Targeting Wnt signaling in therapy-resistant ovarian cancer

项目总结 PARP抑制剂(PARPI)在临床上的应用正在扩大到多种癌症类型，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反应和耐药性的最佳模型系统。我们已经开发了一个小组 独特的同基因PARPI敏感和耐药的HGSOC细胞株和患者来源的异种移植(PDX) 模特们。我们发表了Wnt/-catenin通路的过度激活促进了PARPI抵抗。穿过 根据目前的文献和我们的初步调查，我们发现Wnt介导的PARPI抗性 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/-catenin信号直接抑制 效应T细胞分化，促进促进肿瘤的M2样巨噬细胞。我们将继续 与MD2生物科学公司合作，研究一种一流的变构-连环蛋白抑制剂1525。我们 假设Wnt依赖的PARPI耐药抑制抗肿瘤免疫，并联合ICB和Wnt 抑制将促进免疫激活，以根除耐PARPI的HGSOC。我们正在提议使用 体外和体内模型确定PARPI抵抗和Wnt信号在促进AN中的作用 免疫抑制的环境。在目标1中，我们将使用我们独特的PARPI抗性细胞系模型来 建立-连环蛋白对PD-L1(CD274基因)和IRF1的调控。在目标2中，我们将确定是否 PARPI抵抗细胞分泌因子抑制T细胞活化并促进巨噬细胞M2 差异化。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- 连环蛋白抑制剂联合抗PD-1。拟议的工作有可能对 了解卵巢癌生物学并改进治疗方案。我们预计将结合-连锁素 免疫检查点阻滞剂的抑制将克服PARPI耐药性并提供一种治疗选择 对于那些对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研究人员发起的临床试验。

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.