Development of an Oncogene-Targeted Therapeutic

描述（由申请人提供）：将癌症治疗剂靶向在正常组织中未发现的肿瘤细胞中的特定突变或异常的概念具有对肿瘤的高选择性和相应的低继发毒性的潜在优点。所有人类恶性肿瘤中至少30%显示p21Ras基因中的激活突变，并且可能另外60%显示其他激活突变或p21Ras信号传导途径的过度活性。我们以前发现，过度活动的p21 Ras信号敏感肿瘤细胞凋亡诱导的抑制PKC？活性，其对具有正常水平的p21Ras活性的细胞无毒。这种性质，称为“Ras介导的细胞凋亡”，可以作为一种靶向癌症治疗。我们已经从分子水平对Ras介导的细胞凋亡进行了表征，在体外和体内证明了其选择性，鉴定了特异性靶蛋白激酶C同工酶（PKC？），鉴定了两种用于在含有激活的Ras或Ras途径的肿瘤中诱导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剂的知识产权保护。在这个I期STTR应用中，我们将通过产生特定的类似物来改进和探索先导化合物I，并使用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？特异性、对表达活化Ras蛋白的细胞的细胞毒性的靶向以及异种移植肿瘤模型。然后，我们将把这种化合物推进到正式的临床前研究中。公共卫生相关性：高达70%的人类恶性肿瘤中存在Ras或Ras指导的信号传导通路的突变或激活，申请组织已开发出一种治疗策略，通过该策略可在Ras或Ras通路激活的肿瘤中诱导程序性细胞死亡。该I期STTR提案将对当前的先导候选药物和该化合物的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否则会死于疾病的患者正常生存，并可以减少数十亿美元的年度医疗费用。

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.