Integrated human organ-on-a-chip model for predictive studies of anti-tumor drug efficacy and cardiac safety.
Integrated human organ-on-a-chip model for predictive studies of anti-tumor drug efficacy and cardiac safety.
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DOI：
10.1039/d0lc00424c
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发表时间：
2020-11-24
期刊：
影响因子：
6.1
通讯作者：
Vunjak-Novakovic G
中科院分区：
文献类型：
--
作者：
Chramiec A;Teles D;Yeager K;Marturano-Kruik A;Pak J;Chen T;Hao L;Wang M;Lock R;Tavakol DN;Lee MB;Kim J;Ronaldson-Bouchard K;Vunjak-Novakovic G
传统的药物筛选模型通常无法忠实地再现健康和疾病中的人体生理学，这促使微流体芯片上器官（OOC）平台的发展，该平台可以模拟人体生理学的许多方面，并在此过程中缓解临床前研究和临床试验结果之间的许多差异。Linsitinib是一种新型抗癌药物，在尤文肉瘤（ES）的临床前模型中显示出有希望的结果，其中它抑制肿瘤生长。然而，在几个欧洲中心进行的II期临床试验显示患者复发和/或难治性ES。我们报告了一个集成的，开放的设置，成像和采样访问，聚砜为基础的平台，具有最小的疏水化合物结合。两种生物工程人类组织-骨ES肿瘤和心肌-在隔离或集成平台中培养，并接受临床使用的linsitinib剂量。将测得的抗肿瘤疗效和心脏毒性与临床试验中观察到的结果进行比较。只有工程肿瘤组织，而不是单层，概括了linsitinib靶向的骨微环境途径，以及非转移性和转移性ES肿瘤之间药物反应的临床相关差异。非转移性ES肿瘤组织和心肌对linsitinib的反应更接近于在综合环境中培养的组织的临床试验中观察到的反应，而不是分离培养的组织。对分离组织的药物治疗导致肿瘤存活率和心脏功能显著降低。同时，在综合环境中的药物治疗显示出较差的肿瘤反应和较低的心脏毒性，这与临床试验的结果相匹配。总的来说，在整合平台中整合工程化的人类肿瘤和心脏组织提高了linsitinib的直接和脱靶效应的预测准确性。所提出的方法可以很容易地扩展到其他药物和组织系统。
Traditional drug screening models are often unable to faithfully recapitulate human physiology in health and disease, motivating the development of microfluidic organs-on-a-chip (OOC) platforms that can mimic many aspects of human physiology and in the process alleviate many of the discrepancies between preclinical studies and clinical trials outcomes. Linsitinib, a novel anti-cancer drug, showed promising results in pre-clinical models of Ewing Sarcoma (ES), where it suppressed tumor growth. However, a Phase II clinical trial in several European centers with patients showed relapsed and/or refractory ES. We report an integrated, open setting, imaging and sampling accessible, polysulfone-based platform, featuring minimal hydrophobic compound binding. Two bioengineered human tissues – bone ES tumor and heart muscle – were cultured either in isolation or in the integrated platform and subjected to a clinically used linsitinib dosage. The measured anti-tumor efficacy and cardiotoxicity were compared with the results observed in the clinical trial. Only the engineered tumor tissues, and not monolayers, recapitulated the bone microenvironment pathways targeted by linsitinib, and the clinically-relevant differences in drug responses between non-metastatic and metastatic ES tumors. The responses of non-metastatic ES tumor tissues and heart muscle to linsitinib were much closer to those observed in the clinical trial for tissues cultured in an integrated setting than for tissues cultured in isolation. Drug treatment of isolated tissues resulted in significant decreases in tumor viability and cardiac function. Meanwhile, drug treatment in an integrated setting showed poor tumor response and less cardiotoxicity, which matched the results of the clinical trial. Overall, the integration of engineered human tumor and cardiac tissues in the integrated platform improved the predictive accuracy for both the direct and off-target effects of linsitinib. The proposed approach could be readily extended to other drugs and tissue systems.
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影响因子：
5.2
作者：
Allard JB;Duan C
通讯作者：
Duan C
影响因子：
48
作者：
Burridge, Paul W.;Matsa, Elena;Shukla, Praveen;Lin, Ziliang C.;Churko, Jared M.;Ebert, Antje D.;Lan, Feng;Diecke, Sebastian;Huber, Bruno;Mordwinkin, Nicholas M.;Plews, Jordan R.;Abilez, Oscar J.;Cui, Bianxiao;Gold, Joseph D.;Wu, Joseph C.
通讯作者：
Wu, Joseph C.
DOI：
10.1002/cnm.2838
发表时间：
2017-07-01
影响因子：
2.1
作者：
Kannan, Ravishekar;Chen, Z. J.;Walenga, Ross
通讯作者：
Walenga, Ross
影响因子：
4.6
作者：
Edington CD;Chen WLK;Geishecker E;Kassis T;Soenksen LR;Bhushan BM;Freake D;Kirschner J;Maass C;Tsamandouras N;Valdez J;Cook CD;Parent T;Snyder S;Yu J;Suter E;Shockley M;Velazquez J;Velazquez JJ;Stockdale L;Papps JP;Lee I;Vann N;Gamboa M;LaBarge ME;Zhong Z;Wang X;Boyer LA;Lauffenburger DA;Carrier RL;Communal C;Tannenbaum SR;Stokes CL;Hughes DJ;Rohatgi G;Trumper DL;Cirit M;Griffith LG
通讯作者：
Griffith LG
影响因子：
4.1
作者：
Boudou, Thomas;Legant, Wesley R.;Chen, Christopher S.
通讯作者：
Chen, Christopher S.