Phosphatidylserine Targeted Tumor Cell Lytic Peptoids

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。因为它们是针对癌症的，所以它们使身体的其他部分免受毒副作用的影响。不幸的是，许多类型的癌症都没有合适的蛋白质靶点，即使在有蛋白质标记物的肿瘤中，标记物的表达也存在异质性。这限制了靶向药物对特定患者群体的有效性。因此，迫切需要一种全球性的癌症标志物。脂质磷脂酰丝氨酸（PS）普遍存在于肿瘤血管内皮中，而不存在于健康的正常组织中。PS也在许多类型的癌细胞表面表达。为了专门针对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，二聚体的类肽通过裂解质膜和破坏肿瘤内的肿瘤血管而有效地杀死癌细胞。类肽对正常细胞没有影响。这项提议的总体目标是开发这种肽的不同版本，以识别更有效的化合物。类肽的分子结构将通过两种方式进行修饰：(i)将活性类肽组装成多聚体形式（例如二聚体，三聚体，四聚体等）以增强活性；（ii）将修饰活性序列以提高ps识别。这些衍生物将在许多不同的癌症模型中测试其特定的裂解活性；乳腺癌，前列腺癌，白血病，神经胶质瘤和肺癌。接下来，我们将对ps靶向类肽的作用机制进行研究。类肽的作用是破坏肿瘤的血管，使肿瘤细胞因缺氧和缺乏营养而死亡，并溶解ps阳性肿瘤细胞。动物实验将全面评价这些活动。类肽制备成本低，稳定，可以快速地从结构上提炼出最佳的功效。因此，在这项研究中发现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。

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.