Single-cell functional and chemosensitive profiling of combinatorial colorectal therapy in zebrafish xenografts

Proceedings of the National Academy of Sciences, Год журнала: 2017, Номер 114(39)

Опубликована: Авг. 23, 2017

Significance Despite advances in targeted cancer treatments, we still lack methods to predict how a specific will respond given therapy. As consequence, patients go through rounds of trial-and-error approaches based on guidelines find the best treatment, often subjected unnecessary toxicity. Using cell lines, used zebrafish larvae xenografts as sensors for behavior and therapy guideline screening. Our data show not only sufficient resolution distinguish functional tumor behaviors just 4 days but also differential sensitivity colorectal proof-of-principle, provide evidence similar response therapies patient-derived xenografts. Altogether, our results suggest promising vivo screening platform precision medicine.

Язык: Английский

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Targeting the folate receptor: diagnostic and therapeutic approaches to personalize cancer treatments

Annals of Oncology, Год журнала: 2015, Номер 26(10), С. 2034 - 2043

Опубликована: Июнь 11, 2015

Язык: Английский

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MOLI: multi-omics late integration with deep neural networks for drug response prediction

Bioinformatics, Год журнала: 2019, Номер 35(14), С. i501 - i509

Опубликована: Июнь 6, 2019

Historically, gene expression has been shown to be the most informative data for drug response prediction. Recent evidence suggests that integrating additional omics can improve prediction accuracy which raises question of how integrate omics. Regardless integration strategy, clinical utility and translatability are crucial. Thus, we reasoned a multi-omics approach combined with datasets would relevance.

Язык: Английский

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Cell-to-Cell Variation in p53 Dynamics Leads to Fractional Killing

Cell, Год журнала: 2016, Номер 165(3), С. 631 - 642

Опубликована: Апрель 1, 2016

Язык: Английский

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Targeted nanomedicine for cancer therapeutics: Towards precision medicine overcoming drug resistance

Drug Resistance Updates, Год журнала: 2017, Номер 31, С. 15 - 30

Опубликована: Март 1, 2017

Язык: Английский

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Molecularly targeted cancer therapy: some lessons from the past decade

Trends in Pharmacological Sciences, Год журнала: 2013, Номер 35(1), С. 41 - 50

Опубликована: Дек. 19, 2013

Язык: Английский

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Intratumor Heterogeneity in Hepatocellular Carcinoma

Clinical Cancer Research, Год журнала: 2014, Номер 21(8), С. 1951 - 1961

Опубликована: Сен. 24, 2014

Morphologic intratumor heterogeneity is well known to exist in hepatocellular carcinoma (HCC), but very few systematic analyses of this phenomenon have been performed. The aim study was comprehensively characterize morphologic HCC. Also, taken into account were well-known immunohistochemical markers and molecular changes liver cells that are considered proposed classifications cell neoplasms or discussed as therapeutic targets.In HCC 23 patients without medical pretreatment, a total 120 tumor areas defined. Analyzed tissue morphology, expression the cytokeratin (CK)7, CD44, α-fetoprotein (AFP), epithelial adhesion molecule (EpCAM), glutamine synthetase (GS) along with mutations TP53 CTNNB1, assayed by both Sanger next-generation sequencing.Overall, detectable majority cases (20 23, 87%). Heterogeneity solely on level morphology found 6 (26%), combined 9 (39%), respect morphologic, immunohistochemical, mutational status CTNNB1 5 (22%).Our findings demonstrate represents challenge for establishment robust classification may contribute treatment failure drug resistance many

Язык: Английский

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Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas

PLoS Medicine, Год журнала: 2015, Номер 12(2), С. e1001786 - e1001786

Опубликована: Фев. 10, 2015

Background Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, seldom examined clinical trials or practice. Many studies have had prespecified markers for subpopulations, limiting their generalizability, involved massive efforts such as separate analysis hundreds individual cells, use. We recently developed a general measure based on whole-exome sequencing (WES) bulk DNA, called mutant-allele (MATH). Here, we examine data collected part large, multi-institutional study to validate this determine whether itself related mortality. Methods Findings Clinical WES were obtained from The Cancer Genome Atlas October 2013 305 patients with head neck squamous cell carcinoma (HNSCC), 14 institutions. Initial pathologic diagnoses between 1992 2011 (median, 2008). Median time death 131 deceased was mo; median follow-up living 22 mo. Tumor MATH values calculated results. Despite multiple subsites variety treatments, found retrospective substantial relation high decreased overall survival (Cox proportional hazards analysis: hazard ratio high/low heterogeneity, 2.2; 95% CI 1.4 3.3). This not due heterogeneity's associations other molecular characteristics, including age, human papillomavirus status, grade TP53 mutation, N classification. improved prognostication over that provided by traditional maintained significant multivariate analyses, distinguished outcomes among having oral-cavity laryngeal cancers even when standard disease staging taken into account. Prospective studies, however, will be required before can used prognostically Such need homogeneously treated HNSCC at specific subsites, influence cancer therapy values. Analysis outcome human-papillomavirus-positive oropharyngeal particularly needed. Conclusions To our knowledge first combine patients, institutions, document any type cancer. suggest applying simply metric prospective types.

Язык: Английский

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Inference of Tumor Evolution during Chemotherapy by Computational Modeling and In Situ Analysis of Genetic and Phenotypic Cellular Diversity

Cell Reports, Год журнала: 2014, Номер 6(3), С. 514 - 527

Опубликована: Янв. 23, 2014

Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis cellular heterogeneity for genetic and phenotypic features their spatial distribution in breast pre- post-neoadjuvant chemotherapy. We found intratumor diversity was tumor-subtype specific, it did not with partial or no response. However, lower pretreatment significantly associated pathologic complete In contrast, different between posttreatment samples. also observed significant changes cells distinct features. used these experimental data to develop stochastic computational model infer growth patterns evolutionary dynamics. Our results highlight importance integrated genotypes phenotypes single intact tissues predict evolution.

Язык: Английский

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Genetic profiling of hepatocellular carcinoma using next-generation sequencing

Journal of Hepatology, Год журнала: 2016, Номер 65(5), С. 1031 - 1042

Опубликована: Июнь 2, 2016

Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, both clinically and from molecular standpoint. The advent of next-generation sequencing technologies has provided new opportunities to extensively analyze defects in HCC samples. This uncovered major cancer driver genes associated oncogenic pathways operating HCC. More sophisticated analyses data have linked specific nucleotide patterns external toxic agents defined so-called ‘mutational signatures’ Molecular signatures, taking into account intra- inter-tumor heterogeneity, their functional validation could provide useful predict treatment response therapies. In this review we will focus on the current knowledge deep its foreseeable clinical impact.

Язык: Английский

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