Integrated human organ-on-a-chip model for predictive studies of anti-tumor drug efficacy and cardiac safety

Chramiec, Alan; Teles, Diogo; Yeager, Keith; Marturano-Kruik, Alessandro; Pak, Joseph; Chen, Timothy; Hao, Luke; Wang, Miranda; Lock, Roberta; Tavakol, Daniel Naveed; Lee, Marcus Busub; Kim, Jin-Ho; Ronaldson-Bouchard, Kacey; Vunjak‐Novakovic, Gordana

doi:10.1039/d0lc00424c

Cited by 80 publications

(66 citation statements)

References 57 publications

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“…For instance, a recent study demonstrated that linsitinib, a promising drug candidate to treat Ewing sarcoma, significantly reduced tumor viability and cardiac function when both of these engineered tissues were cultured separately under perfusion in an organ-on-a-chip system. However, when they were cultured in an integrated way in the same platform, linsitinib showed poor tumor response and less cardiotoxicity, which was in agreement with the unfortunate clinical trial outcome of this drug 199 . Testing the targeted or off-targeted effect of new cardiovascular drugs will require advancing the physiological relevance in which cardiac engineered tissues are cultured.…”

Section: Unlocking Cardiac Tissue Engineering For Precision Medicinesupporting

confidence: 72%

Next generation of heart regenerative therapies: progress and promise of cardiac tissue engineering

et al. 2021

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The adult heart is a vital and highly specialized organ of the human body, with limited capability of self-repair and regeneration in case of injury or disease. Engineering biomimetic cardiac tissue to regenerate the heart has been an ambition in the field of tissue engineering, tracing back to the 1990s. Increased understanding of human stem cell biology and advances in process engineering have provided an unlimited source of cells, particularly cardiomyocytes, for the development of functional cardiac muscle, even though pluripotent stem cell-derived cardiomyocytes poorly resemble those of the adult heart. This review outlines key biology-inspired strategies reported to improve cardiomyocyte maturation features and current biofabrication approaches developed to engineer clinically relevant cardiac tissues. It also highlights the potential use of this technology in drug discovery science and disease modeling as well as the current efforts to translate it into effective therapies that improve heart function and promote regeneration.

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Section: Unlocking Cardiac Tissue Engineering For Precision Medicinesupporting

confidence: 72%

Next generation of heart regenerative therapies: progress and promise of cardiac tissue engineering

et al. 2021

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“…[ 24 ] Such multiorgan devices have been used to simultaneously evaluate drug efficacy and safety aspects on a systemic level. [ 24–27 ] Probing off‐target toxicity of compounds in multiorgan systems has proven to be particularly useful for prodrugs that are inactive without hepatic metabolism. [ 26–31 ] Multiorgan systems represent a potential solution to capture the full extent of complex DDI events—ranging from metabolizing organs to drug target organs—and to predict the safety of critical drug combinations.…”

Section: Introductionmentioning

confidence: 99%

Predicting Metabolism‐Related Drug–Drug Interactions Using a Microphysiological Multitissue System

et al. 2020

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Pharmacokinetic DDIs arise upon modulation of the absorption, distribution, and metabolism or excretion (ADME) properties of one drug by co-administration of another drug and can lead to massive changes of drug plasma concentrations with potentially life-threatening consequences. [6] Most commonly, a perpetrator drug modulates the metabolism of a victim drug by chemical inhibition or transcriptional induction of drug-metabolizing enzymes. In both cases, such an interaction leads to an altered metabolic fate of the victim drug. [7] The clinical implications of such interactions can result in a lack of efficacy, especially in the context of so-called prodrugs. Prodrugs are drug variants with enhanced solubility or lifetime, which rely on in vivo bioconversion to exert their pharmacological activity. [8] Positive treatment outcomes in prodrug therapies strongly depend on the ability of the patient to endogenously bioactivate the prodrug compound to its pharmacologically active metabolite(s). [9] Drug metabolism predominantly occurs in the liver and is mainly catalyzed by enzymes of the cytochrome P450 (CYP) family. These enzymes oxidize, reduce, and hydrolyze a wide range of drugs or chemical entities. Therefore, it does not come as a surprise that inhibition or induction of CYP enzymes is largely involved in clinical DDIs and has led to severe ADRs and the withdrawal of multiple drugs from the market. [10] In many cases, DDIs manifest themselves in secondary organs, to which liver-generated metabolites are transported through systemic circulation. Such tissues include kidney, heart, brain, gut, and lungs, and drug target tissues, such as tumors. [11] Oncology patients are considered especially prone to toxic DDI events owing to i) the wide use of anticancer prodrugs, [12,13] ii) the inherent toxicity of anticancer agents and their very narrow therapeutic index, iii) the likelihood of cancer patients to receive many different medications for the management of other illnesses, [14] and iv) the increasing use of combination therapies with more than one anticancer medication. [15] Hence, clinicians are confronted with the growing risk of prescribing drug combinations that can inadvertently lead to severe clinical implications. [16] Additionally, genetic polymorphisms in the liver can lead to individual patterns of CYP-enzyme-mediated metabolism for different patients. [17] Management of DDIs is, therefore, crucial in oncology therapy, where the altered Drug-drug interactions (DDIs) occur when the pharmacological activity of one drug is altered by a second drug. As multimorbidity and polypharmacotherapy are becoming more common due to the increasing age of the population, the risk of DDIs is massively increasing. Therefore, in vitro testing methods are needed to capture such multiorgan events. Here, a scalable, gravity-driven microfluidic system featuring 3D microtissues (MTs) that represent different organs for the prediction of drug-drug interactions is used. Human liver microtissues (hLiMTs) are combined with tumor m...

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“…12 Ultimately, this 5-year program provided proof of principle that tissue chips could accurately recapitulate human physiology and drug responses. 12 While DARPA funding ended in 2017, the NIH MPS program has continued and since evolved to look at various tissue chip technology end uses, including disease modeling and efficacy testing; [74][75][76][77][78][79] modeling opioid use disorders; using tissue chips to improve clinical trial design and execution; and creating independent validation/testing centers 59,[80][81][82] plus a publicly accessible database 83,84 for MPS data. In addition to the NIH and DARPA MPS programs, the US Environmental Protection Agency established the "Science to Achieve Results" (STAR) grant program, one goal of which is to further the development of organotypic culture models, including organs-on-chips (OoCs) for predictive toxicology.…”

Section: Impact Statementmentioning

confidence: 99%

“…Recently, researchers at Columbia developed a bone cancer tumor (Ewing Sarcoma) and heart muscle integrated system, which they subjected to the clinically used dosage of the novel anti-cancer drug, Linsitinib. 79 They measured the anti-tumor efficacy as well as the cardiotoxicity of the drug and compared these results with recent clinical trial results. Linsitinib treatment in the integrated platform matched the clinical trial results, with poor tumor response and mild cardiotoxicity, indicating that the integrated tissue platform was able to accurately predict both the direct and off-target effects of the drug.…”

Section: Multi-organ Mps Platform Integrationmentioning

confidence: 99%

Microphysiological systems: What it takes for community adoption

Hargrove-Grimes

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2021

Exp Biol Med (Maywood)

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Microphysiological systems (MPS) are promising in vitro tools which could substantially improve the drug development process, particularly for underserved patient populations such as those with rare diseases, neural disorders, and diseases impacting pediatric populations. Currently, one of the major goals of the National Institutes of Health MPS program, led by the National Center for Advancing Translational Sciences (NCATS), is to demonstrate the utility of this emerging technology and help support the path to community adoption. However, community adoption of MPS technology has been hindered by a variety of factors including biological and technological challenges in device creation, issues with validation and standardization of MPS technology, and potential complications related to commercialization. In this brief Minireview, we offer an NCATS perspective on what current barriers exist to MPS adoption and provide an outlook on the future path to adoption of these in vitro tools.

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Integrated human organ-on-a-chip model for predictive studies of anti-tumor drug efficacy and cardiac safety

Abstract: Traditional drug screening models are often unable to faithfully recapitulate human physiology in health and disease. Linsitinib, a novel anti-cancer drug, showed promising results in pre-clinical models of Ewing Sarcoma...

Cited by 80 publications

References 57 publications

Next generation of heart regenerative therapies: progress and promise of cardiac tissue engineering

Next generation of heart regenerative therapies: progress and promise of cardiac tissue engineering

Predicting Metabolism‐Related Drug–Drug Interactions Using a Microphysiological Multitissue System

Microphysiological systems: What it takes for community adoption

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