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Role of Ly6K in TGF-beta and immune escape pathways of triple negative breast cancer

Ly6K 在 TGF-β 和三阴性乳腺癌免疫逃逸途径中的作用

基本信息

批准号：
10229403
负责人：
Geeta Upadhyay
金额：
$ 39.92万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-03 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229403
关键词：
4T1 Address Affect Award Binding Biological Biological Markers Breast Cancer Cell Breast Cancer cell line Cell Surface Proteins Cells Clinical Developmental Therapeutics Program Disease Female Growth Head Cancer Immune Immunologic Surveillance Immunotherapy Interferon Type II Knockout Mice Label Laboratories Link Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of urinary bladder Mediating Modeling Mus Neck Cancer Normal Cell Normal tissue morphology Organ Outcome PDL1 pathway Pathway interactions Pharmaceutical Preparations Pharmacology Play Proteins Research Role Sampling Scheme Signal Transduction Spermatogenesis Survival Rate Testing Testis Therapeutic Therapeutic Intervention Time Tissues Transforming Growth Factor beta Treatment Efficacy Tumor Escape Tumor Suppression Up-Regulation Xenograft procedure base cancer cell cancer subtypes cancer type epithelial to mesenchymal transition hormone therapy immune checkpoint in vivo knock-down mRNA Expression malignant breast neoplasm malignant stomach neoplasm mouse model new therapeutic target novel novel therapeutics overexpression patient derived xenograft model programmed cell death ligand 1 selective expression small molecule small molecule inhibitor targeted treatment therapeutic target triple-negative invasive breast carcinoma tumor tumor growth tumor progression tumor xenograft young woman

项目摘要

Project Summary/abstract We have identified that increased expression of Ly6K is associated with poor outcome in triple negative breast cancer (TNBC). Mechanistically, Ly6K is required for activation of TGFβ signaling and increased expression of the immune checkpoint protein PD-L1. We propose that the biomarker Ly6K is an ideal therapeutic target for the treatment of TNBC because this protein is not expressed in normal cells, except in testis, and it is not required for vital organ function, except for spermatogenesis. Thus, targeting this protein for the treatment of TNBC, a disease affecting mostly females, is appropriate and ideal. We have identified small drug-like molecules, which specifically bind to Ly6K and inhibit in vivo tumor growth. Mechanistically, they inhibit TGFβ signaling and PD- L1 expression in TNBC cells in an Ly6K dependent manner. In this proposal, we plan to validate these potential novel therapeutics in a humanized PDX model. This proposal will reveal the missing signaling links downstream of Ly6K, which activate TGFβ signaling and increase PD-L1 expression. We anticipate that the findings from our research will transform the field of developmental therapeutics concerning treatment of TNBC by defining Ly6K as a novel therapeutic target for anti-TGFβ signaling and inhibition of PD-L1 expression.

项目摘要/摘要我们已经发现，Ly6K的高表达与三阴性乳腺的不良预后有关癌症(TNBC)。从机制上讲，Ly6K是转化生长因子β信号的激活和表达增加所必需的。免疫检查点蛋白PD-L1。我们认为生物标记物Ly6K是治疗卵巢癌的理想靶点。治疗TNBC，因为这种蛋白在正常细胞中不表达，除非在睾丸中，而且不是必需的对于重要的器官功能，除了精子发生。因此，针对该蛋白治疗TNBC，一种主要影响女性的疾病，是适当和理想的。我们已经确定了类似药物的小分子，它们特异性结合Ly6K，抑制体内肿瘤生长。在机制上，它们抑制转化生长因子β信号和PD-1。 L1在TNBC细胞中以Ly6K依赖的方式表达。在这份提案中，我们计划验证这些潜力人性化PDX模型中的新疗法。这项提议将揭示下游缺失的信令链路激活转化生长因子β信号转导通路，增加PD-L1的表达。我们预计来自我们的调查结果研究将改变与治疗TNBC有关的发展疗法领域，将Ly6K定义为抗转化生长因子β信号转导和抑制PD-L1表达的新靶点。