New approach based on enzyme stimulating of peptides for targeting drug resistance breast cancers

基于肽酶刺激的新方法用于靶向耐药性乳腺癌

• 批准号: 10713648
• 负责人: Neda Habibi
• 金额: $ 18.03万
• 依托单位: UNIVERSITY OF NORTH TEXAS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-17 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713648
• 关键词: Adult; Alkaline Phosphatase; Amino Acids; Apoptosis; Aromatase Inhibitors; Biochemical Reaction; Biological Assay; Breast Cancer Cell; Breast Cancer Patient; Cancer Cell Growth; Cancerous; Cell Death; Cell Surface Receptors; Cells; Cessation of life; Data; Development; Disease; Dose; Drug Targeting; Drug resistance; Environment; Enzyme Induction; Enzyme Kinetics; Enzymes; Epidermal Growth Factor Receptor; Estrogen Receptors; Exposure to; Eye; Growth; High Pressure Liquid Chromatography; Human; Image; In Vitro; Inhibition of Cancer Cell Growth; Location; MDA MB 231; Medicine; Molecular Target; Nanostructures; Nanotechnology; Napping; Necrosis; Neoplasm Metastasis; Normal Cell; Organ; Pathway interactions; Patients; Peptides; Phase; Phosphoric Monoester Hydrolases; Phosphothreonine; Process; Progesterone Receptors; Protein Dephosphorylation; Protein Tyrosine Phosphatase; Proteins; Receptor Cell; Relapse; Research; Solid; Structure; Tamoxifen; Techniques; Time; Tissues; Trastuzumab; Tyrosine; Western Blotting; cancer cell; cancer type; cellular imaging; chemotherapy; design; effective therapy; efficacy evaluation; embryonic protein; enzyme activity; enzyme substrate; hormone therapy; improved outcome; inorganic phosphate; malignant breast neoplasm; nanofiber; new therapeutic target; novel; novel strategies; peptide drug; peptide structure; protein aminoacid sequence; receptor; response; self assembly; small molecule; three dimensional cell culture; treatment response; triple-negative invasive breast carcinoma; tumor

Abstract Triple-negative breast cancer (TNBC) is a type of breast cancer that does not express the estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) protein which accounts for 15–20 % of all breast cancer cases. TNBC tumors are generally larger, are of higher grade, and are more aggressive than other breast cancer types. TNBC is unlikely to respond to hormonal therapy medicines, including tamoxifen and aromatase inhibitors. TNBC also is unlikely to respond to medicines that target the HER2 protein, such as Herceptin (trastuzumab). Treatment of TNBC patients has been challenging due to the lack of molecular targets. Therefore, there is a critical unmet need to develop more effective therapies for TNBC and drug-resistant breast cancers. The development of new treatments would require radically different approaches that rely on enzymatic reactions specific to TNBC cells rather than the cell receptors. This proposal hypothesizes that properly designed peptide substrates of Eyes Absent enzyme (EYA) can selectively inhibit TNBC cell growth by a self-assembling process. The central hypothesis is that tyrosine phosphatase activity of EYA in TNBC could specifically convert the peptide therapeutics into nanofibers and induce controlled apoptosis of TNBC cells. The preliminary data suggested that a modified sequence of peptides with only one added amino acid could be de-phosphorylated by EYA and self-assemble into nanostructures to inhibit the growth of TNBC cells (MDA-MB-231). In this project, different peptide substrates of EYA will be synthesized by changing variable factors and the correlation of structure to enzyme activity and cell apoptosis will be determined by focusing on the following aims: Aim 1: Design and synthesize self-assembling peptide substrates for EYA enzymes; Aim 2: Determining the efficacy of peptide substrates for inhibiting TNBC in spheroid 3D cell cultures. The correlation between the enzyme kinetic and the activity of nanostructures for targeting EYA will be evaluated. Aim 3: The apoptosis response of the TNBC cells will be determined. This study will lead to finding the potent peptide substrate and the effective dose for inhibiting TNBC cells with apoptosis cell death.

抽象的 三阴性乳腺癌（TNBC）是一种不表达雌激素的乳腺癌 受体（ER），孕酮受体（PR）和人表皮生长因子受体2（HER2） 占所有乳腺癌病例的15-20％的蛋白质。 TNBC肿瘤通常更大，是 高年级，比其他乳腺癌类型更具侵略性。 TNBC不太可能做出回应 到包括他莫昔芬和芳香酶抑制剂在内的马疗治疗药物。 TNBC也不太可能 应对针对HER2蛋白的药物，例如Herceptin（Trastuzumab）。处理 由于缺乏分子靶标，TNBC患者受到了挑战。因此，有一个关键 未满足的需要为TNBC和耐药性乳腺癌开发更有效的疗法。这 开发新疗法将需要依赖酶促的根本不同的方法 对TNBC细胞而不是细胞接收器的反应。 该建议假设没有酶（EYA）的正确设计的眼睛肽底物（EYA） 可以通过自组装过程有选择地抑制TNBC细胞的生长。中心假设是 EYA在TNBC中的酪氨酸磷酸酶活性可以特异性转化为肽治疗 纳米纤维和影响TNBC细胞的受控凋亡。初步数据表明 EYA可以将仅添加的氨基酸的Petides的修饰序列脱磷酸化 并自组装成纳米结构以抑制TNBC细胞的生长（MDA-MB-231）。在这个 项目，EYA的不同肽底物将通过变化的变化因素和 结构与酶活性和细胞凋亡的相关性将通过关注 以下目的： 目标1：设计和合成Eya酶的自组装肽底物；目标2： 确定肽底物在球体3D细胞培养物中抑制TNBC的效率。 酶动力学与靶向EYA的纳米结构活性之间的相关性将会 进行评估。 AIM 3：将确定TNBC细胞的凋亡反应。这项研究会 导致发现有效的肽底物和有效剂量，用于抑制具有的TNBC细胞 细胞凋亡细胞死亡。