Novel CTD inhibitors with synthetic lethality to oncogenic Ras for cancer therapy
新型 CTD 抑制剂对致癌 Ras 具有合成杀伤力,用于癌症治疗
基本信息
- 批准号:8403955
- 负责人:
- 金额:$ 29.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-01-01 至 2014-12-31
- 项目状态:已结题
- 来源:
- 关键词:Antineoplastic AgentsApoptosisC-terminalCDK9 Protein KinaseCancer cell lineCategoriesCell LineCellsClinical TreatmentClinical TrialsColon CarcinomaComplexCyclin-Dependent KinasesDataDevelopmentDevelopmental Therapeutics ProgramDrug KineticsEpithelial CellsEvaluationFutureGene MutationGenetic TranscriptionGoalsGrowthHumanIn VitroInduction of ApoptosisK-ras GeneLeadLungLung NeoplasmsMaintenanceMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of ovaryMolecularMolecular AnalysisMutationNational Cancer InstituteNew AgentsNormal CellNude MiceOncogenesOncogenicOvarianPathway interactionsPersonal CommunicationPhenotypePhosphorylationPlayPredispositionRAS genesRNARNA Polymerase IIRNA SplicingRNA polymerase II largest subunitRenal carcinomaReportingRoleSafetySmall Interfering RNASolidTestingTherapeutic AgentsToxic effectYeastsanaloganti-cancer therapeuticanticancer activityanticancer treatmentantitumor agentcancer cellcancer therapycell transformationcyclin T1cytotoxicflavopiridolin vitro activityin vivoinhibitor/antagonistkillingsmalignant breast neoplasmmutantnovelnovel therapeuticspre-clinicalpreclinical studypreventprotein kinase C iotaprototypepublic health relevanceras Proteinsresearch clinical testingscreeningsmall molecule librariestumortumor xenografttumorigenic
项目摘要
DESCRIPTION (provided by applicant): The oncogenic Ras proteins play critical roles in the development and maintenance of cancer phenotypes and serve as important targets for anticancer treatment. However, oncogenic Ras-targeted therapeutic agents are not yet available. Therefore, it is urgent to develop anticancer agents that can effectively eliminate Ras-mutant cancer cells. We hypothesize that agents that induce synthetic lethality in cancer cells expressing oncogenic Ras genes but not in normal isogenic cells will be valuable prototypes for developing Ras-targeted anticancer therapeutics. In searching for such agents, we screened a chemical library and identified a compound (designated oncrasin-1) that kills immortalized and tumorigenic human ovarian epithelial cells expressing oncogenic K-Ras but not their isogenic normal counterparts. Oncrasin-1 can effectively kill various lung cancer cells with K-Ras mutations. The cytotoxic effects correlated with apoptosis induction by the compounds and could be blocked by K-Ras siRNA or protein kinase C iota (PKCiota) siRNA, suggesting that Ras and/or PKCiota activities are required for oncrasin-induced apoptosis. Treatment of sensitive cancer cells with oncrasin-1, -60, or -231 led to suppression of the phosphorylation of the C-terminal domain (CTD) of the largest subunit of RNA polymerase II, whish is consistent with previous reports that the continuous activity of RNA polymerase II is required to prevent oncogene-induced apoptosis in transformed cells and that mutations compromising CTD function is synthetically lethal with elevated levels of Ras activity in yeast. Treatment with oncrasin-1 also led to co-aggregation of PKCiota and splicing factors in megaspliceosomes and to disruption of the interaction between PKCiota and CDK9/cyclin T1 complex, which phosphorylates the CTD. Thus, we hypothesized that oncrasin compounds are a novel class of CTD inhibitors with selective anticancer activity. The in vivo administration of oncrasin-1 suppressed the growth of human lung tumor xenografts by >70% and prolonged the survival of tumor-bearing nude mice without causing detectable toxicity. Testing some of those analogues on NCI-60 cell lines showed that oncrasins are active against several cell lines derived from lung, colon, breast, ovary, and kidney cancers and oncrasin-60 lies outside the category of adequately studied classes of antitumor agents, indicating its novel anticancer mechanisms. Thus, oncrasin compounds are potentially a novel class of CTD inhibitors that are synthetically lethal to cancers with increased Ras/PKCiota activity. However, in vivo evaluation of the pharmacokinetics, antitumor efficacy, and safety of oncrasin compounds is necessary before they can be evaluated clinically. The goal of this proposal is to determine anti- lung cancer activity of the most active analogues by evaluating their in vitro activities in several lung cancer cell lines with or without Ras gene mutations, their pharmacokinetics, and their in vivo activity and toxicity. The proposed studies will provide solid preclinical data for possible clinical evaluation of oncrasin compounds and may lead to the development of new therapeutic agents that are useful for the treatment of lung cancers.
描述(由申请方提供):致癌Ras蛋白在癌症表型的发展和维持中发挥关键作用,并作为抗癌治疗的重要靶点。然而,致癌Ras靶向治疗药物尚未上市。因此,迫切需要开发能够有效消除Ras突变型癌细胞的抗癌剂。我们假设,在表达致癌Ras基因的癌细胞中诱导合成致死性但在正常等基因细胞中不诱导合成致死性的药剂将是开发Ras靶向抗癌疗法的有价值的原型。在寻找这样的代理商,我们筛选了一个化学库,并确定了一种化合物(命名oncrasin-1),杀死永生化和致瘤的人卵巢上皮细胞表达致癌K-Ras,但不是他们的同基因正常的对应物。Oncrasin-1可有效杀伤多种K-Ras突变的肺癌细胞。细胞毒性作用与化合物诱导的细胞凋亡相关,并且可以被K-Ras siRNA或蛋白激酶C1(PKC 1)siRNA阻断,表明Ras和/或PKC 1活性是oncrasin诱导的细胞凋亡所需的。用oncrasin-1、oncrasin-60或oncrasin-231处理敏感癌细胞导致RNA聚合酶II的最大亚基的C-末端结构域(CTD)的磷酸化受到抑制,这与以前的报道一致,即RNA聚合酶II的持续活性是防止癌基因-在转化细胞中诱导细胞凋亡,并且损害CTD功能的突变在酵母中具有升高的Ras活性水平的情况下是合成致死的。用oncrasin-1处理还导致PKC 1 ota和剪接因子在巨剪接体中的共聚集,并破坏PKC 1 ota和CDK 9/细胞周期蛋白T1复合物之间的相互作用,这使CTD磷酸化。因此,我们假设oncrasin化合物是一类具有选择性抗癌活性的新型CTD抑制剂。oncrasin-1的体内给药抑制了人肺肿瘤异种移植物的生长>70%,并延长了荷瘤裸鼠的存活时间,而没有引起可检测的毒性。在NCI-60细胞系上测试这些类似物中的一些显示,oncrasins对源自肺癌、结肠癌、乳腺癌、卵巢癌和肾癌的几种细胞系具有活性,并且oncrasin-60不在充分研究的抗肿瘤剂类别的范围内,表明其新的抗癌机制。因此,oncrasin化合物可能是一类新的CTD抑制剂,其对具有增加的Ras/PKC 1 ota活性的癌症是合成致死的。然而,在进行临床评价之前,需要对oncrasin化合物的药代动力学、抗肿瘤疗效和安全性进行体内评价。本提案的目的是通过评价其在具有或不具有Ras基因突变的几种肺癌细胞系中的体外活性、其药代动力学以及其体内活性和毒性来确定最具活性的类似物的抗肺癌活性。拟议的研究将为oncrasin化合物的可能临床评价提供可靠的临床前数据,并可能导致开发可用于治疗肺癌的新治疗药物。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Development of synthetic lethality anticancer therapeutics.
- DOI:10.1021/jm500415t
- 发表时间:2014-10-09
- 期刊:
- 影响因子:7.3
- 作者:Fang B
- 通讯作者:Fang B
Antitumor activity of a novel oncrasin analogue is mediated by JNK activation and STAT3 inhibition.
- DOI:10.1371/journal.pone.0028487
- 发表时间:2011
- 期刊:
- 影响因子:3.7
- 作者:Guo W;Wu S;Wang L;Wei X;Liu X;Wang J;Lu Z;Hollingshead M;Fang B
- 通讯作者:Fang B
Prodrug oncrasin-266 improves the stability, pharmacokinetics, and safety of NSC-743380.
- DOI:10.1016/j.bmc.2014.08.006
- 发表时间:2014-10-01
- 期刊:
- 影响因子:3.5
- 作者:Wu S;Wang L;Huang X;Cao M;Hu J;Li H;Zhang H;Sun X;Meng QH;Hofstetter WL;Roth JA;Swisher SG;Fang B
- 通讯作者:Fang B
Expression of sulfotransferase SULT1A1 in cancer cells predicts susceptibility to the novel anticancer agent NSC-743380.
- DOI:10.18632/oncotarget.2814
- 发表时间:2015-01-01
- 期刊:
- 影响因子:0
- 作者:Huang X;Cao M;Wang L;Wu S;Liu X;Li H;Zhang H;Wang RY;Sun X;Wei C;Baggerly KA;Roth JA;Wang M;Swisher SG;Fang B
- 通讯作者:Fang B
Genetic Interactions of STAT3 and Anticancer Drug Development.
STAT3和抗癌药物开发的遗传相互作用。
- DOI:10.3390/cancers6010494
- 发表时间:2014-03-06
- 期刊:
- 影响因子:5.2
- 作者:Fang B
- 通讯作者:Fang B
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BINGLIANG FANG其他文献
BINGLIANG FANG的其他文献
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{{ truncateString('BINGLIANG FANG', 18)}}的其他基金
Research Project 1: PDX-based trials of precision medicine for treatment of KRAS mutant lung cancers
研究项目1:基于PDX的精准医疗治疗KRAS突变肺癌试验
- 批准号:
10681976 - 财政年份:2017
- 资助金额:
$ 29.14万 - 项目类别:
Research Project 1: PDX-based trials of precision medicine for treatment of KRAS mutant lung cancers
研究项目1:基于PDX的精准医疗治疗KRAS突变肺癌试验
- 批准号:
10242644 - 财政年份:2017
- 资助金额:
$ 29.14万 - 项目类别:
Overcoming Resistance to Anti-EGFR Therapy by Drug Repurposing
通过药物再利用克服抗 EGFR 治疗的耐药性
- 批准号:
9752955 - 财政年份:2015
- 资助金额:
$ 29.14万 - 项目类别:
Overcoming Resistance to Anti-EGFR Therapy by Drug Repurposing
通过药物再利用克服抗 EGFR 治疗的耐药性
- 批准号:
9319655 - 财政年份:2015
- 资助金额:
$ 29.14万 - 项目类别:
Novel CTD inhibitors with synthetic lethality to oncogenic Ras for cancer therapy
新型 CTD 抑制剂对致癌 Ras 具有合成杀伤力,用于癌症治疗
- 批准号:
8007354 - 财政年份:2010
- 资助金额:
$ 29.14万 - 项目类别:
Novel CTD inhibitors with synthetic lethality to oncogenic Ras for cancer therapy
新型 CTD 抑制剂对致癌 Ras 具有合成杀伤力,用于癌症治疗
- 批准号:
8197944 - 财政年份:2010
- 资助金额:
$ 29.14万 - 项目类别:
Novel CTD inhibitors with synthetic lethality to oncogenic Ras for cancer therapy
新型 CTD 抑制剂对致癌 Ras 具有合成杀伤力,用于癌症治疗
- 批准号:
7779354 - 财政年份:2010
- 资助金额:
$ 29.14万 - 项目类别:
Expression of Proapoptotic Genes for Cancer Therapy
用于癌症治疗的促凋亡基因的表达
- 批准号:
7064270 - 财政年份:2003
- 资助金额:
$ 29.14万 - 项目类别:
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