Ras Oncoprotein-Targeted Therapy for Cancer

描述(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而进行癌症治疗的概念具有对肿瘤的高选择性和相应的低二次毒性的潜在优势。在所有人类恶性肿瘤中，至少有20%表现出p21RAS基因的激活突变，另外60%可能表现出p21RAS信号通路的其他激活突变(或过度激活)。我们已经发现，p21Ras信号的过度激活使细胞对包括抑制PKC活性在内的多种条件诱导的细胞凋亡敏感，这些条件对p21Ras活性正常的细胞没有毒性。这一特性被命名为“RAS介导的细胞凋亡”，可用于靶向治疗癌症。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，并建议开发这一策略作为癌症的靶向治疗。在这一应用中，我们建议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，最终进入正式的临床前研究。我们还将确定是否其他导致p21Ras信号通路激活的突变，而不是p21Ras本身的点突变，类似地赋予了对RAS介导的细胞凋亡的敏感性。这将大大拓宽RAS介导的细胞凋亡作为一种治疗方式的潜在应用。我们将阐明RAS介导的细胞凋亡的分子机制。最后，我们将采用并不断改进一种新的分子策略(药效团模型)，以寻找更活跃、更特异的RAS介导的细胞凋亡诱导剂。

DESCRIPTION (provided by applicant): The concept of targeting cancer therapeutics towards specific mutations or abnormalities in tumor cells not found in normal tissues has the potential advantages of high selectivity for the tumor and correspondingly low secondary toxicities. At least 20% of all human malignancies display activating mutations in the p21 Ras genes, and perhaps another 60% display other activating mutations (or over-activity) of p21 Ras signaling pathways. We have discovered that over-activity of p21 Ras signaling sensitizes cells to apoptosis induced by a number of conditions, including suppression of PKC activity, which are not toxic to cells with normal levels of p21 Ras 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, and propose to develop this strategy as a targeted therapeutic for cancer. In this application, we propose to use in vitro and in vivo studies to select the optimal inducer of Ras-mediated apoptosis, for eventual advancement into formal preclinical studies. We will also determine if other mutations, which result in activation of p21Ras-signaling pathways without point-mutations in p21 Ras itself, similarly confer sensitivity to Ras-meditated apoptosis. This would substantially broaden the potential application of Ras-mediated apoptosis as a therapeutic modality. We will elucidate the molecular mechanisms leading to Ras-mediated apoptosis. Finally, we will employ, and continuously refine, a new molecular strategy (a pharmacophore model) in the search for more active and more specific inducers of Ras-mediated apoptosis.