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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：
10453713
负责人：
Geeta Upadhyay
金额：
$ 38.85万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453713
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.

项目概要/摘要我们已经确定Ly 6 K表达的增加与三阴性乳腺癌患者的不良结局相关，癌症（TNBC）。从机制上讲，Ly 6 K是激活TGFβ信号传导和增加TGF β 1表达所必需的。免疫检查点蛋白PD-L1。我们认为生物标志物Ly 6 K是治疗乳腺癌的理想治疗靶点治疗TNBC，因为这种蛋白质在正常细胞中不表达，除了在睾丸中，并且不需要重要器官的功能，除了精子生成。因此，靶向这种蛋白质用于治疗TNBC，主要影响女性的疾病，是适当和理想的。我们已经发现了类似药物的小分子，特异性结合Ly 6 K并抑制体内肿瘤生长。从机制上讲，它们抑制TGFβ信号传导和PD-1。 L1在TNBC细胞中以Ly 6 K依赖性方式表达。在本提案中，我们计划验证这些潜力人源化PDX模型中的新治疗剂。该提案将揭示下游缺失的信令链路 Ly 6 K，其激活TGFβ信号传导并增加PD-L1表达。我们预计，研究将通过将Ly 6 K定义为抗TGF β信号传导和抑制PD-L1表达的新型治疗靶点。

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）

NSC243928 Treatment Induces Anti-Tumor Immune Response in Mouse Mammary Tumor Models.

DOI：
10.3390/cancers15051468
发表时间：
2023-02-25
期刊：
Cancers
影响因子：
5.2
作者：
通讯作者：

Experimental and Computational Studies Reveal Novel Interaction of Lymphocytes Antigen 6K to TGF-β Receptor Complex.

DOI：
10.3390/ijms241612779
发表时间：
2023-08-14
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
影响因子：
5.6
作者：
Andrys-Olek, Justyna;Selvanesan, Benson Chellakkan;Varghese, Sheelu;Arriaza, Ricardo Hernandez;Tiwari, Purushottam Babu;Chruszcz, Maksymilian;Borowski, Tomasz;Upadhyay, Geeta
通讯作者：
Upadhyay, Geeta