Molecular mechanism and preclinical development of BETi and PARPi combination therapy
BETi和PARPi联合疗法的分子机制和临床前开发
基本信息
- 批准号:10551997
- 负责人:
- 金额:$ 36.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAnimal ModelBRCA1 geneBiological AssayBiologyBreastBreast Cancer ModelBreast Cancer TreatmentBromodomains and extra-terminal domain inhibitorCD8-Positive T-LymphocytesCancer ModelCell LineCellsChemicalsClinicalClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCombined Modality TherapyDNA DamageDNA RepairDNA Sequence AlterationDevelopmentDoseDrug CombinationsDrug TargetingEnhancersEpigenetic ProcessEssential GenesFDA approvedGene ExpressionGene FusionGenesGeneticGenetic TranscriptionImmune responseImmunocompetentImmunologyImpairmentInterferon Type IIMalignant NeoplasmsMalignant neoplasm of ovaryMethodsModelingMolecularNonhomologous DNA End JoiningOncologyOvarianPARP inhibitionPatientsPharmaceutical PreparationsPharmacodynamicsPoly(ADP-ribose) Polymerase InhibitorPolymerasePre-Clinical ModelProteinsReporterRepressionResearch PersonnelResistanceResourcesRoleScheduleSideSolidT-Cell DepletionTestingTherapeuticToxic effectTranscription ElongationTranslational ResearchWomanXenograft Modelcancer carecancer cellcancer therapycancer typechromosome conformation captureclinical applicationcytokinedesigndrug actiondrug developmentearly phase clinical trialepigenetic drugexperimental studygene repressiongenome editinghomologous recombinationin vivoinhibitorinhibitor therapymalignant breast neoplasmnovelpatient derived xenograft modelpre-clinicalpreclinical developmentpreclinical studyresponsetargeted treatmenttranscriptome sequencingtranslational medicinetumortumor microenvironment
项目摘要
PROJECT SUMMARY
Although poly (ADP-ribose) polymerase inhibitor (PARPi) has emerged as a promising drug for patients with
cancer, primary and acquired resistance is a major clinical problem for PARPi in cancer treatment. Several drug
combination strategies have been designed and evaluated in preclinical and early clinical trials to overcome this
challenge. Therefore, strategies to enhance response to PARPi in primary and acquired homologous
recombination (HR)-proficient tumors would represent a significant advance in cancer care. Bromodomains and
extra-terminal domain inhibitor (BETi) has been rapidly advanced into early clinical trials and has shown
impressive anti-tumor activity. Given that clinical activity of BETi alone may be insufficient to manage patients
according to recent clinical trials, the combination of BETi with other treatment methods need to be designed
and evaluated. Using a drug synergistic screen that combined a PARPi with 20 well-characterized epigenetic
drugs, we identified BETi as a drug that acted synergistically with PARPi in HR-proficient cancer cells. Functional
assays demonstrated that repressed BET activity reduces HR and subsequently enhances PARPi-induced DNA
damage in cancer cells. Chemical inhibition or genetic depletion of BET proteins impairs transcription of several
essential genes in HR. Moreover, BETi treatment sensitized tumors to PARP inhibition in preclinical animal
models of HR-proficient breast and ovarian cancers. Finally, we showed that the BRD4 gene was significantly
and focally amplified across common adult cancers, although its gene fusion was a rare genomic alteration.
Thus, we hypothesize that BETi may suppress HR and enhance NHEJ, thereby sensitizing HR-proficient cancer
cells to PARP inhibition. Aim 1. Characterize the molecular mechanisms by which BETi synergistically acts with
PARPi. Aim 2. Evaluate the combination therapy of BET and PARP inhibitors in preclinical models. Aim 3. Define
immune responses to BETi and PARPi treatment in the tumor microenvironment. Our proposed studies may
provide strong rationale for clinical application of PARPi in the setting of combination with BETi to treat both
cancers with de novo resistance to PARPi therapy and cancers with acquired resistance. Therefore, combination
with BETi could greatly expand the utility of PARP inhibition to patients with HR-proficient cancer.
项目总结
尽管聚(ADP-核糖)聚合酶抑制剂(PARPI)已成为治疗慢性支气管炎患者的一种有前途的药物
肿瘤、原发耐药和获得性耐药是PARPI治疗癌症的主要临床问题。几种药物
在临床前和早期临床试验中,已经设计和评估了联合策略来克服这一点
挑战。因此,在初级和获得性同源细胞中增强对PARPI反应的策略
精通重组(HR)的肿瘤将代表着癌症治疗的重大进步。溴域和
末端外结构域抑制剂(Beti)已迅速进入早期临床试验,并已显示
令人印象深刻的抗肿瘤活性。考虑到仅有Beti的临床活动可能不足以管理患者
根据最近的临床试验,需要设计Beti与其他治疗方法的组合
并进行了评估。使用将PARPI与20个特征良好的表观遗传学相结合的药物协同筛选
药物,我们确定Beti是一种在HR熟练的癌细胞中与PARPI协同作用的药物。功能性
分析表明,抑制的BET活性降低了HR,并随后增强了PARPI诱导的DNA
对癌细胞的损害。BET蛋白的化学抑制或基因耗尽会损害几个基因的转录
人力资源中的必需基因。此外,Beti治疗使临床前动物肿瘤对PARP抑制敏感
精通HR的乳腺癌和卵巢癌模型。最后,我们发现BRD4基因显著地
并在常见的成人癌症中进行焦点扩增,尽管其基因融合是一种罕见的基因组变化。
因此,我们假设Beti可能抑制HR并增强NHEJ,从而使HR熟练的癌症变得敏感
细胞对PARP的抑制作用。目的1.描述Beti协同作用的分子机制
帕尔皮。目的2.在临床前模型中评价BET和PARP抑制剂的联合治疗。目标3.定义
肿瘤微环境中对Beti和PARPI治疗的免疫反应。我们提议的研究可能
为临床应用PARPI结合Beti治疗两者提供了有力的理论依据
对PARPI治疗产生从头耐药的癌症和对获得性耐药的癌症。因此,组合
使用Beti可以极大地扩大PARP抑制对HR熟练的癌症患者的作用。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Targeting the transcription cycle and RNA processing in cancer treatment.
- DOI:10.1016/j.coph.2021.04.001
- 发表时间:2021-06
- 期刊:
- 影响因子:4
- 作者:Zhang L;Zhang Y;Hu X
- 通讯作者:Hu X
Methods for the Study of Long Noncoding RNA in Cancer Cell Signaling.
- DOI:10.1007/978-1-0716-0759-6_7
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Feng Y;Jiang J;Hu Z;Yuan J;Zhang T;Pan Y;Xu M;Li C;Zhang Y;Zhang L;Hu X
- 通讯作者:Hu X
Systematic Characterization of Recurrent Genomic Alterations in Cyclin-Dependent Kinases Reveals Potential Therapeutic Strategies for Cancer Treatment.
- DOI:10.1016/j.celrep.2020.107884
- 发表时间:2020-07
- 期刊:
- 影响因子:8.8
- 作者:Weiwei Shan;Jiao Yuan;Zhongyi Hu;Junjie Jiang;Yueying Wang;Nicki Loo;L. Fan;Zhaoqing Tang;Tianli Zhang;Mu Xu;Yutian Pan;J. Lu;M. Long;J. Tanyi;K. Montone;Yi Fan;Xiaowen Hu;Youyou Zhang;Lin Zhang
- 通讯作者:Weiwei Shan;Jiao Yuan;Zhongyi Hu;Junjie Jiang;Yueying Wang;Nicki Loo;L. Fan;Zhaoqing Tang;Tianli Zhang;Mu Xu;Yutian Pan;J. Lu;M. Long;J. Tanyi;K. Montone;Yi Fan;Xiaowen Hu;Youyou Zhang;Lin Zhang
Characterization of Long Non-coding RNA Associated Proteins by RNA-Immunoprecipitation.
通过 RNA 免疫沉淀表征长链非编码 RNA 相关蛋白。
- DOI:10.1007/978-1-0716-1697-0_3
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Jiang,Junjie;Zhang,Tianli;Pan,Yutian;Hu,Zhongyi;Yuan,Jiao;Hu,Xiaowen;Zhang,Lin;Zhang,Youyou
- 通讯作者:Zhang,Youyou
Detection of Long Non-coding RNA Expression by Non-radioactive Northern Blots.
通过非放射性 Northern 印迹检测长非编码 RNA 表达。
- DOI:10.1007/978-1-0716-1697-0_13
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Wang,Yueying;Xu,Mu;Yuan,Jiao;Hu,Zhongyi;Zhang,Youyou;Zhang,Lin;Hu,Xiaowen
- 通讯作者:Hu,Xiaowen
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Lin Zhang其他文献
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{{ truncateString('Lin Zhang', 18)}}的其他基金
Role of necroptosis in colorectal cancer therapy
坏死性凋亡在结直肠癌治疗中的作用
- 批准号:
10891823 - 财政年份:2023
- 资助金额:
$ 36.09万 - 项目类别:
BET degraders for improving colorectal cancer therapy
BET 降解剂可改善结直肠癌治疗
- 批准号:
10946894 - 财政年份:2023
- 资助金额:
$ 36.09万 - 项目类别:
Targeting CDK7 in high-grade serous ovarian carcinoma
靶向 CDK7 治疗高级别浆液性卵巢癌
- 批准号:
10275795 - 财政年份:2021
- 资助金额:
$ 36.09万 - 项目类别:
BET degraders for improving colorectal cancer therapy
BET 降解剂可改善结直肠癌治疗
- 批准号:
10372054 - 财政年份:2021
- 资助金额:
$ 36.09万 - 项目类别:
Targeting CDK7 in high-grade serous ovarian carcinoma
靶向 CDK7 治疗高级别浆液性卵巢癌
- 批准号:
10683737 - 财政年份:2021
- 资助金额:
$ 36.09万 - 项目类别:
Targeting CDK7 in high-grade serous ovarian carcinoma
靶向 CDK7 治疗高级别浆液性卵巢癌
- 批准号:
10461935 - 财政年份:2021
- 资助金额:
$ 36.09万 - 项目类别:
Role of necroptosis in colorectal cancer therapy
坏死性凋亡在结直肠癌治疗中的作用
- 批准号:
10410392 - 财政年份:2019
- 资助金额:
$ 36.09万 - 项目类别:
Role of necroptosis in colorectal cancer therapy
坏死性凋亡在结直肠癌治疗中的作用
- 批准号:
9882961 - 财政年份:2019
- 资助金额:
$ 36.09万 - 项目类别:
Molecular mechanism and preclinical development of BETi and PARPi combination therapy
BETi和PARPi联合疗法的分子机制和临床前开发
- 批准号:
10082442 - 财政年份:2019
- 资助金额:
$ 36.09万 - 项目类别:
Targeting defective necroptosis in colorectal cancer
靶向结直肠癌中的缺陷性坏死性凋亡
- 批准号:
10916808 - 财政年份:2019
- 资助金额:
$ 36.09万 - 项目类别:
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