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: 10551997
• 负责人: Lin Zhang
• 金额: $ 36.09万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10551997
• 关键词: Adult; Animal Model; BRCA1 gene; Biological Assay; Biology; Breast; Breast Cancer Model; Breast Cancer Treatment; Bromodomains and extra-terminal domain inhibitor; CD8-Positive T-Lymphocytes; Cancer Model; Cell Line; Cells; Chemicals; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; DNA Damage; DNA Repair; DNA Sequence Alteration; Development; Dose; Drug Combinations; Drug Targeting; Enhancers; Epigenetic Process; Essential Genes; FDA approved; Gene Expression; Gene Fusion; Genes; Genetic; Genetic Transcription; Immune response; Immunocompetent; Immunology; Impairment; Interferon Type II; Malignant Neoplasms; Malignant neoplasm of ovary; Methods; Modeling; Molecular; Nonhomologous DNA End Joining; Oncology; Ovarian; PARP inhibition; Patients; Pharmaceutical Preparations; Pharmacodynamics; Poly(ADP-ribose) Polymerase Inhibitor; Polymerase; Pre-Clinical Model; Proteins; Reporter; Repression; Research Personnel; Resistance; Resources; Role; Schedule; Side; Solid; T-Cell Depletion; Testing; Therapeutic; Toxic effect; Transcription Elongation; Translational Research; Woman; Xenograft Model; cancer care; cancer cell; cancer therapy; cancer type; chromosome conformation capture; clinical application; cytokine; design; drug action; drug development; early phase clinical trial; epigenetic drug; experimental study; gene repression; genome editing; homologous recombination; in vivo; inhibitor; inhibitor therapy; malignant breast neoplasm; novel; patient derived xenograft model; pre-clinical; preclinical development; preclinical study; response; targeted treatment; transcriptome sequencing; translational medicine; tumor; tumor microenvironment

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.

项目摘要 虽然聚（ADP-核糖）聚合酶抑制剂（PARPi）已成为治疗糖尿病患者的一种有前途的药物， 癌症、原发性和获得性抗性是PARPi在癌症治疗中的主要临床问题。几种药物 在临床前和早期临床试验中已经设计和评估了组合策略以克服这一点 挑战.因此，在原发性和获得性同源性肿瘤中增强对PARPi的应答的策略， 重组（HR）熟练的肿瘤将代表癌症护理的显著进步。溴结构域和 末端外结构域抑制剂（BETi）已迅速进入早期临床试验， 令人印象深刻的抗肿瘤活性。考虑到单独使用BETi的临床活性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 和评价使用药物协同筛选，将PARPi与20种表征良好的表观遗传 我们将BETi确定为与PARPi在HR熟练癌细胞中协同作用的药物。功能 分析表明，抑制的BET活性会降低HR，随后增强PARPi诱导的DNA 对癌细胞的损害。BET蛋白质的化学抑制或遗传耗竭损害了几种转录因子的转录。 此外，在临床前动物中，BETi治疗使肿瘤对PARP抑制敏感。 HR熟练的乳腺癌和卵巢癌的模型。最后，我们发现BRD 4基因与正常人相比， 并且在常见的成人癌症中局部扩增，尽管其基因融合是一种罕见的基因组改变。 因此，我们假设BETi可以抑制HR并增强NHEJ，从而使HR-熟练的癌症敏感化。 细胞对PARP的抑制作用。目标1.表征BETi协同作用的分子机制 PARPi。目标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治疗的免疫应答。我们建议的研究可能 为PARPi与BETi联合治疗两种疾病的临床应用提供了强有力的依据 对PARPi疗法具有新生抗性的癌症和具有获得性抗性的癌症。因此，组合 与BETi的联合应用可以极大地扩展PARP抑制对具有HR-熟练癌症的患者的效用。

项目成果

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: Current opinion in pharmacology
• 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: Methods in molecular biology (Clifton, N.J.)
• 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: Cell reports
• 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

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: Methods in molecular biology (Clifton, N.J.)
• 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: Methods in molecular biology (Clifton, N.J.)
• 作者: Wang,Yueying;Xu,Mu;Yuan,Jiao;Hu,Zhongyi;Zhang,Youyou;Zhang,Lin;Hu,Xiaowen
• 通讯作者: Hu,Xiaowen