Gene expression patterns within cell lines are predictive of chemosensitivity

Ring, Brian Z.; Chang, Stella; Ring, Ludwig; Seitz, Robert S.; Ross, Douglas T.

doi:10.1186/1471-2164-9-74

Cited by 16 publications

(9 citation statements)

References 27 publications

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“…The p values were fitted to a-beta-uniform mixture-BUM model to calculate the corresponding false discovery rate (FDR) [ 31 – 33 ]. FDR <0.2 was considered significant [ 34 ]. To compare protein expression levels across multiple generations, a g-statistic was used [ 35 ].…”

Section: Methodsmentioning

confidence: 99%

Ability to Generate Patient-Derived Breast Cancer Xenografts Is Enhanced in Chemoresistant Disease and Predicts Poor Patient Outcomes

et al. 2015

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BackgroundBreast cancer patients who are resistant to neoadjuvant chemotherapy (NeoCT) have a poor prognosis. There is a pressing need to develop in vivo models of chemo resistant tumors to test novel therapeutics. We hypothesized that patient-derived breast cancer xenografts (BCXs) from chemo- naïve and chemotherapy-exposed tumors can provide high fidelity in vivo models for chemoresistant breast cancers.MethodsPatient tumors and BCXs were characterized with short tandem repeat DNA fingerprinting, reverse phase protein arrays, molecular inversion probe arrays, and next generation sequencing.ResultsForty-eight breast cancers (24 post-chemotherapy, 24 chemo-naïve) were implanted and 13 BCXs were established (27%). BCX engraftment was higher in TNBC compared to hormone-receptor positive cancer (53.8% vs. 15.6%, p = 0.02), in tumors from patients who received NeoCT (41.7% vs. 8.3%, p = 0.02), and in patients who had progressive disease on NeoCT (85.7% vs. 29.4%, p = 0.02). Twelve patients developed metastases after surgery; in five, BCXs developed before distant relapse. Patients whose tumors developed BCXs had a lower recurrence-free survival (p = 0.015) and overall survival (p<0.001). Genomic losses and gains could be detected in the BCX, and three models demonstrated a transformation to induce mouse tumors. However, overall, somatic mutation profiles including potential drivers were maintained upon implantation and serial passaging. One BCX model was cultured in vitro and re-implanted, maintaining its genomic profile.ConclusionsBCXs can be established from clinically aggressive breast cancers, especially in TNBC patients with poor response to NeoCT. Future studies will determine the potential of in vivo models for identification of genotype-phenotype correlations and individualization of treatment.

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Section: Methodsmentioning

confidence: 99%

Ability to Generate Patient-Derived Breast Cancer Xenografts Is Enhanced in Chemoresistant Disease and Predicts Poor Patient Outcomes

et al. 2015

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“…There is an increasing interest in interfacing the studies on drug cytotoxicity based on the NCI's tumor screening panels with gene expression databases and the mechanisms of drug action, cell sensitivity and resistance [ 8 , 14 ]. These complementary approaches should provide clues about the mechanisms of some molecules, which ultimately can be developed as antitumor agents [ 10 , 14 , 15 ]. Drugs binding noncovalently to DNA have been in cancer treatment since the 60's, and a detailed structural and functional data on these molecules is available [ 4 ], including quantitative data on their binding to DNA as well as the GI 50 determined in the NCI-60 cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…While it is worth characterizing cancer cells to predict chemosensitivity to any particular drug [ 12 ], and to link changes in gene expression to cytotoxicity [ 8 , 13 - 15 ] it is also of utmost importance a deeper understanding of the mechanism of action of drugs, which includes the dissection of forces driving their noncovalent binding to DNA, and to use this information to help in the development of new anti-cancer agents with higher activity [ 9 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of molecular descriptors for antitumor drugs with respect to noncovalent binding to DNA and antiproliferative activity

Portugal

2009

BMC Pharmacol

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Background: Small molecules that bind reversibly to DNA are among the antitumor drugs currently used in chemotherapy. In the pursuit of a more rational approach to cancer chemotherapy based upon these molecules, it is necessary to exploit the interdependency between DNA-binding affinity, sequence selectivity and cytotoxicity. For drugs binding noncovalently to DNA, it is worth exploring whether molecular descriptors, such as their molecular weight or the number of potential hydrogen acceptors/donors, can account for their DNA-binding affinity and cytotoxicity.

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“…To uncover possible interactions between two entities i (ϭ metabolite) and j (ϭ transcript), the Pearson or Spearman's rank correlation coefficient ij has been calculated for each pair within the obtained dataset. The significance of each pair of metabolite and transcript was assessed using the false discovery rate (FDR), according to reported studies (41). Then by eliminating the associations with lower ij pairs (n ϭ 20), we selected the networks that contained only highly significant correlated entities.…”

Section: Methodsmentioning

confidence: 99%

Characterization of dietary protein-dependent amino acid metabolism by linking free amino acids with transcriptional profiles through analysis of correlation

Noguchi

Shikata

Furuhata

et al. 2008

Physiological Genomics

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This study aims to characterize diet-dependent amino acid metabolism by linking profiles of amino acids concentrations ("aminograms") with transcript datasets through the analysis of correlation. We used a dietary model of protein restriction-to-excess, where rats were fed diets with different levels of casein (5, 10, 15, 20, 30, 50, and 70%) for 2 wk. Twenty-five different amino acids in the plasma, liver, kidney, small intestine, and muscle and 71 gene transcripts in these compartments were measured together with general physiological variables. Under low-protein diet (LPD) conditions, the plasma aminogram for EAA was similar to that of the liver and the small intestine, respectively. Under the high-protein diet (HPD), however, the plasma aminogram for EAA became like that of muscle, while that of NEAA was similar with that of both liver and muscle. To assess the impact of gene expressions in each tissue on the plasma aminograms, correlations were obtained between aminograms and transcripts in each tissue under a diet with different protein levels. Based on the correlations obtained, amino acids and transcripts were systematically connected and then a metabolite-to-gene network was constructed for either LPD or HPD condition. The networks obtained and some other metabolically meaningful relationships such as ureagenesis and serine metabolism clearly illustrated activation of either body protein breakdown with LPD or amino acid catabolism with HPD.

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Gene expression patterns within cell lines are predictive of chemosensitivity

Cited by 16 publications

References 27 publications

Ability to Generate Patient-Derived Breast Cancer Xenografts Is Enhanced in Chemoresistant Disease and Predicts Poor Patient Outcomes

Ability to Generate Patient-Derived Breast Cancer Xenografts Is Enhanced in Chemoresistant Disease and Predicts Poor Patient Outcomes

Evaluation of molecular descriptors for antitumor drugs with respect to noncovalent binding to DNA and antiproliferative activity

Characterization of dietary protein-dependent amino acid metabolism by linking free amino acids with transcriptional profiles through analysis of correlation

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