Evaluation of HSPD1 (Heat Shock Protein, 60) as a theranostic target for breast cancer

HSPD1（热休克蛋白，60）作为乳腺癌治疗靶点的评估

• 批准号: 10241242
• 负责人: Deepa Bedi
• 金额: $ 36.75万
• 依托单位: TUSKEGEE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241242
• 关键词: Accounting; Affinity; Bacteriophages; Binding; Bioinformatics; Breast; Breast Cancer Cell; Breast Cancer Patient; Breast cancer metastasis; Cause of Death; Cells; Chaperonin 60; Complex; Data Set; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Distant; Drug Delivery Systems; Drug Targeting; Epithelial; Evaluation; Event; Fibroblasts; Funding; Goals; Heat shock proteins; Immunoblotting; Indolent; Invaded; Laboratories; Ligands; Malignant Neoplasms; Mesenchymal; Metastatic breast cancer; Metastatic to; Mitochondria; Morphology; Neoplasm Metastasis; Oncogenes; Oncogenic; Organ; Organ failure; Outcome Study; Patients; Peptides; Phage Display; Phenotype; Play; Prognosis; Property; Proteins; Research; Role; Seeds; Site; Specificity; Survival Rate; System; Techniques; Technology; Therapeutic; Therapeutic Agents; Time; Tissues; Transitional Cell; Up-Regulation; Woman; aggressive breast cancer; base; breast cancer progression; breast cancer survival; cancer cell; clinical biomarkers; clinical decision-making; clinically relevant; epithelial to mesenchymal transition; imaging agent; insight; malignant breast neoplasm; mammary epithelium; novel; peptidomimetics; prognostic; protein aminoacid sequence; receptor; targeted biomarker; theranostics; tumor; tumor growth

Our laboratory has used a novel subtractive phage display technique to identify phage ligands that can specifically and selectively bind to epithelial to mesenchymal transitioned (EMT) breast cancer cells. We selected and characterized several phages that had affinity to EMT cells. One of the phages with the foreign peptide sequence CLGLRGSLC bound with greater affinity and specificity to EMT breast cancer and EMT fibroblasts cells. We identified HSPD1 (heat shock protein, 60Kda) as a putative binding partner to CLGLRGSLC phage. Subsequent studies, including bioinformatics dataset analysis, immunoblotting of indolent vs aggressive breast cancer cells, immunohistochemical analysis of primary and metastatic breast cancer tissues showed increased expression of HSPD1 during disease progression and correlates with survival of breast cancer patients. This preliminary engenders the novel hypothesis that HSPD1 might play a role in metastatic progression of breast cancer and the discovery of HSPD1-binding peptide also suggests the use of novel imaging and therapeutic agents based on the selective binding. We hypothesize that HSPD1 is a novel oncogene that can serve as a clinically relevant marker for breast cancer metastasis and an ideal receptor that can be utilized for tumor-targeted drug delivery to metastatic sites. Following specific aims will be pursued: a) to determine if HSPD1 expression correlates with metastatic disease. b) to determine the oncogenic role of HSPD1 in breast cancer development and progression invitro and invivo, c) will aim to develop peptidomimetic targeting system to suppress metastasis based on HSPD1-binding phage peptide fused to proapoptotic moiety D(KLAKLAK)2.

本实验室利用一种新的噬菌体消减展示技术， 可以特异性和选择性地结合上皮细胞到间充质细胞的配体， (EMT)乳腺癌细胞我们选择了几个具有亲和力的化合物， 到EMT细胞其中一个与外源肽序列CLGLRGSLC结合的引物 对EMT乳腺癌和EMT成纤维细胞具有更大的亲和力和特异性。我们 鉴定出热休克蛋白1（60Kda）作为推定的结合伴侣， CLGLRGSLC噬菌体。后续研究，包括生物信息学数据集分析， 惰性与侵袭性乳腺癌细胞的免疫印迹，免疫组织化学 原发性和转移性乳腺癌组织的分析显示， 与乳腺癌患者生存期相关 患者这初步产生了一个新的假设，即HSPD 1可能在 乳腺癌转移进展和HSPD 1结合肽的发现 还建议使用基于选择性的新的成像和治疗剂， 约束力我们假设HSPD 1是一个新的癌基因，可以作为临床上的一个靶基因。 乳腺癌转移的相关标志物和可利用的理想受体 用于肿瘤转移部位的靶向药物递送。具体目标如下： 追求： a）确定HSPD 1表达是否与转移性疾病相关。 B）确定HSPD 1在乳腺癌发展中的致癌作用，和 体外和体内进展， c）将致力于开发肽模拟物靶向系统，以基于 HSPD 1结合噬菌体肽融合到促凋亡部分D（KLAKLAK）2。