Co-targeting MADD and Wnt/β-catenin signaling in Anaplastic Thyroid Cancer

甲状腺未分化癌中 MADD 和 Wnt/β-catenin 信号的共同靶向

基本信息

批准号：
9885983
负责人：
Bellur S Prabhakar
金额：
--
依托单位：
JESSE BROWN VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9885983
关键词：
AKT Signaling Pathway Ablation Address Aggressive behavior Apoptosis BAY 54-9085 BRAF gene Basement membrane CRISPR/Cas technology CTNNB1 gene Cessation of life Clinical Data Death Domain Distant Drug Targeting Drug resistance Epithelial Epithelial Cells Epithelium Exhibits Gene Proteins Growth High Prevalence Hyperactive behavior In Vitro Incidence Knock-out MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of thyroid Mediating Mesenchymal Metastatic Neoplasm to the Lung Mitogen-Activated Protein Kinases Mus Mutation Nature Neoplasm Metastasis Nodal Normal Cell Oncogenes Operative Surgical Procedures PTEN gene Palliative Care Pathway interactions Patient Self-Report Patients Pharmaceutical Preparations Phenotype Phosphorylation Population Proteins Proto-Oncogene Proteins c-akt Publishing Radiation exposure Radioactive Iodine Resistance Role Services Signal Pathway Signal Transduction Site Small Interfering RNA TNF gene Testing Treatment Efficacy Tumor Suppressor Proteins Tumor Tissue Ubiquitination Undifferentiated United States Veterans WNT Signaling Pathway advanced disease agent orange anaplastic thyroid cancer base beta catenin cancer cell effective therapy high risk in vivo in vivo evaluation inhibitor/antagonist knock-down mouse model novel novel therapeutics outcome forecast patient population prevent protein expression protein function standard care stemness targeted treatment therapeutic development therapeutic target therapy resistant treatment strategy tumor tumor growth

项目摘要

Project Description: Thyroid cancer incidence is rapidly increasing in the United States. Veterans are at even higher risk of developing thyroid cancer in their lifetime due to the increased potential of radiation exposure in the armed services. Furthermore, veterans who suffered from thyroid cancer self-reported a higher prevalence of Agent Orange exposure, increasing the relevance of this malignancy to the VA population. Despite the use of a range of combinations of treatments, ATC exhibits a dismal prognosis with a median survival of < six months. ATC tumors possess a greater mutation burden than all other forms of thyroid cancer which impart significant growth benefit and high metastatic potential Therefore, it is important to identify proteins that function at “nodal points” of different signaling pathways implicated in ATC, and thus could represent ATC “Achilles Heel.” The CTNNB1 (β-catenin) is an effector molecule of Wnt signaling which is critical for epithelial-mesenchymal transition (EMT) required for metastasis. PI3K/Akt/GSK3β signaling is hyperactive in ATC due to mutations. This can enhance β-catenin activity and also phosphorylate Map kinase Activating Death Domain-containing protein (MADD) and contribute to its pro-survival function. pMADD renders ATC cells resistant to apoptosis. Thus in ATC, pMADD and β-catenin can serve as two potential “nodal points.” Most importantly, our recent novel findings have shown that MADD knockdown can significantly inhibit TNFα mediated activation of β-catenin signaling by preventing pERK activation and consequent pGSK3β activation. Lack of GSK3β phosphorylation by ERK, facilitated ubiquitination of β-catenin leading to its degradation and resultant blockage of EMT activation. Furthermore, intra-tumoral administration of MADD siRNA significantly reduced orthotpic ATC tumor growth and lung metastasis in treated mice. Therefore, MADD is a potential therapeutic target in ATC either alone or in combination with Wnt/β-catenin inhibitors. Based on a very strong scientific premise, we hypothesize that MADD down modulation can be effective in inhibiting growth and overcoming resistance to drugs targeting hyperactive MAPK, PI3K/Akt and Wnt/β-catenin signaling, which are hallmarks of ATC. To address this, in aim-1, we will functionally characterize the impact of CRISPR/CAS9 mediated MADD gene knock-out in ATC cells on Wnt signaling in vitro and ex vivo; in aim-2, we will determine the impact of down-modulating MADD expression, and MAPK and PI3K/Akt signaling pathways, on Wnt signaling; and in aim-3, we will test the in vivo therapeutic efficacy of combination treatment with MADD knockdown in orthotopic and spontaneous mouse models of ATC. ATC disproportionately accounts for the majority of thyroid cancer-related deaths. Cancer cell-specific expression of MADD, its role in activating several key signaling pathways, and its ability to act as a pro-survival factor and promote metastasis in ATC makes it an ideal target for therapeutic development. Importantly, MADD deletion had no apparent effect on normal cells. Thus the proposed novel studies are highly relevant to veterans.

项目描述：美国退伍军人的甲状腺癌发病率正在迅速增加。由于辐射暴露的可能性增加，一生中罹患甲状腺癌的风险更高此外，患有甲状腺癌的退伍军人自我报告患病率较高。尽管使用了橙剂，但仍增加了这种恶性肿瘤与退伍军人管理局人群的相关性。通过一系列治疗组合，ATC 的预后较差，中位生存期< 6 个月。 ATC 肿瘤比所有其他形式的甲状腺癌具有更大的突变负担，这会导致显着的突变。生长效益和高转移潜力因此，识别在“节点”发挥作用的蛋白质非常重要 ATC 涉及的不同信号通路的“点”，因此可以代表 ATC 的“致命弱点”。 CTNNB1（β-连环蛋白）是 Wnt 信号传导的效应分子，对上皮间质细胞至关重要由于突变，ATC 中转移所需的 PI3K/Akt/GSK3β 信号转导过度活跃。可以增强 β-catenin 活性，还可以磷酸化包含 Map 激酶激活死亡结构域的蛋白质 (MADD) 并有助于其促生存功能，从而使 ATC 细胞抵抗细胞凋亡。 ATC、pMADD 和 β-catenin 可以作为两个潜在的“节点”。最重要的是，我们最近的新发现表明 MADD 敲低可以显着抑制 TNFα 通过阻止 pERK 激活和随后的 pGSK3β 介导 β-连环蛋白信号传导的激活 ERK 缺乏 GSK3β 磷酸化，促进 β-连环蛋白泛素化，从而导致其泛素化。此外，MADD siRNA 的肿瘤内给药。显着减少治疗小鼠中的 ATC 肿瘤生长和肺转移，因此，MADD 是一种有效的治疗方法。 ATC 的潜在治疗靶点，无论是单独使用还是与 Wnt/β-连环蛋白抑制剂联合使用。基于非常有力的科学前提，我们努力使 MADD 下调制能够有效抑制生长和克服针对高活性 MAPK、PI3K/Akt 和 Wnt/β-catenin 的耐药性药物为了解决这个问题，在目标 1 中，我们将从功能上描述 ATC 的影响。在imai-2中，CRISPR/CAS9介导ATC细胞中Wnt信号传导的MADD基因敲除；将确定下调 MADD 表达以及 MAPK 和 PI3K/Akt 信号通路的影响，在Wnt信号传导方面；在aim-3中，我们将测试与MADD联合治疗的体内疗效 ATC 的原位和自发小鼠模型中的敲低。 ATC 不成比例地占甲状腺癌相关死亡的大多数。 MADD 的表达、其在激活几个关键信号通路中的作用及其作为促生存因子的能力因素并促进 ATC 转移，使其成为治疗开发的理想靶标。删除对正常细胞没有明显影响，因此拟议的新研究与退伍军人高度相关。