scholarly journals Predicting cancer drug TARGETS - TreAtment Response Generalized Elastic-neT Signatures

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Nicholas R. Rydzewski ◽  
Erik Peterson ◽  
Joshua M. Lang ◽  
Menggang Yu ◽  
S. Laura Chang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Treatment Response ◽  
Drug Response ◽  
Predictive Biomarkers ◽  
Elastic Net ◽  
The Cancer Genome Atlas ◽  
Molecular Medicine ◽  
Cancer Drug ◽  
Clinical Samples

AbstractWe are now in an era of molecular medicine, where specific DNA alterations can be used to identify patients who will respond to specific drugs. However, there are only a handful of clinically used predictive biomarkers in oncology. Herein, we describe an approach utilizing in vitro DNA and RNA sequencing and drug response data to create TreAtment Response Generalized Elastic-neT Signatures (TARGETS). We trained TARGETS drug response models using Elastic-Net regression in the publicly available Genomics of Drug Sensitivity in Cancer (GDSC) database. Models were then validated on additional in-vitro data from the Cancer Cell Line Encyclopedia (CCLE), and on clinical samples from The Cancer Genome Atlas (TCGA) and Stand Up to Cancer/Prostate Cancer Foundation West Coast Prostate Cancer Dream Team (WCDT). First, we demonstrated that all TARGETS models successfully predicted treatment response in the separate in-vitro CCLE treatment response dataset. Next, we evaluated all FDA-approved biomarker-based cancer drug indications in TCGA and demonstrated that TARGETS predictions were concordant with established clinical indications. Finally, we performed independent clinical validation in the WCDT and found that the TARGETS AR signaling inhibitors (ARSI) signature successfully predicted clinical treatment response in metastatic castration-resistant prostate cancer with a statistically significant interaction between the TARGETS score and PSA response (p = 0.0252). TARGETS represents a pan-cancer, platform-independent approach to predict response to oncologic therapies and could be used as a tool to better select patients for existing therapies as well as identify new indications for testing in prospective clinical trials.

scholarly journals NFAT2-HDAC1 signaling contributes to the malignant phenotype of glioblastoma

2019 ◽  
Vol 22 (1) ◽  
pp. 46-57 ◽  
Author(s):  
Yifu Song ◽  
Yang Jiang ◽  
Dongxia Tao ◽  
Zixun Wang ◽  
Run Wang ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Transcriptional Activity ◽  
The Cancer Genome Atlas ◽  
Clinical Samples ◽  
Nuclear Factor ◽  
Malignant Phenotype ◽  
Histone Deacetylase 1 ◽  
Downstream Target

Abstract Background Deregulation of the nuclear factor of activated T cell (NFAT) pathway has been reported in several human cancers. Particularly, NFAT2 is involved in the malignant transformation of tumor cells and is identified as an oncogene. However, the role of NFAT2 in glioblastoma (GBM) is largely unknown. Methods The expression and prognostic value of NFAT2 were examined in the databases of the Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas (TCGA) and clinical samples. The functional effects of silencing or overexpression of NFAT2 were evaluated in glioma stem cell (GSC) viability, invasion, and self-renewal in vitro and in tumorigenicity in vivo. The downstream target of NFAT2 was investigated. Results High NFAT2 expression was significantly associated with mesenchymal (MES) subtype and recurrent GBM and predicted poor survival. NFAT2 silencing inhibited the invasion and clonogenicity of MES GSC-enriched spheres in vitro and in vivo. NFAT2 overexpression promoted tumor growth and MES differentiation of GSCs. A TCGA database search showed that histone deacetylase 1 (HDAC1) expression was significantly correlated with that of NFAT2. NFAT2 regulates the transcriptional activity of HDAC1. Rescue of HDAC1 in NFAT2-knockdown GSCs partially restored tumor growth and MES phenotype. Loss of NFAT2 and HDAC1 expression resulted in hyperacetylation of nuclear factor-kappaB (NF-κB), which inhibits NF-κB–dependent transcriptional activity. Conclusion Our findings suggest that the NFAT2-HDAC1 pathway might play an important role in the maintenance of the malignant phenotype and promote MES transition in GSCs, which provide potential molecular targets for the treatment of GBMs.

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 MCM5 Aggravates the HDAC1-Mediated Malignant Progression of Lung Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Lin-lin Zhang ◽  
Qi Li ◽  
Dian-sheng Zhong ◽  
Wei-jian Zhang ◽  
Xiao-jie Sun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Animal Experiments ◽  
Malignant Progression ◽  
The Cancer Genome Atlas ◽  
Clinical Samples ◽  
Astragaloside Iv ◽  
Mesenchymal Transition ◽  
Histone Deacetylase 1

BackgroundHistone deacetylase 1 (HDAC1) is essential in the malignant progression of tumors. However, there is no obvious relationship between the expression of HDAC1 and the survival of lung cancer patients. Herein, we explored the involvement of minichromosome maintenance complex component 5 (MCM5) and HDAC1 interaction in the epithelial-to-mesenchymal transition (EMT)-dependent malignant progression of lung cancer.MethodsWe analyzed the expression of MCM5 and HDAC1 in The Cancer Genome Atlas database and clinical samples, as well as their impact on patient survival. Cell and animal experiments were performed to verify the promotion of EMT in lung cancer cells mediated by MCM5 and HDAC1.ResultsWe found that lung adenocarcinoma patients with high expression of MCM5 and HDAC1 had poor survival time. Overexpression of MCM5 and HDAC1 in A549 and H1975 cells can promote proliferation and invasion in vitro and tumor growth and metastasis in vivo. Moreover, astragaloside IV can block the interaction between HDAC1 and MCM5, which can then inhibit the malignant progression of lung cancer in vivo and in vitro.ConclusionThe interaction between MCM5 and HDAC1 aggravated the EMT-dependent malignant progression of lung cancer. Astragaloside IV can block the interaction between MCM5 and HDAC1 to inhibit the progression of lung cancer.

scholarly journals Integrative analysis reveals CRHBP inhibits renal cell carcinoma progression by regulating inflammation and apoptosis

2019 ◽  
Vol 27 (7-8) ◽  
pp. 607-618 ◽  
Author(s):  
Kang Yang ◽  
Yusha Xiao ◽  
Tao Xu ◽  
Weimin Yu ◽  
Yuan Ruan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Gene Expression Omnibus ◽  
Integrative Analysis ◽  
The Cancer Genome Atlas ◽  
Clinical Samples ◽  
Apoptotic Pathway

Abstract Patients with renal cell carcinoma (RCC) usually develop drug resistance and have poor prognosis owing to its insensitive property. However, the underlying mechanisms of RCC are still unclear. We implemented an integrative analysis of The Cancer Genome Atlas and Gene Expression Omnibus datasets. Three genes (CRHBP, RAB25 and PSAT1) were found to be potential biomarkers in ccRCC and validated by four independent cohorts. Then, ccRCC patients with a decreased expression of CRHBP in tumor tissues had significantly poor survival by TCGA ccRCC datasets and verified by clinical samples as well as RCC cell lines. Overexpression of CRHBP suppressed cell proliferation, migration, invasion as well as apoptosis in vitro and in vivo. Moreover, the results of western blot analysis showed the effects of CRHBP via upregulating NF-κB and p53-mediated mitochondria apoptotic pathway. Our results suggested that CRHBP may be an effective target to treat ccRCC patients.

scholarly journals SNHG10 Is a Prognostic Biomarker Correlated With Immune Infiltrates in Prostate Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Qiang Chen ◽  
Xiaorong Yang ◽  
Binbin Gong ◽  
Wenjie Xie ◽  
Ming Ma ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prognostic Biomarker ◽  
The Cancer Genome Atlas ◽  
Receiver Operating Curve ◽  
Migration And Invasion ◽  
Immune Infiltration ◽  
Receiver Operating Curve Analysis ◽  
Non Coding Rna ◽  
Underlying Mechanisms

SNHG10 is a long non-coding RNA (lncRNA) found to be overexpressed in multiple human cancers including prostate cancer (PC). However, the underlying mechanisms of SNHG10 driving the progression of PC remains unclear. In this study, we investigated the role of SNHG10 in PC and found that SNHG10 expression was significantly increased in datasets extracted from The Cancer Genome Atlas. Increased expression of SNHG10 was related to advanced clinical parameters. Receiver operating curve analysis revealed the significant diagnostic ability of SNHG10 (AUC = 0.805). In addition, immune infiltration analysis, and GSEA showed that SNHG10 expression was correlated with oxidative phosphorylation and immune infiltrated cells. Finally, we determined that SNHG10 regulated cell proliferation, migration, and invasion of PC in vitro. In conclusion, our data demonstrated that SNHG10 was correlated with progression and immune infiltration, and could serve as a prognostic biomarker for PC.

scholarly journals The prostate cancer drug enzalutamide shortens anogenital distance in male rat offspring by blocking the androgen receptor

2019 ◽  
Author(s):  
Camilla Lindgren Schwartz ◽  
Terje Svingen ◽  
Camilla Taxvig ◽  
Sofie Christiansen ◽  
Mikael Pedersen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Mechanism Of Action ◽  
Model Compound ◽  
Male Rat ◽  
Cancer Drug ◽  
Anogenital Distance ◽  
Fetal Plasma ◽  
Androgen Synthesis

Abstract Background: Enzalutamide is a non-steroidal anti-androgen drug used to treat prostate cancer. It is a potent androgen receptor (AR) antagonist, with an in vitro Lowest Observed Effect Concentration (LOEC) of 0.05 μM. In this study, we wanted to assess its utility as a model compound for future mechanistic studies aimed at delineating mechanism-of-action of anti-androgenic effects in the developing fetus. Methods: Enzalutamide in vitro activity was tested using an Androgen receptor reporter assay (AR-EcoScreenTM) and a steroidogenesis assay (H295R assay). For in vivo characterization, pregnant Sprague-Dawley rats were exposed to 10 mg/kg bw/day enzalutamide from gestational day 7-21. At gestational day 21, enzalutamide exposure concentrations were measured both in amniotic fluids and fetal plasma, alongside Anogenital distance (AGD). Fetal testes were collected and for testosterone measurements and gene expression profiling. Results: Enzalutamide was a strong AR antagonist in vitro and we also observed disrupted androgen synthesis in the H295R steroidogenic assay with a LOEC of 3.1 μM. In utero exposure resulted in about 20% shorter anogenital distance (AGD) in male fetuses., as well as signs of dysregulated expression of the steroidogenic genes Star, Cyp11a1 and Cyp17a1 in the fetal testes at gestational day 21. Intra-testicular testosterone levels were unaffected. Conclusions: Based on these observations, together with in vitro LOECs and the fetal plasma levels of enzalutamide, we propose that the effect on male AGD was caused by AR antagonism rather than suppressed androgen synthesis. Due to the characteristic mechanism of action of enzalutamide, we suggest to use it as a new model compound in research on anti-androgenic environmental chemicals.

DCUN1D1 promotes tumor progress in prostate cancer and its effect on DU145 in vitro

2020 ◽  
pp. 1-16
Author(s):  
Shun-tan Huang ◽  
Ze-zhen Liu ◽  
Fu-Neng Jiang ◽  
Hui-chan He ◽  
Wei-De Zhong
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Disease Free Survival ◽  
Cross Sectional Study ◽  
Molecular Medicine ◽  
Cross Sectional ◽  
Normal Prostate ◽  
Tissue Samples ◽  
Cancer Tissues

Abstract Objective: To compare the expression levels of Defective In Cullin Neddylation 1 Domain Containing 1 oncogene in prostate cancer tissues and normal prostate tissues, to explored its effect on cancerous  cells, and to investigate its underlying mechanisms on such cells in vitro. Methods: The cross-sectional study was conducted at Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics from Jan 03,2017 to Nov 05,2018, and comprised prostate tissue samples on which immunohistochemistry was used to detect the expression of Defective In Cullin Neddylation 1 Domain Containing 1 oncogene. Short hairpin ribonucleic acid expression plasmid targeting the oncogene was constructed and transferred into prostate cance cell line DU145. The roles of the oncogene in prostate cancer progression were confirmed in vitro. The expression of vimentin and epithelial cadherin influenced by the oncogene were detected using Western blot. Data was analysed using SPSS 24. Results: Of the 80 samples, 3(3.75%) were normal prostate tissues, 7(8.75%) adjacent normal prostate tissues, 20(25%) hyperplasia, and 50(62.5%) prostate cancer tissues. Defective In Cullin Neddylation 1 Domain Containing 1 oncogene expression in prostate cancerous tissues was significantly associated with high Gleason score (p<0.001), metastasis (p<0.05) and pathological stage (p<0.001). The oncogene was found to be an independent prognostic factor for disease-free survival of prostate cancer patients (p=0.0108). In vitro analysis confirmed the tumour promotive role of the oncogene through cell proliferation, invasion and migration assays. Continuous...

scholarly journals Enhanced Co-Expression Extrapolation (COXEN) Gene Selection Method for Building Anti-Cancer Drug Response Prediction Models

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 1070 ◽  
Author(s):  
Yitan Zhu ◽  
Thomas Brettin ◽  
Yvonne A. Evrard ◽  
Fangfang Xia ◽  
Alexander Partin ◽  
...  
Keyword(s):  
Drug Response ◽  
Prediction Models ◽  
Gene Selection ◽  
Expression Patterns ◽  
Response Prediction ◽  
Cancer Drug ◽  
P Value ◽  
In Vitro Drug Screening ◽  
Multiple Drugs

The co-expression extrapolation (COXEN) method has been successfully used in multiple studies to select genes for predicting the response of tumor cells to a specific drug treatment. Here, we enhance the COXEN method to select genes that are predictive of the efficacies of multiple drugs for building general drug response prediction models that are not specific to a particular drug. The enhanced COXEN method first ranks the genes according to their prediction power for each individual drug and then takes a union of top predictive genes of all the drugs, among which the algorithm further selects genes whose co-expression patterns are well preserved between cancer cases for building prediction models. We apply the proposed method on benchmark in vitro drug screening datasets and compare the performance of prediction models built based on the genes selected by the enhanced COXEN method to that of models built on genes selected by the original COXEN method and randomly picked genes. Models built with the enhanced COXEN method always present a statistically significantly improved prediction performance (adjusted p-value ≤ 0.05). Our results demonstrate the enhanced COXEN method can dramatically increase the power of gene expression data for predicting drug response.

scholarly journals miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro

2020 ◽  
Vol 9 (3) ◽  
pp. 670 ◽  
Author(s):  
Markus Krebs ◽  
Antonio Giovanni Solimando ◽  
Charis Kalogirou ◽  
André Marquardt ◽  
Torsten Frank ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Kinase Inhibitors ◽  
The Cancer Genome Atlas ◽  
Luciferase Reporter ◽  
Cell Renal Cell Carcinoma ◽  
Cancer Specific Survival ◽  
Escape Mechanism ◽  
Pc3 Cells

Downregulation of miR-221-3p expression in prostate cancer (PCa) predicted overall and cancer-specific survival of high-risk PCa patients. Apart from PCa, miR-221-3p expression levels predicted a response to tyrosine kinase inhibitors (TKI) in clear cell renal cell carcinoma (ccRCC) patients. Since this role of miR-221-3p was explained with a specific targeting of VEGFR2, we examined whether miR-221-3p regulated VEGFR2 in PCa. First, we confirmed VEGFR2/KDR as a target gene of miR-221-3p in PCa cells by applying Luciferase reporter assays and Western blotting experiments. Although VEGFR2 was mainly downregulated in the PCa cohort of the TCGA (The Cancer Genome Atlas) database, VEGFR2 was upregulated in our high-risk PCa cohort (n = 142) and predicted clinical progression. In vitro miR-221-3p acted as an escape mechanism from TKI in PC3 cells, as displayed by proliferation and apoptosis assays. Moreover, we confirmed that Sunitinib induced an interferon-related gene signature in PC3 cells by analyzing external microarray data and by demonstrating a significant upregulation of miR-221-3p/miR-222-3p after Sunitinib exposure. Our findings bear a clinical perspective for high-risk PCa patients with low miR-221-3p levels since this could predict a favorable TKI response. Apart from this therapeutic niche, we identified a partially oncogenic function of miR-221-3p as an escape mechanism from VEGFR2 inhibition.

scholarly journals Gene Panel of Persister Cells as a Prognostic Indicator for Tumor Repopulation After Radiation

2020 ◽  
Vol 10 ◽  
Author(s):  
Yucui Zhao ◽  
Yanwei Song ◽  
Ruyi Zhao ◽  
Minghui Zhao ◽  
Qian Huang
Keyword(s):  
Cox Regression ◽  
Risk Index ◽  
Predictive Biomarkers ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Persister Cells ◽  
Cox Regression Analysis ◽  
Cytotoxic Treatment

Tumor repopulation during cycles of radiotherapy limits the radio-response in ensuing cycles and causes failure of treatment. It is thus of vital importance to unveil the mechanisms underlying tumor repopulating cells. Increasing evidence suggests that a subpopulation of drug-tolerant persister cancer cells (DTPs) could survive the cytotoxic treatment and resume to propagate. Whether these persister cells contribute to development of radio-resistance remains elusive. Based on the genetic profiling of DTPs by integrating datasets from Gene Expression Omnibus database, this study aimed to provide novel insights into tumor-repopulation mediated radio-resistance and identify predictive biomarkers for radio-response in clinic. A prognostic risk index, grounded on four persister genes (LYNX1, SYNPO, GADD45B, and PDLIM1), was constructed in non-small-cell lung cancer patients from The Cancer Genome Atlas Program (TCGA) using stepwise Cox regression analysis. Weighted gene co-expression network analysis further confirmed the interaction among persister-gene based risk score, radio-response and overall survival time. In addition, the predictive role of risk index was validated in vitro and in other types of TCGA patients. Gene set enrichment analysis was performed to decipher the possible biological signaling, which indicated that two forces behind persister cells, stress response and survival adaptation, might fuel the tumor repopulation after radiation. Targeting these persister cells may represent a new prognostic and therapeutic approach to enhance radio-response and prevent radio-resistance induced by tumor repopulation.

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