Systems Pharmacology Assessment of the 5-Fluorouracil Pathway

Muhale, Filipe; Wetmore, Barbara A.; Thomas, Russell S.; McLeod, Howard L.

doi:10.2217/pgs.10.188

Cited by 42 publications

(31 citation statements)

References 38 publications

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“…Although a further analysis will be needed in patient cohorts with data on detailed drug treatment records, these observations suggested that our PDXGEM predictor could be not only predictive of response to gemcitabine, but could also have a prognostic value in terms of predicting for a long-term outcome OS in patients with PDAC. According to a gene ontology analysis of the biomarkers, the most significantly enriched function was amino acid catabolic process, which is in agreement with that 5-FU drug pathway is regulated via a complex network of anabolic and catabolic genes 35 .…”

Section: Pdxgem For Predicting Response To Gemcitabine In Pancreatic supporting

confidence: 80%

PDXGEM: Patient-Derived Tumor Xenograft based Gene Expression Model for Predicting Clinical Response to Anticancer Therapy in Cancer Patients

Kim

Cao

et al. 2019

Preprint

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Background: Cancer is a highly heterogeneous disease and shows varying responses to anti-cancer drugs. Although several approaches have been attempted to predict the drug responses by analyzing molecular profiling data of tumors from preclinical cancer models or cancer patients, there is still a great need of developing highly accurate prediction models of response to the anti-cancer drugs for clinical applications toward personalized medicine. Here, we present PDXGEM pipeline to build a predictive gene expression model (GEM) for cancer patients' drug responses on the basis of data on gene expression and drug activity in patient-derived xenograft (PDX) models.Results: Drug sensitivity biomarkers were identified by an association analysis between gene expression levels and post-treatment tumor volume changes in PDX models. Only biomarkers with concordant coexpression patterns between the PDX and cancer patient tumors were used in random-forest algorithm to build a drug response prediction model, so called PDXGEM. We applied PDXGEM to several cytotoxic chemotherapy as well as targeted therapy agents that are used to treat breast cancer, pancreatic cancer, colorectal cancer, or non-small cell lung cancer. Significantly accurate predictions of PDXGEM for pathological and survival outcomes were observed through extensive validation analyses of multiple independent cancer patient datasets obtained from retrospective observational study and prospective clinical trials. Conclusion:Our results demonstrated a strong potential of utilizing molecular profiles and drug activity data of PDX tumors for developing a clinically translatable predictive cancer biomarkers for cancer patients. PDXGEM web application is publicly available at http://pdxgem.moffitt.org. Abstract Word Count: 244 KeywordsPatient-derived Xenograft, PDX, gene expression, predictive cancer biomarker, anti-cancer drug response prediction

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Section: Pdxgem For Predicting Response To Gemcitabine In Pancreatic supporting

confidence: 80%

PDXGEM: Patient-Derived Tumor Xenograft based Gene Expression Model for Predicting Clinical Response to Anticancer Therapy in Cancer Patients

Kim

Cao

et al. 2019

Preprint

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“…Muhale et al [28] showed that UCK2 , along with other genes involved in the 5-FU anabolic pathway, produced a phenotype of cell sensitivity to 5-FU following knockdown. Our stratified analysis using the NKI dataset showed that among patients with stage II breast cancer, chemotherapy significantly improved DFS ( p =0.008) and OS ( p =0.050) in patients with UCK2 -low expression, but not in those with UCK2 -high expression ( p =0.107 for OS and p =0.243 for DFS, respectively), a finding that might be attributed to the sample size of the study.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Uridine-Cytidine Kinase 2 Correlates with Breast Cancer Progression and Poor Prognosis

Shen

Mao

et al. 2017

J Breast Cancer

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PurposeUridine-cytidine kinase (UCK) 2 is a rate-limiting enzyme involved in the salvage pathway of pyrimidine-nucleotide biosynthesis. Recent studies have shown that UCK2 is overexpressed in many types of cancer and may play a crucial role in activating antitumor prodrugs in human cancer cells. In the current study, we evaluated the potential prognostic value of UCK2 in breast cancer.MethodsWe searched public databases to explore associations between UCK2 gene expression and clinical parameters in patients with breast cancer. Gene set enrichment analysis (GSEA) was performed to identify biological pathways associated with UCK2 gene expression levels. Survival analyses were performed using 10 independent large-scale breast cancer microarray datasets.ResultsWe found that UCK2 mRNA expression was elevated in breast cancer tissue compared with adjacent nontumorous tissue or breast tissue from healthy controls. High UCK2 levels were correlated with estrogen receptor negativity (p<0.001), advanced tumor grade (p<0.001), and poor tumor differentiation (p<0.001). GSEA revealed that UCK2-high breast cancers were enriched for gene sets associated with metastasis, progenitor-like phenotypes, and poor prognosis. Multivariable Cox proportional hazards regression analyses of microarray datasets verified that high UCK2 gene expression was associated with poor overall survival in a dose-response manner. The prognostic power of UCK2 was superior to that of TNM staging and comparable to that of multiple gene signatures.ConclusionThese findings suggest that UCK2 may be a promising prognostic biomarker for patients with breast cancer.

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“…Some of these genes encode drug resistance enzymes (UMPS; ref. 36) or cell-cycle regulators through P27 function (GFER; refs. 37,38).…”

Section: /Cd24mentioning

confidence: 99%

ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

et al. 2013

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Cancer stem-like cells (CSC) have been widely studied, but their clinical relevance has yet to be established in breast cancer. Here, we report the establishment of primary breast tumor-derived xenografts (PDX) that encompass the main diversity of human breast cancer and retain the major clinicopathologic features of primary tumors. Successful engraftment was correlated with the presence of ALDH1-positive CSCs, which predicted prognosis in patients. The xenografts we developed showed a hierarchical cell organization of breast cancer with the ALDH1-positive CSCs constituting the tumorigenic cell population. Analysis of gene expression from functionally validated CSCs yielded a breast CSC signature and identified a core transcriptional program of 19 genes shared with murine embryonic, hematopoietic, and neural stem cells. This generalized stem cell program allowed the identification of potential CSC regulators, which were related mainly to metabolic processes. Using an siRNA genetic screen designed to target the 19 genes, we validated the functional role of this stem cell program in the regulation of breast CSC biology. Our work offers a proof of the functional importance of CSCs in breast cancer, and it establishes the reliability of PDXs for use in developing personalized CSC therapies for patients with breast cancer. Cancer Res; 73(24); 7290-300. Ó2013 AACR.

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Systems Pharmacology Assessment of the 5-Fluorouracil Pathway

Cited by 42 publications

References 38 publications

PDXGEM: Patient-Derived Tumor Xenograft based Gene Expression Model for Predicting Clinical Response to Anticancer Therapy in Cancer Patients

PDXGEM: Patient-Derived Tumor Xenograft based Gene Expression Model for Predicting Clinical Response to Anticancer Therapy in Cancer Patients

Overexpression of Uridine-Cytidine Kinase 2 Correlates with Breast Cancer Progression and Poor Prognosis

ALDH1-Positive Cancer Stem Cells Predict Engraftment of Primary Breast Tumors and Are Governed by a Common Stem Cell Program

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