Non-Oncogene Addiction as a Targeted Therapy for Pancreatic Cancer

非癌基因成瘾作为胰腺癌的靶向治疗

• 批准号: 8601296
• 负责人: Douglas V Faller
• 金额: $ 19.77万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601296
• 关键词: Adverse effects; Apoptosis; Cancer cell line; Cell Death; Cells; Chemicals; Dependency; Down-Regulation; Future; Growth; Human; In Vitro; Induction of Apoptosis; Isoenzymes; Ki-ras Gene; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modality; Modeling; Modification; Molecular; Mus; Mutate; Mutation; Normal Cell; Normal tissue morphology; Oncogenic; Organism; Pancreatic carcinoma; Pathway interactions; Phase II Clinical Trials; Pilot Projects; Positioning Attribute; Predisposition; Proteins; Refractory; Signal Transduction; Testing; Therapeutic; Toxic effect; Work; Xenograft procedure; addiction; analog; cancer stem cell; chemotherapy; cytotoxicity; drug candidate; in vivo; in vivo Model; inhibitor/antagonist; mutant; neoplastic cell; non-oncogenic; novel; novel therapeutics; oncogene addiction; pancreatic cancer cells; pharmacophore; preclinical study; public health relevance; tumor

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.

描述（由申请人提供）：将癌症治疗剂靶向肿瘤细胞中特异性突变或异常的概念，在正常组织中未发现的肿瘤细胞具有高选择性的潜在优势，并且相应低的继发性毒性。至少93％的胰腺癌在Ki-Ras基因中的位置12处具有相同的激活突变。我们先前发现，当抑制PKCD活性时，P21RAS信号的过度活性会导致肿瘤细胞凋亡。相反，正常细胞的存活和生长（具有野生型RAS）并不需要PKCD活性。因此，Ras突变肿瘤细胞对PKCD活性的绝对依赖性可以被用作靶向癌症治疗。 （这种新型的分子方法可避免正常细胞，靶向含有突变的致癌蛋白的肿瘤细胞的依赖性，这是肿瘤存活所需的第二个非癌蛋白，有时称为“非癌基因成瘾”）。在迄今为止的工作中，我们已经表征了这种合成的致死性方法分子，在体外和体内证明了它的选择性，并鉴定了两种铅化合物，以有效地诱导含有活化Ras的肿瘤中的细胞死亡。 在此提案中，我们将通过产生特定的类似物来完善和探索铅PKCD抑制剂，然后使用体外和体内研究选择“最佳”候选药物来诱导胰腺癌中的合成致死性。在未来的工作中，我们将将选定的化合物向前移动到正式的临床前研究中。我们有着从学术环境中开发从发现到第二阶段试验的新型治疗剂的出色记录。此外，我们将继续采用并不断地完善我们的分子策略（一种高度预测性的药效团模型），以寻找更具活性和更具体的RAS靶向合成致死性的诱导剂。此外，我们的靶向方法似乎对胰腺癌干细胞具有实质性活性，这通常对常规化学疗法难治。我们的目标是：i。）当前铅PKCD抑制剂的靶向化学修饰； ii。）在人胰腺癌细胞中测试这些新的PKCD抑制剂，以诱导凋亡； iii。）在人类胰腺癌的体内模型中验证这种靶向RAS的方法。这种新颖的治疗方式有选择地靶向胰腺瘤，将对胰腺癌的治疗方式产生重大影响。

项目成果

MicroRNA let-7 downregulates STAT3 phosphorylation in pancreatic cancer cells by increasing SOCS3 expression.

• DOI: 10.1016/j.canlet.2014.01.020
• 发表时间: 2014-05-28
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Patel, Kripa;Kollory, Anita;Takashima, Asami;Sarkar, Sibaji;Faller, Douglas V.;Ghosh, Sajal K.
• 通讯作者: Ghosh, Sajal K.