Targeting Wnt signaling in therapy-resistant ovarian cancer

靶向治疗耐药性卵巢癌中的 Wnt 信号传导

基本信息

批准号：
10448507
负责人：
Benjamin G Bitler
金额：
$ 35.21万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2021-07-09 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10448507
关键词：
Anti-Inflammatory Agents Attenuated B-Lymphocytes Biological Markers Biological Models Biological Sciences CD8-Positive T-Lymphocytes CSF2 gene Cancer Biology Cancer Model Cancer cell line Cell Death Cell Line Cells Cessation of life Clinic Clinical Clinical Data Clinical Management Clinical Trials Colorado Complement Factor D DNA Repair Data Detection Disease Resistance Down-Regulation Effectiveness Environment Enzyme-Linked Immunosorbent Assay Epithelial ovarian cancer Future Genes Genetic Genetic Transcription Goals IL6 gene IRF1 gene Immune Immune Evasion Immune signaling Immunosuppression Immunotherapy In Vitro Infiltration Inflammation Inflammatory Interferons Investigation Light Literature Macrophage Activation Malignant neoplasm of ovary Measures Mediating Modeling Mutate Ovarian Serous Adenocarcinoma PD-1/PD-L1 Paracrine Communication Pathway interactions Patients Pharmacology Poly(ADP-ribose) Polymerases Prognosis Progression-Free Survivals Proteins Publishing Recurrence Regulation Regulatory T-Lymphocyte Research Personnel Resistance Role Serous Serum Signal Transduction T cell differentiation T-Cell Activation T-Lymphocyte TNF gene Testing Therapeutic Tumor Immunity Tumor Suppressor Proteins Universities Up-Regulation WNT Signaling Pathway Work Xenograft Model anti-PD-1 anti-tumor immune response antitumor effect beta catenin brca gene cancer cell cancer type chromatin immunoprecipitation cytokine differential expression effector T cell efficacy testing homologous recombination humanized mouse immune activation immune checkpoint immune checkpoint blockade immune checkpoint blockers immunogenic improved in vivo Model inhibitor innovation knock-down macrophage mouse model mutant neoplastic cell novel novel therapeutics overexpression paracrine patient derived xenograft model pre-clinical programmed cell death ligand 1 refractory cancer response success therapy resistant tumor tumor-immune system interactions

项目摘要

PROJECT SUMMARY PARP inhibitor (PARPi) use in the clinic is expanding into multiple cancer types, and consequently, PARPi resistance is a growing clinical problem. High grade serous ovarian cancer (HGSOC) tumors and cells remain an optimal model system to assess PARPi response and resistance. We have developed a panel of unique isogenic PARPi sensitive and resistance HGSOC cell lines and patient-derived xenograft (PDX) models. We published that hyperactivation of the Wnt/-catenin pathway promotes PARPi resistance. Through the current literature and our preliminary investigation, we have discovered that Wnt-mediated PARPi resistant HGSOC cells have increased expression of the immune checkpoint, PD-L1, and reduced expression of the tumor suppressor, interferon regulatory factor 1 (IRF1). Further, Wnt/-catenin signaling directly inhibits effector T cell differentiation and promotes a tumor-promoting, M2-like macrophage. We will continue to collaborate with MD2 Biosciences to investigate a first-in-class allosteric -catenin inhibitor, 1525. We hypothesize that Wnt-dependent PARPi resistance inhibits anti-tumor immunity, and combining ICB with Wnt inhibition will promote immune activation to eradicate PARPi resistant HGSOC. We are proposing to use both in vitro and in vivo models to determine the role of PARPi resistance and Wnt signaling in promoting an immune-suppressive environment. In Aim 1, we will use our unique PARPi resistant cell line models to establish -catenin regulation of PD-L1 (gene – CD274) and IRF1. In Aim 2, we will determine whether secreted factors from PARPi resistant cells attenuates T cell activation and promotes macrophage M2 differentiation. In Aim 3, we will use our novel syngeneic and humanized mouse models to assess the 1525 - catenin inhibitor combined with anti-PD-1. The proposed work has the potential for a high impact on understanding ovarian cancer biology and improving therapeutic options. We anticipate combining -catenin inhibition with an immune checkpoint blocker will overcome PARPi resistance and provide a therapeutic option for those who are no longer responding to PARP inhibitors. Thus, the proposed work's long-term goal is to develop an investigator-initiated clinical trial at the University of Colorado.

项目概要 PARP 抑制剂 (PARPi) 在临床上的使用正在扩展到多种癌症类型，因此， PARPi 耐药性是一个日益严重的临床问题。仍然是评估 PARPi 反应和抵抗力的最佳模型系统，我们开发了一个面板。独特的同基因 PARPi 敏感且耐药的 HGSOC 细胞系和患者来源的异种移植物 (PDX) 我们发表了 Wnt/-catenin 通路的过度激活可促进 PARPi 耐药性。根据目前的文献和我们的初步调查，我们发现Wnt介导的PARPi抵抗 HGSOC 细胞免疫检查点 PD-L1 的表达增加，而免疫检查点 PD-L1 的表达减少肿瘤抑制因子干扰素调节因子 1 (IRF1) 此外，Wnt/-连环蛋白信号传导直接抑制。效应 T 细胞分化并促进促进肿瘤的 M2 样巨噬细胞，我们将继续研究。与 MD2 Biosciences 合作研究一流的变构 -连环蛋白抑制剂 1525。我们 Wnt依赖性PARPi抗性抑制抗肿瘤免疫，并将ICB与Wnt结合抑制将促进免疫激活，以根除 PARPi 耐药的 HGSOC。体外和体内模型以确定 PARPi 抗性和 Wnt 信号传导在促进在目标 1 中，我们将使用我们独特的 PARPi 耐药细胞系模型来建立 PD-L1（基因 - CD274）和 IRF1 的 β-连环蛋白调节在目标 2 中，我们将确定是否。 PARPi 耐药细胞分泌的因子减弱 T 细胞活化并促进巨噬细胞 M2 在目标 3 中，我们将使用我们的新型同基因和人源化小鼠模型来评估 1525 连环蛋白抑制剂与抗 PD-1 相结合，这项工作有可能对癌症产生重大影响。了解卵巢癌生物学并改善治疗选择。使用免疫检查点阻断剂进行抑制将克服 PARPi 耐药性并提供治疗选择对于那些不再对 PARP 抑制剂有反应的人来说，这项工作的长期目标是在科罗拉多大学开展一项由研究者发起的临床试验。