Transcriptomic mechanisms underlying the immune modulating function and therapeutic efficacy of PARP inhibitors

PARP抑制剂免疫调节功能和治疗功效的转录组机制

• 批准号: 10669071
• 负责人: Timothy Anthony Yap
• 金额: $ 36.32万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-10 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669071
• 关键词: ADP ribosylation; Address; Adenosine Diphosphate Ribose; Animal Model; Antitumor Response; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Biological Markers; Blood specimen; CD276 gene; Cancer Model; Cell model; Cells; Characteristics; Chromatin; Clinical; Clinical Research; Clinical Trials; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Disorder; Data; Defect; Development; Dissociation; Future; Genes; Genetic Transcription; Goals; Immune; Immune checkpoint inhibitor; Immune response; Immunooncology; Immunotherapy; Knowledge; Laboratories; Lead; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mammary Neoplasms; Mediating; Molecular; Molecular Target; Nicotinamide adenine dinucleotide; PD-1 inhibitors; PDL1 inhibitors; Patient Selection; Patients; Poly(ADP-ribose) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Polymerase; Promoter Regions; Proteins; Regulator Genes; Role; Single-Stranded DNA; Specimen; Testing; Therapeutic; Transcriptional Regulation; Translating; Treatment Efficacy; Tumor Immunity; bak protein; cancer cell; cancer subtypes; carcinogenesis; clinical application; clinical development; clinically relevant; efficacy evaluation; homologous recombination; immune checkpoint; immune checkpoint blockade; immune modulating agents; immunoregulation; individual patient; inhibitor; inhibitor therapy; innate immune pathways; innovation; insight; malignant breast neoplasm; molecular subtypes; mutant; neoplastic cell; novel; pancreatic neoplasm; pre-clinical; preclinical study; predictive marker; programmed cell death ligand 1; programmed cell death protein 1; recombinational repair; response; response biomarker; sensor; single-cell RNA sequencing; synthetic lethal interaction; transcriptomics; tumor; tumor DNA; tumor-immune system interactions

Transcriptomic mechanisms underlying the immune modulating function and therapeutic efficacy of PARP inhibitors Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are approved for the treatment of ovarian cancer, as well as BRCA1 or BRCA2 (BRCA1/2) mutant breast and pancreatic cancers. Our current understanding is that one of the main mechanisms responsible for the efficacy of PARPis is through synthetic lethality, specifically in cancers with homologous recombination repair defects (‘BRCAness’). While PARP1-mediated PARylation is an essential regulator of gene transcription, it remains unknown how PARPi-induced transcriptomic changes contribute to its therapeutic efficacy. While our preclinical and clinical studies assessing PARPis in combination with programmed cell death-ligand 1 (PD-L1)/PD-1 inhibitors (PD-1/L1is) showed durable responses in different cancers, the responses were heterogeneous between patients, and surprisingly, the therapeutic benefit of this combination did not correlate with known predictive biomarkers for PARPis, such as BRCA1/2 mutations. These data suggest that the immunomodulating function of PARPis may be different from or independent of the existing ‘BRCAness’ paradigm underlying the therapeutic efficacy of PARPis. To determine the molecular mechanisms underlying the immunomodulating function of PARPis, we utilized single-cell RNA sequencing to assess the transcriptomic impact of PARPis on tumor cells and the tumor immune microenvironment. Surprisingly, we identified that PARPi-induced PARP1-trapping to DNA may upregulate B7-H3 (CD276), a key immune checkpoint protein. Based on our preliminary studies, we hypothesize that PARPis transcriptionally regulate cancer-cell intrinsic B7-H3 expression by trapping the PARP1 protein to the B7-H3 promoter region, which may serve as a key regulatory node for the immunomodulating function and therapeutic efficacy of PARPis. We will use cell and animal models, as well as patient specimens from clinical trials of PARPi-based therapies to test this hypothesis. We will test three aims: Aim 1: Determine mechanisms by which PARPis transcriptionally induce cancer cell intrinsic B7-H3 expression through PARP1-chromatin trapping. Aim 2: Determine if B7-H3 functions as a key regulatory node for the immunomodulating function and efficacy of PARPis in preclinical animal models. Aim 3: Validate PARPi-induced B7-H3 expression as a biomarker in determining the efficacy of PARPis as immunomodulating agents by analysing patient tumor and blood samples from multiple clinical trials. We believe that our proposal is highly innovative because it fills key gaps in our knowledge of the therapeutic efficacy of PARPis as immunomodulating agents through transcriptional regulation, which goes beyond the current mechanistic paradigm of PARPis. If successful, our study will have a significant impact on expanding the clinical applications of PARPis as immunomodulating agents by promoting antitumor immunity and enhancing the efficacy of immunotherapy. This may also lead to the clinical development of rational PARPi combinations with an B7-H3 inhibitor and/or a PD-1/L1i, depending on the immune characteristics of the individual patient tumor.

免疫调节功能和治疗效果的转录调控机制 PARP抑制剂 聚(ADP-核糖)聚合酶(PARP)抑制剂(PARPis)被批准用于卵巢癌的治疗，AS 以及BRCA1或BRCA2(BRCA1/2)突变的乳腺癌和胰腺癌。我们目前的理解是 PARPis疗效的主要机制之一是通过合成致死性，特别是在 具有同源重组修复缺陷的癌症(‘BRCAness’)。而PARP1介导的PAR化是 作为基因转录的重要调节因子，目前尚不清楚PARPI是如何诱导转录变化的 有助于提高其治疗效果。虽然我们的临床前和临床研究联合评估了PARPis 程序性细胞死亡配体1(PD-L1)/PD-1抑制剂(PD-1/L1is)在 不同的癌症，患者之间的反应是不同的，令人惊讶的是，治疗 这种组合的益处与已知的PARPi预测生物标记物，如BRCA1/2无关 突变。这些数据表明，PARPis的免疫调节功能可能不同于或 独立于PARPis治疗效果背后的现有‘BRCAness’范例。 为了确定PARPis免疫调节功能的分子机制，我们利用 单细胞RNA测序评估PARPis对肿瘤细胞和肿瘤的转录影响 免疫微环境。令人惊讶的是，我们发现PARPI诱导的PARP1捕获DNA可能 上调关键免疫检查点蛋白B7-H3(CD276)。根据我们的初步研究，我们 假设PARPis通过捕获B7-H3基因转录调控癌细胞固有的B7-H3表达 PARP1蛋白结合到B7-H3启动子区域，可能是B7-H3启动子区的关键调控节点。 PARPis的免疫调节作用及治疗效果。我们将使用细胞和动物模型，以及 来自基于PARPI的治疗的临床试验的患者样本来验证这一假设。我们将测试三个目标： 目的1：确定PARPis转录诱导癌细胞内源性B7-H3的机制 通过PARP1-染色质捕捉法表达。目标2：确定B7-H3是否作为关键调控节点发挥作用 PARPis在临床前动物模型中的免疫调节功能和疗效。目标3：验证 PARPI诱导B7-H3表达作为判断PARPis免疫调节效果的生物标志物 通过分析患者肿瘤和来自多个临床试验的血液样本来分析药物。我们相信我们的建议 是高度创新的，因为它填补了我们对PARPis AS治疗效果认识的关键空白 通过转录调节的免疫调节剂，这超越了目前的机制 PARPis的范例。如果成功，我们的研究将对扩大临床应用产生重大影响 PARPis作为免疫调节剂在提高抗肿瘤免疫和增强免疫功能中的应用 免疫治疗的疗效。这也可能导致合理的PARPI与 B7-H3抑制剂和/或PD-1/L1I，取决于个别患者肿瘤的免疫特征。