A preclinical platform for assessing antitumor effects and systemic toxicities of cancer drug targets.
A preclinical platform for assessing antitumor effects and systemic toxicities of cancer drug targets.
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DOI：
10.1073/pnas.2110557119
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发表时间：
2022-04-26
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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许多新的抗癌药物由于疗效不佳和/或毒性过高而在临床阶段失败，尽管这是否反映了靶标或药物的缺陷通常尚不清楚。为了更早地了解可能影响体内靶标抑制治疗指数的因素，我们将诱导性 RNA 干扰和体细胞工程技术相结合，产生了一个具有成本效益的平台，能够在同一只小鼠的正常组织和肿瘤细胞中对候选靶标进行系统性和诱导性抑制。通过比较遗传和药理学 CDK9 抑制的后果，我们建立了该平台的实用性来预测影响治疗指数的因素。此外，我们的研究为 CDK9 抑制剂的临床开发提供了支持和一些警告。抗癌药物开发活动经常因对区分药物抗癌功效及其对宿主的靶向毒性的治疗指数的不完全了解而失败。为了解决这个问题，我们建立了一个多功能的临床前平台，在该平台中，使用体细胞组织工程在转基因小鼠中产生基因定义的癌症，这些转基因小鼠含有针对目标靶点的多西环素诱导的短发夹RNA。在该系统中，通过添加多西环素实现目标抑制，从而能够同时评估同一动物的功效和毒性。作为概念验证，我们重点关注 CDK9——一种癌症靶点，其临床开发一直受到靶点特异性知之甚少和不可接受的毒性的化合物的阻碍。我们系统地将基因 Cdk9 抑制产生的表型与使用最近开发的高度特异性小分子 CDK9 抑制剂获得的表型进行比较，发现这两种扰动都会导致强大的抗肿瘤反应。值得注意的是，无毒水平的 CDK9 抑制可以实现显着的治疗效果，并且长期抑制 CDK9 产生的剂量依赖性毒性在 Cdk9 恢复或停药后很大程度上可逆。总体而言，这些结果建立了一个多功能的体内靶点验证平台，可用于快速分类治疗靶点，并为旨在推进 CDK9 抑制剂用于癌症治疗的努力提供支持。
Many new cancer drugs fail at the clinical stage owing to poor efficacy and/or excessive toxicity, though whether this reflects shortcomings of the target or the drug is often unclear. To gain earlier insights into factors that can influence the therapeutic index of target inhibition in vivo, we combine inducible RNA interference and somatic engineering technologies to produce a cost-effective platform that enables systemic and inducible suppression of candidate target in normal tissues and tumor cells in the same mouse. By comparing the consequences of genetic and pharmacological CDK9 inhibition, we establish the utility of this platform to predict factors influencing the therapeutic index. Additionally, our studies provide support, and some cautionary notes, for the clinical development of CDK9 inhibitors. Anticancer drug development campaigns often fail due to an incomplete understanding of the therapeutic index differentiating the efficacy of the agent against the cancer and its on-target toxicities to the host. To address this issue, we established a versatile preclinical platform in which genetically defined cancers are produced using somatic tissue engineering in transgenic mice harboring a doxycycline-inducible short hairpin RNA against the target of interest. In this system, target inhibition is achieved by the addition of doxycycline, enabling simultaneous assessment of efficacy and toxicity in the same animal. As proof of concept, we focused on CDK9—a cancer target whose clinical development has been hampered by compounds with poorly understood target specificity and unacceptable toxicities. We systematically compared phenotypes produced by genetic Cdk9 inhibition to those achieved using a recently developed highly specific small molecule CDK9 inhibitor and found that both perturbations led to robust antitumor responses. Remarkably, nontoxic levels of CDK9 inhibition could achieve significant treatment efficacy, and dose-dependent toxicities produced by prolonged CDK9 suppression were largely reversible upon Cdk9 restoration or drug withdrawal. Overall, these results establish a versatile in vivo target validation platform that can be employed for rapid triaging of therapeutic targets and lend support to efforts aimed at advancing CDK9 inhibitors for cancer therapy.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
EFC6663的最终结果：一项多中心，国际，第2阶段研究的Alvocidib研究，针对氟达拉滨 - 难治性慢性淋巴细胞性白血病患者。
影响因子：
2.7
作者：
Lanasa MC;Andritsos L;Brown JR;Gabrilove J;Caligaris-Cappio F;Ghia P;Larson RA;Kipps TJ;Leblond V;Milligan DW;Janssens A;Johnson AJ;Heerema NA;Bühler A;Stilgenbauer S;Devin J;Hallek M;Byrd JC;Grever MR
通讯作者：
Grever MR
黄叶替醇在复发多发性骨髓瘤中进行的I期试验。
影响因子：
3
作者：
Hofmeister, Craig C.;Poi, Ming;Bowers, Mindy A.;Zhao, Weiqiang;Phelps, Mitch A.;Benson, Don M.;Kraut, Eric H.;Farag, Sherif;Efebera, Yvonne A.;Sexton, Jennifer;Lin, Thomas S.;Grever, Michael;Byrd, John C.
通讯作者：
Byrd, John C.
影响因子：
10.5
作者：
Huang CH;Lujambio A;Zuber J;Tschaharganeh DF;Doran MG;Evans MJ;Kitzing T;Zhu N;de Stanchina E;Sawyers CL;Armstrong SA;Lewis JS;Sherr CJ;Lowe SW
通讯作者：
Lowe SW
影响因子：
8.8
作者：
通讯作者：
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