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

• 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
• 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

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.

项目摘要 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。高级别浆液性卵巢癌（HGSOC）肿瘤和细胞 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 独特的同基因PARPi敏感和抗性HGSOC细胞系和患者来源的异种移植物（PDX） 模型我们发表了Wnt/β-连环蛋白通路的超活化促进PARPi抗性。通过 目前的文献和我们的初步调查，我们已经发现，Wnt介导的PARPi抗性， HGSOC细胞具有免疫检查点PD-L1的表达增加和免疫检查点PD-L1的表达减少。 肿瘤抑制因子干扰素调节因子1（IRF 1）。此外，Wnt/β-catenin信号直接抑制 效应T细胞分化和促进肿瘤促进，M2样巨噬细胞。我们将继续 与MD 2 Biosciences合作研究一流的变构β-连环蛋白抑制剂1525。我们 假设Wnt依赖性PARPi抗性抑制抗肿瘤免疫，并将ICB与Wnt组合 抑制将促进免疫活化以根除PARPi抗性HGSOC。我们建议使用 在体外和体内模型中，以确定PARPi抗性和Wnt信号传导在促进免疫应答中的作用。 免疫抑制环境。在目标1中，我们将使用我们独特的PARPi抗性细胞系模型， 建立PD-L1（基因-CD 274）和IRF 1 β-连环蛋白调节。在目标2中，我们将确定 PARPi抗性细胞分泌的因子减弱T细胞活化并促进巨噬细胞M2 分化在目标3中，我们将使用我们的新的同基因和人源化小鼠模型来评估1525个基因， 连环蛋白抑制剂与抗PD-1联合。拟议的工作有可能对以下方面产生重大影响： 了解卵巢癌生物学和改善治疗选择。我们预计β-连环蛋白 用免疫检查点阻断剂抑制将克服PARPi抗性并提供治疗选择 对PARP抑制剂不再有反应的人。因此，拟议工作的长期目标是 在科罗拉多大学开展一项由兴奋剂引发的临床试验。