Preclinical target validation using patient-derived cells

Edwards, A.M.; Arrowsmith, C.H.; Bountra, C.; Bunnage, Mark E.; Feldmann, Marc; Knight, Julian C.; Patel, Dhavalkumar D.; Prinos, Panagiotis; Taylor, Michael D.; Sundström, M.; Barker, Phil; Barsyte, Dalia; Bengtson, Mário H.; Bell, Cindy; Bowness, Paul; Boycott, Kym M.; Buser-Doepner, Carolyn; Carpenter, Christopher L.; Carr, Andrew; Clark, Kirk; Das, Anuk; Dhanak, Dashyant; Dirks, Peter B.; Ellis, James; Fantin, Valeria R.; Flores, Christopher M.; Fon, Edward A.; Frail, Donald E.; Gileadi, O.; O’Hagan, Ronan; Howe, Trevor; Isaac, John T.R.; Jabado, Nada; Jakobsson, Per‐Johan; Klareskog, Lars; Knapp, S.; Lee, Wen‐Hwa; Lima‐Fernandes, Evelyne; Lundberg, Ingrid E.; Marshall, John C.; Massirer, Katlin B.; MacKenzie, Alex; Maruyama, Tetsuyuki; Mueller‐Fahrnow, Anke; Muthuswamy, Senthil K.; Nanchahal, Jagdeep; O’Brien, Catherine A.; Oppermann, Udo; Ostermann, Nils; Petrecca, Kevin; Pollock, Bruce G.; Poupon, Viviane; Prinjha, Rab K.; Rosenberg, Saul H.; Rouleau, Guy A.; Skingle, M.; Slutsky, Arthur S.; Smith, Garth A. M.; Verhelle, Dominique; Widmer, Hans; Young, L. Trevor

doi:10.1038/nrd4565

Cited by 45 publications

(28 citation statements)

References 3 publications

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“…To date, most in vitro screening studies, based on cultured cancer cells, have utilized a two-dimensional (2D) culture model, which entails an adherent monolayer culture system. However, this model has its limitations, which have led to the high rate of clinical trial failures for new molecules derived from these screenings (Edwards et al, 2015;Sams-Dodd, 2005). Indeed, cancer cells grown in a 2D culture model lack certain characteristics of in vivo cancer cells, such as cell-cell and cell-matrix interactions (Baker and Chen, 2012;Kimlin et al, 2013), a hypoxic microenvironment and capacity for drug resistance (Wartenberg et al, 2003).…”

Section: Dandelion Extracts Inhibited the Breast Cancer Stem Cell Promentioning

confidence: 99%

Taraxacum officinale dandelion extracts efficiently inhibited the breast cancer stem cell proliferation

Trinh¹,

Dang²,

Tran³

et al. 2016

Biomed Res Ther

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Abstract-Introduction:Breast cancer stem cells (BCSCs) play an important role in breast cancer initiation, metastasis, recurrence, and drug resistance. Therefore, targeting BCSCs is an essential strategy to suppress cancer growth. This study aimed to evaluate the effects of dandelion Taraxacum officinale extracts on BCSC proliferation in vitro in 2D and 3D cell culture platforms. Methods: The BCSCs were maintained understandard conditions, verified for expression of CD44 and CD24 surface markers, and transfected with GFP before use in experiments. In the 2D model, the BCSCs were cultured as adherent cells in standard culture plates; in the 3D model, the BCSCs were cultured on low-adherent plates to form spheroids. The effect of Dandelion extracts on proliferation of BCSC was assessed by evaluating induction of cell death, expression of genes of death receptor signaling pathways, and production of reactive oxygen species (ROS) by BCSCs. Results: BCSCs formed spheroids as microtumors in vitro and exhibited some in vivo characteristics of tumors, such as increased expression of N-cadherin and Slug, decreased expression of E-cadherin, capacity to invade into the extracellular matrix (ECM), and presence of a hypoxic environment at the core of tumor spheroids. The dandelion extracts significantly inhibited BCSC proliferation in both two-dimensional (2D) and three-dimensional (3D) models of BCSCs. However, the IC50 value of dandelion extracts in BCSCs in the 3D model was much higher than that in the 2D model. The results also demonstrated that BCSCs treated with Dandelion extracts showed increased expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL receptor 2 (TRAILR2; i.e. death receptor 5;DR5). Moreover, treatment induced expression of DR4. Treatment with methanol dandelion extract enhanced production of ROS in BCSCs. Conclusion: Dandelion extracts are promising extracts for the treatment of breast tumors. The effect of methanol dandelion extract was better than that for ethanol extract. Importantly, BCSCs in 3D exhibited stronger drug resistance than those in 2D. In summary, our results indicate the strong potential of dandelion extracts as anti-cancer agents and rational use for drug development.

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Section: Dandelion Extracts Inhibited the Breast Cancer Stem Cell Promentioning

confidence: 99%

Taraxacum officinale dandelion extracts efficiently inhibited the breast cancer stem cell proliferation

Trinh¹,

Dang²,

Tran³

et al. 2016

Biomed Res Ther

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“…The genetic-and cell-based in vitro tool demonstrated in the present study may therefore have application potential (1) in drug-discovery where it provides a platform for assessing drug specificity or selectivity in vitro and (2) in personalized cancer care where it enables testing drugs in primary cultures and consequently may contribute to drug-selection in adjuvant chemotherapy 4 . Furthermore, pharmacological mechanism of a drug can be studied using this tool, since certain genetic alteration or multiple genetic alterations can be followed during the drug-treatment.…”

Section: Discussionmentioning

confidence: 99%

“…On the other side, because of this cellular heterogeneity, primary cultures resemble their original tumors far better than clonal cells in established cell lines 2 . More importantly, primary cultures are patient-specific and may enable individualized drug testing [2][3][4] . An essential issue is therefore the development of a method for determination of the proportion of tumor cells in mixed cultures including primary cultures.…”

Section: Introductionmentioning

confidence: 99%

Assessing Specificity of Anticancer Drugs <em>In Vitro</em>

Kluwe

2016

JoVE

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A procedure for assessing specificity of anticancer drugs in vitro using cultures containing both tumor and non-tumor cells is demonstrated. The key element is the quantitative determination of a tumor-specific genetic alteration in relation to a universal sequence using a dual-probe digital PCR assay and the subsequent calculation of the proportion of tumor cells. The assay is carried out on a culture containing tumor cells of an established line and spiked-in non-tumor cells. The mixed culture is treated with a test drug at various concentrations. After the treatment, DNA is prepared directly from the survived adhesive cells in wells of 96-well plates using a simple and inexpensive method, and subjected to a dualprobe digital PCR assay for measuring a tumor-specific genetic alteration and a reference universal sequence. In the present demonstration, a heterozygous deletion of the NF1 gene is used as the tumor-specific genetic alteration and a RPP30 gene as the reference gene. Using the ratio NF1/RPP30, the proportion of tumor cells was calculated. Since the dose-dependent change of the proportion of tumor cells provides an in vitro indication for specificity of the drug, this genetic and cell-based in vitro assay will likely have application potential in drug discovery. Furthermore, for personalized cancer-care, this genetic-and cell-based tool may contribute to optimizing adjuvant chemotherapy by means of testing efficacy and specificity of candidate drugs using primary cultures of individual tumors.

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“…Preclinical drug testing against a diverse human genetic background has the potential to refine drug response-to-genotype correlations, prevent the release of cytotoxic chemicals to the clinic, and enable informed decisions about drug prescriptions based on gender, ethnic group, disease status, etc. A growing body of evidence indicates that hiPSC-CMs can offer the pharmaceutical industry a powerful, human, and physiologically relevant tool for validating new drug candidates in early drug development stages (65).…”

Section: A Safety and Efficacy Assessment Of Novel Compounds In Precmentioning

confidence: 99%

Human Induced Pluripotent Stem Cells as a Platform for Personalized and Precision Cardiovascular Medicine

Matsa

Ahrens

2016

Physiological Reviews

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Human induced pluripotent stem cells (hiPSCs) have revolutionized the field of human disease modeling, with an enormous potential to serve as paradigm shifting platforms for preclinical trials, personalized clinical diagnosis, and drug treatment. In this review, we describe how hiPSCs could transition cardiac healthcare away from simple disease diagnosis to prediction and prevention, bridging the gap between basic and clinical research to bring the best science to every patient.

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Preclinical target validation using patient-derived cells

Abstract: The Structural Genomics Consortium (SGC) and its clinical, industry and disease-foundation partners are launching open-source preclinical translational medicine studies.

Cited by 45 publications

References 3 publications

Taraxacum officinale dandelion extracts efficiently inhibited the breast cancer stem cell proliferation

Taraxacum officinale dandelion extracts efficiently inhibited the breast cancer stem cell proliferation

Assessing Specificity of Anticancer Drugs <em>In Vitro</em>

Human Induced Pluripotent Stem Cells as a Platform for Personalized and Precision Cardiovascular Medicine

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