Targeting HuR to improve a synthetic lethal therapy for pancreatic cancer

摘要 尽管最近取得了进展，但转移性胰腺癌仍然是一种致命的疾病， 生存时间不到一年。迫切需要新的靶向治疗。识别和扩展 从有希望的靶向药物中获益最多的患者亚组将立即影响患者 结果。我们提案的主要影响涉及PARP抑制剂的临床应用， 利用针对胰腺癌亚群的经证实的个性化合成致死治疗策略 患者最近100例胰腺癌的全基因组测序突出了使用 PARP抑制剂治疗靶向具有“DNA修复-BRCA-签名”亚型的肿瘤。我们的工作将 拓展三条研究创新战线，努力优化最有前途的药物类别 胰腺导管腺癌患者。目标1将扩展我们最近的发现，即一个后- 由mRNA稳定因子HuR驱动的转录机制，提供了一种耐药机制， 胰腺癌细胞暴露于PARP抑制剂。在这个目标中，我们将扩展我们的临床前小鼠 建模以建立HuR作为PARP抑制剂抗性的促进剂，并建立抑制HuR 可使所有胰腺肿瘤（无论DNA修复状态如何）对PARP抑制剂敏感。目标2将进一步 使用最先进的分子和细胞技术和测定，定义PARP抑制剂机制， 取决于新的HuR调节靶点的作用[即，聚（ADP-核糖）糖水解酶 （PARG）]。目标3将利用我们对HuR生物学的分子理解和两个小的 HuR的分子抑制剂开发新的和可翻译的策略，以增强PARP抑制剂的功效 使用患者导出的（即，类器官技术），来自正在进行的PARP抑制剂试验的活体生物库 由本提案的调查员进行。我们工作的翻译意义涉及到 我们的努力，以改善一个有前途的，个性化的方法，胰腺癌，通过增加 了解最近发现的PARP抑制剂耐药机制。我们的最终目标是 优化目前仅限于携带DNA修复缺陷的肿瘤的同类最佳治疗策略， 因此，这种治疗策略可以扩展到包括所有胰腺癌，而不管 DNA修复状态（即，BRCA 2突变体和野生型）。

ABSTRACT Despite recent advancements, metastatic pancreatic cancer remains a lethal disease with an average survival of less than one year. New targeted treatments are desperately needed. Identifying and expanding patient subgroups that would benefit most from promising targeted agents will immediately impact patient outcomes. The primary impact of our proposal relates to the clinical implementation of PARP inhibitors, harnessing a proven synthetic lethal therapeutic strategy personalized for a subset of pancreatic cancer patients. Recent whole genome sequencing of 100 pancreatic cancers highlighted the opportunity to use PARP inhibitor therapy targeted for tumors with a `DNA repair-BRCA-signature' subtype. Our work will expand three fronts of investigation and innovation in an effort to optimize the most promising drug class for pancreatic ductal adenocarcinoma patients. Aim 1 will expand our recent discovery that a post- transcriptional mechanism driven by the mRNA stability factor HuR, provides a resistance mechanism for pancreatic cancer cells exposed to PARP inhibitors. In this aim, we will extend our pre-clinical mouse modeling to establish HuR as a facilitator of PARP inhibitor resistance and establish that inhibiting HuR may sensitize all pancreatic tumors, regardless of DNA repair status, to PARP inhibitors. Aim 2 will further define, using cutting edge molecular and cell-based techniques and assays, a PARP inhibitor mechanism of action which is contingent upon a novel HuR-regulated target [i.e., (Poly(ADP-ribose) glycohydrolase (PARG)]. Aim 3 will leverage our molecular understanding of HuR biology and the identification of two small molecule inhibitors of HuR to develop novel and translatable strategies to enhance PARP inhibitor efficacy using a patient derived (i.e., organoid technology), live biobank from an ongoing PARP inhibitor trial conducted by investigators from the present proposal. The translational significance of our work relates to our efforts to improve upon a promising, personalized approach to pancreatic cancer through increased understanding of a recently discovered PARP inhibitor resistance mechanism. Our ultimate aim is to optimize a best-in-class treatment strategy presently limited to tumors harboring DNA repair deficiencies, so that this therapeutic strategy may be extended to include all pancreatic cancers, regardless of the DNA-repair status (i.e., BRCA2 mutant and wild type).