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：
10082442
负责人：
Lin Zhang
金额：
$ 36.83万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10082442
关键词：
Adult Animal Model BRCA1 gene Biological Assay Biology Breast Breast Cancer Model Breast Cancer Treatment Bromodomain 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 Lead Malignant Neoplasms Malignant neoplasm of ovary Methods Modeling Molecular Nonhomologous DNA End Joining Oncology Ovarian PARP inhibition Patients Pharmaceutical Preparations Pharmacodynamics Poly(ADP-ribose) Polymerases Pre-Clinical Model Proteins Reporter 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 chromosome conformation capture clinical application cytokine design drug development early phase clinical trial epigenetic drug experimental study genome editing homologous recombination in vivo inhibitor/antagonist malignant breast neoplasm novel patient derived xenograft model pre-clinical preclinical development preclinical study response targeted treatment transcriptome sequencing translational medicine tumor tumor 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.

项目概要尽管聚（ADP-核糖）聚合酶抑制剂（PARPi）已成为治疗患有以下疾病的患者的一种有前景的药物：癌症、原发性和获得性耐药是 PARPi 在癌症治疗中的一个主要临床问题。几种药物已在临床前和早期临床试验中设计并评估了联合策略，以克服这一问题挑战。因此，增强原发性和获得性同源细胞对 PARPi 反应的策略重组（HR）熟练的肿瘤将代表癌症治疗的重大进步。溴结构域和额外末端结构域抑制剂（BETi）已迅速进入早期临床试验，并显示令人印象深刻的抗肿瘤活性。鉴于仅 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并进行了评价。使用将 PARPi 与 20 个充分表征的表观遗传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。功能性测定表明，抑制 BET 活性会降低 HR，随后增强 PARPi 诱导的 DNA 癌细胞受损。 BET 蛋白的化学抑制或基因缺失会损害多种蛋白的转录 HR 中的必需基因。此外，BETi 治疗使临床前动物的肿瘤对 PARP 抑制敏感 HR 熟练的乳腺癌和卵巢癌模型。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，但它在常见的成人癌症中集中扩增。因此，我们假设 BETi 可能抑制 HR 并增强 NHEJ，从而使 HR 丰富的癌症变得敏感细胞对 PARP 的抑制。目标 1. 表征 BETi 协同作用的分子机制 PARPi。目标 2. 在临床前模型中评估 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。我们提出的研究可能为 PARPi 与 BETi 联合治疗两者的临床应用提供强有力的理论依据对 PARPi 疗法具有从头耐药性的癌症和具有获得性耐药性的癌症。因此，组合与 BETi 一起使用可以极大地扩展 PARP 抑制对 HR 熟练的癌症患者的效用。