Development of an Oncogene-Targeted Therapeutic

描述（由申请人提供）：针对正常组织中未发现的肿瘤细胞中的特定突变或异常的癌症治疗的概念具有对肿瘤的高选择性和相应的低继发性毒性的潜在优势。至少30%的人类恶性肿瘤显示p21Ras基因的激活突变，另外60%可能显示其他激活突变或p21Ras信号通路的过度活性。我们之前发现p21Ras信号的过度活性使肿瘤细胞对PKC抑制诱导的凋亡敏感。活性，对p21Ras活性正常的细胞没有毒性。这种特性被称为“ras介导的细胞凋亡”，可以作为一种靶向癌症治疗方法。我们对Ras介导的细胞凋亡进行了分子表征，证明了其在体外和体内的选择性，鉴定了特异性靶PKC同工酶（PKC?），鉴定了两种诱导含有活化Ras或Ras通路的肿瘤细胞死亡的先导化合物，并获得了Ras介导的细胞凋亡作为治疗药物的知识产权保护。在这个I期STTR应用中，我们将通过生成特异性类似物来完善和探索先导化合物I，并通过体外和体内研究来选择ras介导的细胞凋亡的最佳诱导剂。检测将包括PKC的评估。特异性，针对表达活化Ras蛋白的细胞的细胞毒性，以及异种移植肿瘤模型。然后，我们将把这种化合物推进正式的临床前研究。公共卫生相关性：多达70%的人类恶性肿瘤发生Ras或Ras定向信号通路的突变或激活，申请组织已经开发出一种治疗策略，通过激活Ras或Ras通路可以诱导肿瘤中的程序性细胞死亡。该I期STTR提案旨在对当前的主要候选药物及其类似物进行进一步的临床前测试，以选择最佳化合物进入临床试验。这种治疗方法的成功开发可以使许多原本会死于疾病的患者正常生存，并可以减少每年数十亿美元的医疗费用。

DESCRIPTION (provided by applicant): The concept of targeting cancer therapeutics towards specific mutations or abnormalities in tumor cells which are not found in normal tissues has the potential advantages of high selectivity for the tumor and correspondingly low secondary toxicities. At least 30% of all human malignancies display activating mutations in the p21Ras genes, and perhaps another 60% display other activating mutations or over- activity of p21Ras-signaling pathways. We previously discovered that over-activity of p21Ras signaling sensitizes tumor cells to apoptosis induced by suppression of PKC? activity, which is not toxic to cells with normal levels of p21Ras activity. This property, designated "Ras-mediated apoptosis", can be exploited as a targeted cancer therapeutic. We have characterized Ras-mediated apoptosis molecularly, demonstrated its selectivity in vitro and in vivo, identified the specific target PKC isozyme (PKC?), identified two lead compounds for inducing cell death in tumors containing activated Ras or Ras pathways, and gained intellectual property protection on Ras-mediate apoptosis as a therapeutic. In this Phase I STTR application, we will refine and explore Lead Compound I by generating specific analogs, and use in vitro and in vivo studies to select the optimal inducer of Ras-mediated apoptosis. Assays will include assessment of PKC? specificity, targeting of cytotoxicity for cells expressing an activated Ras protein, and xenograft tumor models. We will then move this compound forward into formal preclinical studies. PUBLIC HEALTH RELEVANCE: Mutation or activation of Ras or Ras-directed signaling pathways occur in up to 70% of human malignancies, and the applicant organization has developed a therapeutic strategy by which programmed cell death can be induced in tumors with activation of Ras or Ras pathways. This Phase I STTR proposal is to carry out further preclinical testing of the current lead drug candidate, and analogs of this compound, to select the optimal compound to move into clinical trials. Successful development of this therapeutic could allow normal survival of many patients who would otherwise die of their disease, and could reduce annual medical care costs by billions of dollars.