Non-Oncogene Addiction as a Targeted Therapy for Pancreatic Cancer

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93%的胰腺癌在Ki-Ras基因的第12位有相同的激活突变。我们之前发现，当PKCd活性被抑制时，p21Ras信号的过度活性会导致肿瘤细胞凋亡。相比之下，PKCd活性不需要正常细胞（野生型Ras）的存活和生长。因此，ras突变肿瘤细胞对PKCd活性的绝对依赖性可以作为一种靶向癌症治疗方法。（这种新的分子方法不涉及正常细胞，针对的是肿瘤细胞对含有突变的致癌蛋白的第二种非致癌蛋白的依赖，这种非致癌蛋白是肿瘤存活所必需的，有时被称为“非致癌基因成瘾”）。在我们迄今为止的工作中，我们从分子上表征了这种合成致死性方法，证明了它在体外和体内的选择性，并确定了两种先导化合物，可有效诱导含有活化Ras的肿瘤细胞死亡。在本课题中，我们将通过生成特异性类似物来完善和探索我们的PKCd抑制剂，然后通过体外和体内研究来选择诱导胰腺癌合成致死的“最佳”候选药物。在未来的工作中，我们将把选定的化合物推进正式的临床前研究。我们有一个良好的跟踪记录，从发现到二期临床试验，在学术环境中开发新的治疗方法。此外，我们将继续采用并不断完善我们的分子策略（高预测性药效团模型），以寻找更活跃、更特异性的ras靶向合成致死性诱导剂。此外，我们的靶向方法似乎对胰腺癌干细胞具有实质性的活性，而胰腺癌干细胞通常对常规化疗难以耐受。我们的目标是：1)现有铅基PKCd抑制剂的靶向化学修饰二)。在人胰腺癌细胞中检测这些新的PKCd抑制剂诱导细胞凋亡的作用iii)。在人胰腺癌的体内模型中验证这种ras靶向方法。这种选择性靶向胰腺癌的新型治疗方式将对胰腺癌的治疗方式产生重大影响。

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 93% of pancreatic cancers have the identical activating mutation at position 12 in the Ki-Ras gene. We previously discovered that over-activity of p21Ras signaling causes tumor cell apoptosis when PKCd activity is suppressed. In contrast, PKCd activity is not required for the survival and growth of normal cells (with wild-type Ras). This absolute dependency of Ras-mutant tumor cells on PKCd activity can therefore be exploited as a targeted cancer therapeutic. (This novel molecular approach, which spares normal cells, targets the dependency of tumor cells containing a mutated oncogenic protein on a second, non-oncogenic protein required for survival of the tumor, sometimes termed "non-oncogene addiction"). In our work to date, we have characterized this synthetic lethality approach molecularly, demonstrated its selectivity in vitro and in vivo, and identified two lead compounds for efficiently inducing cell death in tumors containing activated Ras. In this proposal, we will refine and explore our lead PKCd inhibitor by generating specific analogs, and then use in vitro and in vivo studies to select the "optimal" candidate drug for inducing synthetic lethality in pancreatic carcinoma. In future work, we will then move the selected compound forward, into formal preclinical studies. We have an excellent track record of developing novel therapeutics from discovery through phase II trials from within an academic setting. In addition, we will continue to employ, and continuously refine, our molecular strategy (a highly-predictive pharmacophore model) in the search for even more active and more specific inducers of Ras-targeted synthetic lethality. Furthermore, our targeted approach appears to have substantial activity against pancreatic cancer stem cells, which are generally refractory to conventional chemotherapy. Our Aims are: i.) Targeted chemical modifications of current lead PKCd inhibitor; ii.) Test these new PKCd inhibitors in human pancreatic cancer cells for induction of apoptosis; iii.) Validate this Ras-targeted approach in in vivo models of human pancreatic carcinoma. This novel therapeutic modality, selectively targeting pancreatic carcinomas, would make a significant impact on the way pancreatic carcinoma is treated.