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; 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 尽管聚（ADP-核糖）聚合酶抑制剂（PARPI）已成为一种有前途的药物 癌症，原发性和获得性抗性是癌症治疗中PARPI的主要临床问题。几种药物 在临床前和早期临床试验中设计和评估了组合策略，以克服这一点 挑战。因此，增强对主要和获得同源的PARPI反应的策略 重组（HR） - 成熟的肿瘤将代表癌症护理的重大进展。溴构和 末端结构域抑制剂（BETI）已迅速发展为早期临床试验，并已显示 令人印象深刻的抗肿瘤活性。鉴于仅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 并评估。使用将PARPI与20个特征良好的表观遗传学结合的药物协同屏幕 药物，我们将BETI鉴定为一种药物，在HR癌细胞中与PARPI协同作用。功能 测定表明抑制活性减少了人力资源，随后增强了parpi诱导的DNA 癌细胞的损害。 BET蛋白的化学抑制或遗传耗竭损害了几种的转录 人力资源中的必要基因。此外，BETI治疗使临床前动物的肿瘤敏感抑制 富有HR的乳腺癌和卵巢癌的模型。最后，我们表明BRD4基因显着 尽管其基因融合是一种罕见的基因组改变，但在常见的成年癌中局灶性扩增。 因此，我们假设BETI可以抑制人力资源并增强NHEJ，从而使HR增强癌症敏感 细胞抑制。目标1。表征Beti协同作用的分子机制 parpi。 AIM 2。评估临床前模型中BET和PARP抑制剂的联合疗法。目标3。定义 肿瘤微环境中对BETI和PARPI治疗的免疫反应。我们提出的研究可能 为PARPI在与Beti的组合设置中的临床应用中提供了强大的理由，以治疗两者 对parpi疗法的抗药性和获得抗药性的癌症的癌症。因此，组合 使用BETI可以极大地扩展PARP抑制作用对HR癌症患者的效用。