Pharma Firms Push for Sharing of Cancer Trial Data

Bhattacharjee, Yudhijit

doi:10.1126/science.338.6103.29

Cited by 34 publications

(22 citation statements)

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“…Cancer therapy for advanced cancers is far from being efficient to date (Scannell et al, 2012). Despite some key therapeutic success in targeted therapy, the current fail rate of anti-cancer compounds in clinic trials is 96% (Bhattacharjee, 2012). Clearly, there is an urgent need for more innovative pre-clinical in vitro models to thoroughly test promising compounds before proceeding into clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Comparison of cancer cells cultured in 2D vs 3D reveals differences in AKT/mTOR/S6-kinase signaling and drug response

Riedl

Schlederer

Pudelko

et al. 2016

Journal of Cell Science

349

293

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Three-dimensional (3D) cancer models are used as preclinical systems to mimic physiologic drug responses. We provide evidence for strong changes of proliferation and metabolic capacity in three dimensions by systematically analyzing spheroids of colon cancer cell lines. Spheroids showed relative lower activities in the AKT, mammalian target of rapamycin (mTOR) and S6K (also known as RPS6KB1) signaling pathway compared to cells cultured in two dimensions. We identified spatial alterations in signaling, as the level of phosphorylated RPS6 decreased from the spheroid surface towards the center, which closely coordinated with the tumor areas around vessels in vivo. These 3D models displayed augmented antitumor responses to AKT-mTOR-S6K or mitogen-activated protein kinase (MAPK) pathway inhibition compared to those in 2D models. Inhibition of AKT-mTOR-S6K resulted in elevated ERK phosphorylation in 2D culture, whereas under these conditions, ERK signaling was reduced in spheroids. Inhibition of MEK1 (also known as MAP2K1) led to decreased AKT-mTOR-S6K signaling in 3D but not in 2D culture. These data indicate a distinct rewiring of signaling in 3D culture and during treatment. Detached tumor-cell clusters in vessels, in addition to circulating single tumor cells, play a putative role in metastasis in human cancers. Hence, the understanding of signaling in spheroids and the responses in the 3D models upon drug treatment might be beneficial for anti-cancer therapies.

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Section: Discussionmentioning

confidence: 99%

Comparison of cancer cells cultured in 2D vs 3D reveals differences in AKT/mTOR/S6-kinase signaling and drug response

Riedl

Schlederer

Pudelko

et al. 2016

Journal of Cell Science

349

293

View full text Add to dashboard Cite

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“…Due to poor correlations of preclinical in vitro data to drug efficacy in patients, particularly in the field of cancer (Bhattacharjee, ), new 3D tumor models arise, such as spheroids, microfluidic devices, organoids, and matrix‐based approaches (Alemany‐Ribes and Semino, ; Edmondson et al ., ; Xu et al ., ). The generally high proliferation rate in 2D cell cultures is one reason for false‐positive predictions of cytostatic compounds (Cree et al ., ).…”

Section: Introductionmentioning

confidence: 99%

A combined tissue‐engineered/in silico signature tool patient stratification in lung cancer

Göttlich

Kunz²,

Zapp³

et al. 2018

Molecular Oncology

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Patient‐tailored therapy based on tumor drivers is promising for lung cancer treatment. For this, we combined in vitro tissue models with in silico analyses. Using individual cell lines with specific mutations, we demonstrate a generic and rapid stratification pipeline for targeted tumor therapy. We improve in vitro models of tissue conditions by a biological matrix‐based three‐dimensional (3D) tissue culture that allows in vitro drug testing: It correctly shows a strong drug response upon gefitinib (Gef) treatment in a cell line harboring an EGFR‐activating mutation (HCC827), but no clear drug response upon treatment with the HSP90 inhibitor 17AAG in two cell lines with KRAS mutations (H441, A549). In contrast, 2D testing implies wrongly KRAS as a biomarker for HSP90 inhibitor treatment, although this fails in clinical studies. Signaling analysis by phospho‐arrays showed similar effects of EGFR inhibition by Gef in HCC827 cells, under both 2D and 3D conditions. Western blot analysis confirmed that for 3D conditions, HSP90 inhibitor treatment implies different p53 regulation and decreased MET inhibition in HCC827 and H441 cells. Using in vitro data (western, phospho‐kinase array, proliferation, and apoptosis), we generated cell line‐specific in silico topologies and condition‐specific (2D, 3D) simulations of signaling correctly mirroring in vitro treatment responses. Networks predict drug targets considering key interactions and individual cell line mutations using the Human Protein Reference Database and the COSMIC database. A signature of potential biomarkers and matching drugs improve stratification and treatment in KRAS‐mutated tumors. In silico screening and dynamic simulation of drug actions resulted in individual therapeutic suggestions, that is, targeting HIF1A in H441 and LKB1 in A549 cells. In conclusion, our in vitro tumor tissue model combined with an in silico tool improves drug effect prediction and patient stratification. Our tool is used in our comprehensive cancer center and is made now publicly available for targeted therapy decisions.

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“…In fact, large pharmaceutical companies have already started creating consortia for sharing clinical trials data, such as Yale Open Data Access and Project DataSphere. 5 Similar efforts were instrumental in developing and characterizing a novel clinical outcomes measure for multiple sclerosis 6 and raising critical questions about a commonly used, imaging-based surrogate marker of disease progression. 7 Data sharing is especially valuable in rare diseases with complex gene-environment interactions and variable disease progression rates such as ALS.…”

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confidence: 99%

The PRO-ACT database

et al. 2014

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Objective: To pool data from completed amyotrophic lateral sclerosis (ALS) clinical trials and create an open-access resource that enables greater understanding of the phenotype and biology of ALS.Methods: Clinical trials data were pooled from 16 completed phase II/III ALS clinical trials and one observational study. Over 8 million de-identified longitudinally collected data points from over 8,600 individuals with ALS were standardized across trials and merged to create the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. This database includes demographics, family histories, and longitudinal clinical and laboratory data. Mixed effects models were used to describe the rate of disease progression measured by the Revised ALS Functional Rating Scale (ALSFRS-R) and vital capacity (VC). Cox regression models were used to describe survival data. Implementing Bonferroni correction, the critical p value for 15 different tests was p 5 0.003. Results:The ALSFRS-R rate of decline was 1.02 (62.3) points per month and the VC rate of decline was 2.24% of predicted (66.9) per month. Higher levels of uric acid at trial entry were predictive of a slower drop in ALSFRS-R (p 5 0.01) and VC (p , 0.0001), and longer survival (p 5 0.02). Higher levels of creatinine at baseline were predictive of a slower drop in ALSFRS-R (p 5 0.01) and VC (p , 0.0001), and longer survival (p 5 0.01). Finally, higher body mass index (BMI) at baseline was associated with longer survival (p , 0.0001). Conclusion:The PRO-ACT database is the largest publicly available repository of merged ALS clinical trials data. We report that baseline levels of creatinine and uric acid, as well as baseline BMI, are strong predictors of disease progression and survival. Neurology ® 2014;83:1719-1725 GLOSSARY ALS 5 amyotrophic lateral sclerosis; ALSFRS 5 ALS Functional Rating Scale; ALSFRS-R 5 revised ALS Functional Rating Scale; BMI 5 body mass index; CDS 5 common data structure; CI 5 confidence interval; HR 5 hazard ratio; PRO-ACT 5 Pooled Resource Open-Access ALS Clinical Trials; VC 5 vital capacity.Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that affects motor neurons in the brain and spinal cord. People with ALS have progressive voluntary muscle weakness involving the arms, legs, speech, swallowing, and breathing. Because ALS is a rare disease with an annual incidence of 2/100,000, 2 clinical trials have typically been relatively small, with the largest studies including fewer than 1,000 participants. Therefore, aggregation of studies is needed to allow enough statistical power to answer important questions about ALS natural history and clinical symptoms in order to overcome some of the barriers associated with drug development for orphan diseases.The Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database was designed to provide just such an opportunity. This database represents the largest aggregation of ALS clinical trial data available. Sixteen phase II and III ALS trials and one large observational s...

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Pharma Firms Push for Sharing of Cancer Trial Data

Abstract: A consortium of pharmaceutical companies hopes to improve the success rate of experimental cancer therapies by getting cancer researchers to share data from clinical trials.

Cited by 34 publications

References 0 publications

Comparison of cancer cells cultured in 2D vs 3D reveals differences in AKT/mTOR/S6-kinase signaling and drug response

Comparison of cancer cells cultured in 2D vs 3D reveals differences in AKT/mTOR/S6-kinase signaling and drug response

A combined tissue‐engineered/in silico signature tool patient stratification in lung cancer

The PRO-ACT database

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