This study leverages numerous pharmacogenomic and tissue databases to examine drug repositioning for glioblastoma. RNAseq of glioblastoma tumor samples from The Cancer Genome Atlas (TCGA, n=117) were compared to “normal” frontal lobe samples from Genotype-Tissue Expression Portal (GTEX, n=120) to find differentially expressed genes (DEGs). Using compound-gene expression data and drug activity data from the Library of Integrated Network-Based Cellular Signatures (LINCS, n=66,512 compounds) CCLE (71 glioma cell lines), and Chemical European Molecular Biology Laboratory (ChEMBL) platforms, we employed a summarized reversal gene expression metric (sRGES) to “reverse” the resultant disease signature for GBM and its subtypes. A multi-parametric strategy was employed to stratify compounds capable of blood brain barrier penetrance with a favorable pharmacokinetic profile (CNS-MPO). Results Significant correlations were identified between sRGES and drug efficacy in GBM cell lines in both ChEMBL(r=0.37,p<.001) and Cancer Therapeutic Response Portal (CTRP) databases (r=0.35, p<0.001). Our multiparametric algorithm identified two classes of drugs with highest sRGES and CNS-MPO: HDAC inhibitors (vorinostat and entinostat) and topoisomerase inhibitors suitable for drug repurposing. Conclusions Our studies suggest that reversal of glioblastoma disease signature correlates with drug potency for various GBM subtypes. This multiparametric approach may set the foundation for an early-phase personalized -omics clinical trial for glioblastoma by effectively identifying drugs that are capable of reversing the disease signature and have favorable pharmacokinetic and safety profiles.

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