Pancreatic Cancer Vulnerabilities Downstream of Cooperating Oncogenic Mutations

协同致癌突变下游的胰腺癌脆弱性

基本信息

批准号：
8868072
负责人：
Hartmut Land
金额：
$ 41.26万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-11 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8868072
关键词：
Acute Address Advanced Malignant Neoplasm Affect Amino Acids Apoptosis Automobile Driving Autophagocytosis Autophagosome CDKN2A gene Cancer Intervention Cell Death Cell physiology Complement Cysteine Data Dependence Disease Doxycycline Engineering Epithelial Epithelium Event Frequencies Gene Expression Genes Genetic Health Intervention Intestines Investigation KRAS2 gene Knockout Mice Lentivirus Vector Lysosomes Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Metabolism Modeling Monitor Mus Mutation Normal tissue morphology Oncogenic Oxidative Stress Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Phenotype Play Process Refractory Reporter Reporting Role Series Signal Pathway Stress TP53 gene Testing Tumor Biology base cancer cell cell transformation improved in vivo inhibition of autophagy malignant phenotype mutant neoplastic cell novel novel strategies outcome forecast research study response small hairpin RNA success targeted treatment therapeutic target tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The prognosis of pancreatic ductal adenocarcinoma (PDA) has improved only marginally in the past decade. PDA is a disease with remarkable homogeneity across several key loci, namely KRAS, p53, and the INK4A/ Arf locus; related to this, PDA has been refractory to the many genetically guided therapies targeting activated oncogenic molecules that have offered success in other tumor types. Previously, we have identified a set of ~95 genes cooperatively regulated by mutation of RAS and p53, that are critical to the malignant phenotype of a variety of epithelial cancer cells in vivo. We have termed these non-mutated genes driving the cancer phenotype 'cooperation response genes' (CRGs). CRGs control a range of cellular processes and pathways (signaling, metabolism, transport etc.) and offer novel approaches to targeted cancer interventions with potential relevance to a variety of diverse cancers. Given the high frequency of cooperating KRAS and P53 pathway mutations found in PDA (>90% of tumors) we have specifically evaluated CRG expression levels in the pancreatic epithelium where we find a subset of these genes similarly deregulated pointing towards their importance in pancreatic oncogenesis. Our preliminary data indicate that one such cooperatively regulated gene with previously unknown function, Plac8, localizes to lysosomes functionally facilitating autophagosome- lysosome (AL) fusion, and that its genetic silencing leads to a block in autophagy and inhibition of tumor growth. Furthermore, genetic inactivation of Plac8 in an engineered murine PDA model impedes the progression of advanced tumors extending survival. In contrast, Plac8 knockout mice are minimally affected by loss of this gene. Thus, Plac8 and the lysosomal processes it regulates appear well suited as therapeutic targets in PDA and other RAS/p53 mutant GI cancers, as Plac8 inhibition has both a high impact on tumor biology and a minimal impact on normal cellular function. Based on these data we hypothesize that i) Plac8 facilitates AL fusion in cancer cells, and ii) that this mechanism is essential to the malignant phenotype PDA, thus providing rationale for targeted pancreatic cancer intervention. These hypotheses will be tested in a series of experiments investigating 1) the role of Plac8 in pancreatic cancer progression and cancer maintenance, 2) the role of autophagosome-lysosome fusion as an essential function in cancer, and 3) the impact of Plac8 on lysosome integrity in cancer. The role and relevance of both autophagosome/ lysosome fusion and active protection of lysosomal integrity in cancer remains virtually unexplored. Investigation of the mechanisms involved is thus likely to reveal novel opportunities for targeted cancer-specific interventions, particularly as Plac8 is non-essential for normal tissue function.

描述（由申请人提供）：在过去十年中，胰腺导管腺癌（PDA）的预后仅略有改善。 PDA是一种在几个关键基因座（即KRAS，p53）和Ink4a/ arf基因座的疾病中具有显着同质性的疾病。与此相关的是，PDA与靶向激活的致癌分子的许多遗传引导的疗法具有难治性，这些疗法在其他肿瘤类型中都取得了成功。以前，我们已经确定了一组约95个基因，该基因由Ras和p53的突变合作调节，这对于体内各种上皮癌细胞的恶性表型至关重要。我们已经称为这些非突变基因推动了癌症表型“合作反应基因”（CRGS）。 CRG控制着一系列细胞过程和途径（信号，代谢，运输等），并为靶向癌症干预提供了新的方法，并与各种不同的癌症相关。鉴于在PDA中发现的KRAS和p53途径突变的高频率（> 90％的肿瘤）我们已经特别评估了胰腺上皮中的CRG表达水平，在那里我们发现这些基因的子集类似地对其在胰腺肿瘤中的重要性表明了它们的重要性。我们的初步数据表明，具有以前未知功能的一个合作调节基因PLAC8本地定位于功能上促进自噬体溶酶体（AL）融合的溶酶体，其遗传沉默会导致自噬和抑制肿瘤生长的障碍。此外，工程鼠PDA模型中PLAP8的遗传失活阻碍了延伸生存的晚期肿瘤的进展。相反，PLAC8敲除小鼠受该基因丢失的影响最小。因此，在PDA和其他RAS/p53突变GI癌症中，PLAC8和它调节的溶酶体过程似乎非常适合作为治疗靶标，因为PLAC8抑制作用既对肿瘤生物学具有很高的影响，又对正常细胞功能产生了最小的影响。基于这些数据，我们假设i）plap8促进了癌细胞中的融合，ii）这种机制对于恶性表型PDA至关重要，从而为靶向胰腺癌干预提供了基本原理。这些假设将在研究的一系列实验中进行检验1）PLAC8在胰腺癌进展和癌症维持中的作用，2）自噬体 - 溶酶体融合作为癌症的重要功能的作用，以及3）PLEC8对乳糖体完整性在癌症中的影响。自噬体/溶酶体融合和溶酶体完整性在癌症中的作用和相关性几乎没有探索。因此，对所涉及机制的研究可能揭示了针对癌症特异性干预措施的新机会，尤其是因为PLAC8对于正常组织功能而言是非必需的。