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Diversity Supplement - Targeting Wnt signaling in therapy-resistant ovarian cancer

多样性补充 - 靶向治疗耐药性卵巢癌中的 Wnt 信号传导

基本信息

批准号：
10793115
负责人：
Benjamin G Bitler
金额：
$ 8.17万
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/10793115
关键词：
Attenuated Biological Models Biological Sciences Cancer Biology Cancer cell line Cell Line Cells Clinic Clinical Clinical Trials Collaborations Colorado Environment Genes Goals IRF1 gene Immune Immune Evasion In Vitro Investigation Literature Macrophage Malignant neoplasm of ovary Mediating Modeling Pathway interactions Poly(ADP-ribose) Polymerase Inhibitor Publishing Regulation Research Personnel Resistance Role Serous Signal Transduction T cell differentiation T-Cell Activation Therapeutic Tumor Immunity Tumor Promotion Tumor Suppressor Proteins Universities WNT Signaling Pathway Work anti-PD-1 anti-tumor immune response antitumor effect beta catenin cancer cell cancer type effector T cell humanized mouse immune activation immune checkpoint immune checkpoint blockade immune checkpoint blockers improved in vivo Model inhibitor mouse model novel patient derived xenograft model programmed cell death ligand 1 response therapy resistant tumor

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-连环蛋白途径的过度激活会促进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抗性细胞的分泌因子减弱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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Small cell carcinoma of the ovary hypercalcemic type (SCCOHT): A review and novel case with dual germline SMARCA4 and BRCA2 mutations.

DOI：
10.1016/j.gore.2022.101077
发表时间：
2022-12
期刊：
GYNECOLOGIC ONCOLOGY REPORTS
影响因子：
1.2
作者：
Sanders, Brooke E.;Wolsky, Rebecca;Doughty, Elizabeth S.;Wells, Kristen L.;Ghosh, Debashis;Ku, Lisa;Pressey, Joseph G.;Bitler, Benjamin B.;Brubaker, Lindsay W.
通讯作者：
Brubaker, Lindsay W.

Claudin-4 localization in epithelial ovarian cancer.

DOI：
10.1016/j.heliyon.2022.e10862
发表时间：
2022-10
期刊：
HELIYON
影响因子：
4
作者：
Neville, Margaret C.;Webb, Patricia G.;Baumgartner, Heidi K.;Bitler, Benjamin G.
通讯作者：
Bitler, Benjamin G.

Distinct roles of treatment schemes and BRCA2 on the restoration of homologous recombination DNA repair and PARP inhibitor resistance in ovarian cancer.

DOI：
10.1038/s41388-022-02491-8
发表时间：
2022-11
期刊：
ONCOGENE
影响因子：
8
作者：
Huang, Tzu-Ting;Burkett, Sandra Sczerba;Tandon, Mayank;Yamamoto, Tomomi M.;Gupta, Nitasha;Bitler, Benjamin G.;Lee, Jung-Min;Nair, Jayakumar R.
通讯作者：
Nair, Jayakumar R.

The Spatial Context of Tumor-Infiltrating Immune Cells Associates with Improved Ovarian Cancer Survival.