An implantable microdevice to perform high-throughput in vivo drug sensitivity testing in tumors

Jonas, O; Landry, H. M.; Fuller, J. E.; Santini, J. T.; Baselga, J; Tepper, R. I.; Cima, M J; Langer, R.

doi:10.1126/scitranslmed.3010564

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An implantable microdevice to perform high-throughput in vivo drug sensitivity testing in tumors

Author(s): O. Jonas , H. M. Landry , J. E. Fuller , J. T. Santini , J. Baselga , R. I. Tepper , M. J. Cima , R. Langer

Publication date Created: April 22 2015

Publication date (Print): April 22 2015

Journal: Science Translational Medicine

Publisher: American Association for the Advancement of Science (AAAS)

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Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks.

Michael J. Lee, Albert S. Ye, Alexandra K. Gardino … (2012)

Crosstalk and complexity within signaling pathways and their perturbation by oncogenes limit component-by-component approaches to understanding human disease. Network analysis of how normal and oncogenic signaling can be rewired by drugs may provide opportunities to target tumors with high specificity and efficacy. Using targeted inhibition of oncogenic signaling pathways, combined with DNA-damaging chemotherapy, we report that time-staggered EGFR inhibition, but not simultaneous coadministration, dramatically sensitizes a subset of triple-negative breast cancer cells to genotoxic drugs. Systems-level analysis-using high-density time-dependent measurements of signaling networks, gene expression profiles, and cell phenotypic responses in combination with mathematical modeling-revealed an approach for altering the intrinsic state of the cell through dynamic rewiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to DNA damage-induced cell death by reactivation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state. Copyright © 2012 Elsevier Inc. All rights reserved.

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Small-scale systems for in vivo drug delivery.

David Laván, Terry McGuire, Robert S. Langer (2003)

Recent developments in the application of micro- and nanosystems for drug administration include a diverse range of new materials and methods. New approaches include the on-demand activation of molecular interactions, novel diffusion-controlled delivery devices, nanostructured 'smart' surfaces and materials, and prospects for coupling drug delivery to sensors and implants. Micro- and nanotechnologies are enabling the design of novel methods such as radio-frequency addressing of individual molecules or the suppression of immune response to a release device. Current challenges include the need to balance the small scale of the devices with the quantities of drugs that are clinically necessary, the requirement for more stable sensor platforms, and the development of methods to evaluate these new materials and devices for safety and efficacy.

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The productivity crisis in pharmaceutical R&D.

Fabio Pammolli, Laura Magazzini, Massimo Riccaboni (2011)

Advances in the understanding of the molecular basis of diseases have expanded the number of plausible therapeutic targets for the development of innovative agents in recent decades. However, although investment in pharmaceutical research and development (R&D) has increased substantially in this time, the lack of a corresponding increase in the output in terms of new drugs being approved indicates that therapeutic innovation has become more challenging. Here, using a large database that contains information on R&D projects for more than 28,000 compounds investigated since 1990, we examine the decline of R&D productivity in pharmaceuticals in the past two decades and its determinants. We show that this decline is associated with an increasing concentration of R&D investments in areas in which the risk of failure is high, which correspond to unmet therapeutic needs and unexploited biological mechanisms. We also investigate the potential variations in productivity with regard to the regional location of companies and find that although companies based in the United States and Europe differ in the composition of their R&D portfolios, there is no evidence of any productivity gap.