Phosphatidylserine Targeted Tumor Cell Lytic Peptoids

磷脂酰丝氨酸靶向肿瘤细胞裂解肽

• 批准号: 8918247
• 负责人: Damith Gomika Udugamasooriya
• 金额: $ 29.47万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8918247
• 关键词: Adverse effects; Affinity; Animals; Antibodies; Antineoplastic Agents; Apoptosis; Applications Grants; Binding; Biodistribution; Biological; Biological Markers; Breast; Cancer Detection; Cancer Model; Cancer Patient; Cell membrane; Cells; Cessation of life; Clinical Trials; Cytolysis; Cytotoxic agent; Development; Drug Targeting; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Glioma; Goals; Health; Heterogeneity; Human; In Vitro; Libraries; Lipids; Lung; Lytic; MDA MB 231; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Medicine; Methods; Modeling; Molecular; Molecular Structure; Molecular Target; Monitor; Mus; Neoplasms in Vascular Tissue; Normal Cell; Normal tissue morphology; Nutrient; Oxygen; PC3 cell line; Patients; Penetrance; Peptide antibodies; Peptides; Peptoids; Pharmaceutical Preparations; Phosphatidylserines; Prostate; Proteins; Reporting; Rest; Safety; Serum; Starvation; Structure; Surface; Testing; Time; Toxic effect; Validation; Vascular Endothelial Cell; Vascular Endothelium; cancer cell; cancer imaging; cancer therapy; cancer type; cell type; cost; cost effective; cytotoxic; dimer; docetaxel; drug discovery; flexibility; imaging agent; improved; in vivo; interest; irradiation; killings; leukemia; malignant breast neoplasm; molecular size; neoplastic cell; patient population; peptidomimetics; programs; research study; response; scaffold; small molecule; success; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): New drugs that target cancer cells promise to revolutionize cancer medicine. Because they are cancer-specific, they spare the rest of the body from toxic side effects. Unfortunately, suitable protein targets are not available for many types o cancer and there is heterogeneity in marker expression even in tumors for which protein markers are available. This limits the usefulness of targeted drugs to selected groups of patients. Thus, there is a pressing need for a global marker of cancer. The lipid phosphatidylserine (PS) is universally present on the tumor vascular endothelium and absent from healthy normal tissues. PS is also expressed on the surface of many types of cancer cells. To target PS specifically, a peptide-like molecule, called a peptoid, was selected from a large library. The dimeric version of the peptoid potently killed cancer cells by lysing their plasma membrane and disrupted tumor blood vessels inside tumors in an animal tumor model. The peptoid had no effect on normal cells. The overall goal of this proposal is to develop different versions of this peptoid to identify even more effective compounds. The molecular structure of the peptoid will be modified in 2 ways: (i) The active peptoid will be assembled into multimeric forms (e.g. dimers, trimers, tetramers etc.) to enhance the activity and (ii) The active sequence will be modified to improve PS-recognition. These derivatives will be tested for specific lytic activity in many different cancer models; breast, prostate, leukemia, glioma and lung. Next, the mechanism of action of the PS-targeting peptoids will be investigated. The peptoids are expected to act by destroying the tumor's blood vessels, resulting in death of tumor cells through starvation of oxygen and nutrients, and by lysing PS-positive tumor cells. Animal studies will comprehensively evaluate these activities. Peptoids are inexpensive to prepare, stable and can be rapidly refined structurally for optimal efficacy. Thus, the peptoids identified n this study could constitute a new class of drugs with the potential to make a major impact on the treatment of multiple types of cancer.

描述（由申请人提供）：针对癌细胞的新药有望彻底改变癌症医学。由于它们具有癌症特异性，因此可以使身体的其他部位免受毒副作用的影响。不幸的是，对于许多类型的癌症来说，没有合适的蛋白质靶点，并且即使在有蛋白质标记物可用的肿瘤中，标记物表达也存在异质性。这限制了靶向药物对特定患者群体的用途。因此，迫切需要一种全球癌症标记物。脂质磷脂酰丝氨酸（PS）普遍存在于肿瘤血管内皮上，而健康正常组织中不存在。 PS 也在许多类型的癌细胞表面表达。为了特异性地靶向 PS，从一个大型文库中选择了一种称为类肽的肽样分子。在动物肿瘤模型中，类肽的二聚体通过裂解癌细胞的质膜并破坏肿瘤内的肿瘤血管来有效杀死癌细胞。类肽对正常细胞没有影响。该提案的总体目标是开发该类肽的不同版本，以识别更有效的化合物。类肽的分子结构将以两种方式进行修饰：（i）活性类肽将被组装成多聚体形式（例如二聚体、三聚体、四聚体等）以增强活性；（ii）活性序列将被修饰为提高 PS 识别能力。这些衍生物将在许多不同的癌症模型中测试特定的裂解活性；乳腺癌、前列腺癌、白血病、神经胶质瘤和肺癌。接下来，将研究 PS 靶向类肽的作用机制。预计类肽的作用是破坏肿瘤血管，导致肿瘤细胞因缺氧和营养而死亡，并裂解 PS 阳性肿瘤细胞。动物研究将全面评估这些活动。类肽的制备成本低廉、稳定，并且可以快速进行结构精炼以获得最佳功效。因此，本研究中鉴定的类肽可能构成一类新的药物，有可能对多种癌症的治疗产生重大影响。