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

基本信息

批准号：
10095875
负责人：
Timothy Anthony Yap
金额：
$ 37.06万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
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/10095875
关键词：
ADP ribosylation Address Adenosine Diphosphate Ribose Animal Model Antitumor Response BRCA mutations BRCA1 gene 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 Fill-It Future Genes Genetic Transcription Goals Immune Immune checkpoint inhibitor Immune response Immunomodulators Immunooncology Immunotherapy Knowledge Laboratories Lead Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Mammary Neoplasms Mediating Molecular Molecular Target Nicotinamide adenine dinucleotide Patient Selection Patients Poly(ADP-ribose) Polymerases Promoter Regions Proteins Regulator Genes Role Single-Stranded DNA Specimen Testing Therapeutic Transcriptional Regulation Translating Treatment Efficacy Tumor Immunity bak protein base brca gene cancer cell cancer subtypes clinical application clinical development clinically relevant homologous recombination immune checkpoint immune checkpoint blockade individual patient inhibitor/antagonist 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 transcriptome sequencing transcriptomics tumor tumor DNA tumor-immune system interactions

项目摘要

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率的基础的转录组机制 PARP抑制剂聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPI）被批准用于治疗卵巢癌，如以及BRCA1或BRCA2（BRCA1/2）突变乳腺和胰腺癌。我们目前的理解是负责Parpis效率的主要机制之一是通过合成的致死性，特别是在具有同源重组修复缺陷（“ Brcaness”）的癌症。虽然PARP1介导的Parylation是基因转录的基本调节剂，仍然未知parpi诱导的转录组如何变化促进其治疗效率。而我们的临床前和临床研究评估了Parpis的组合用编程的细胞死亡配体1（PD-L1）/PD-1抑制剂（PD-1/L1IS）显示出持久的响应不同的癌症，患者之间的反应是异质的，令人惊讶的是治疗性这种组合的好处与Parpis的已知预测生物标志物无关，例如BRCA1/2 突变。这些数据表明，Parpis的免疫调节功能可能与OR不同独立于帕尔皮斯的治疗效率基础的现有“ Brcaness”范式。为了确定Parpis免疫调节功能的分子机制，我们使用了单细胞RNA测序以评估parpis对肿瘤细胞和肿瘤的转录组影响免疫微环境。令人惊讶的是，我们确定Parpi诱导的PARP1捕获到DNA可能上调B7-H3（CD276），一种关键的免疫检查点蛋白。根据我们的初步研究，我们假设Parpis在转录中调节癌细胞内在的B7-H3表达 PARP1蛋白到B7-H3启动子区域，该区域可以用作关键的调节节点 Parpis的免疫调节功能和治疗效率。我们将使用细胞和动物模型，以及来自基于PARPI的疗法的临床试验的患者标本来检验该假设。我们将测试三个目标： AIM 1：确定parpis转录诱导癌细胞固有的B7-H3的机制通过PARP1-染色质诱捕表达。 AIM 2：确定B7-H3是否充当关键调节节点用于临床前动物模型中PARPI的免疫调节功能和效率。目标3：验证 parpi诱导的B7-H3表达是确定parpis的效率作为免疫调节的生物标志物通过分析的患者肿瘤和来自多个临床试验的血液样本的药物。我们相信我们的建议具有高度创新性，因为它填补了我们对Parpis的治疗效率的了解通过转录调控使免疫调节剂超出当前机械 Parpis的范式。如果成功，我们的研究将对扩大临床产生重大影响通过促进抗肿瘤免疫组织化学并增强parpis作为免疫调节剂的应用免疫疗法的功效。这也可能导致合理PARPI组合的临床发展与 B7-H3抑制剂和/或PD-1/L1I，具体取决于单个患者肿瘤的免疫特征。