Utilizing HuR to optimize the treatment of pancreatic cancer

利用 HuR 优化胰腺癌的治疗

• 批准号: 8702474
• 负责人: Jonathan Brody
• 金额: $ 20.23万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702474
• 关键词: Abraxane; Acute; Adenocarcinoma Cell; Adjuvant; Aspirate substance; Binding; Biochemical; Biological Assay; Biological Markers; Biology; Cancer Etiology; Cancer Patient; Cell Nucleus; Cellular Assay; Cessation of life; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Country; Cytoplasm; DNA; Data; Deoxycytidine Kinase; Detection; Development; Diagnostic tests; Disease; Enzymes; Excision; Exhibits; Fluorouracil; Foundations; Gene Expression Regulation; Goals; HuR protein; Human; In Vitro; Institution; International; Investigation; Knowledge; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Measurement; Mediating; Messenger RNA; Metabolic; Metabolism; Molecular; NMR Spectroscopy; Needle biopsy procedure; Operative Surgical Procedures; Outcome; Pancreatic Ductal Adenocarcinoma; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Pilot Projects; Play; Pre-Clinical Model; Process; Prodrugs; Proteins; RNA-Binding Proteins; RRM2 gene; Randomized Clinical Trials; Regimen; Regulation; Resectable; Resected; Role; Sampling; Scientist; Specimen; Staging; Techniques; Testing; Therapeutic; Transcript; Translating; Translations; Treatment Efficacy; United States; Unresectable; Validation; Vertebral column; Work; advanced disease; base; biobank; cancer cell; cancer genome; cancer therapy; chemotherapeutic agent; chemotherapy; cohort; drug efficacy; drug metabolism; experience; gemcitabine; gemzar; genome-wide; improved; inhibitor/antagonist; insight; neoplastic cell; new therapeutic target; novel; novel therapeutics; nucleoside analog; pancreatic cancer cells; prospective; protein expression; public health relevance; randomized trial; research study; response; standard of care; stressor; therapy design; trial comparing; tumor

DESCRIPTION (provided by applicant): Pancreatic cancer genome-wide sequencing and the complementary search for targeted therapies against pancreatic cancer have distracted the field from focusing on optimizing one of the most clinically utilized agents (gemcitabine) against this devastating disease. Prospective and randomized clinical trials reveal that a select set of human pancreatic cancers exhibit sensitivity to the chemotherapeutic agent gemcitabine. While this subset is small (for instance, CONKO-001 demonstrates that 10% of patients experience a durable response to gemcitabine in the adjuvant setting), these findings unique to gemcitabine provide a rationale to devise molecular strategies to expand the efficacy to more patients or predict which patients might best benefit from gemcitabine-based therapies. Gemcitabine monotherapy remains the standard of care in the adjuvant setting and a recent positive trial in advanced patients has established gemcitabine-Abraxane as a preferred front line regimen. In the present proposal, we will establish an unprecedented predictive marker for gemcitabine efficacy using samples from a multi-institution phase III trial and develop a biomarker assay applicable to all patients (both localized and advanced). In addition, we will gain insights into molecular mechanisms that govern the metabolism of gemcitabine. In a prior study, we demonstrated that post-transcriptional gene regulation in pancreatic cancer cells plays an important role in gemcitabine efficacy. We demonstrated that the RNA binding protein, HuR (ELAV1), up-regulates deoxycytidine kinase (dCK), an enzyme that produces DNA precursor molecules and also metabolizes the nucleoside analog, gemcitabine. Validating our in vitro findings, patient tumors with increased cytoplasmic HuR protein expression were associated with improved survival after resection in patients treated with gemcitabine. We hypothesize that dCK (stabilized by HuR) efficiently metabolizes the prodrug gemcitabine, thereby enhancing drug efficacy against cancer cells. Recently, we identified CMPK1 and RRM2 as two additional HuR targets that play a central role in gemcitabine metabolism. Herein, we will 1) firmly establish HuR as a bona fide predictive marker of gemcitabine efficacy for pancreatic cancer treatment using surgical specimens from a multi-institutional, randomized, clinical trial of adjuvant gemcitabine therapy for pancreatic cancer (ESPAC3); 2) evaluate the feasibility and accuracy of cytologic aspirates to determine HuR status (compared to surgical specimens), which will expand the relevance of the test to patients with advanced disease; and 3) determine precisely how HuR regulates gemcitabine efficacy (both as single agent and with Abraxane) through biochemical and cellular assays, and spectroscopic analyses of gemcitabine metabolites in pancreatic cancer cells. We expect results of these studies to yield immediate improvement in our ability to identify which patients are most likely to benefit from gemcitabine-based therapies. In addition, we expect that mechanistic insights gained into HuR's global control of gemcitabine metabolism will eventually lead to therapeutic strategies that enhance gemcitabine response.

描述（由申请人提供）：胰腺癌全基因组测序和针对胰腺癌靶向治疗的补充搜索已经分散了该领域对优化临床上最常用的药物之一（吉西他滨）来对抗这种毁灭性疾病的注意力。前瞻性和随机临床试验表明，一组选定的人类胰腺癌对化疗药物吉西他滨表现出敏感性。虽然这个子集很小（例如，CONKO-001 表明 10% 的患者在辅助治疗中对吉西他滨产生持久反应），但吉西他滨独特的这些发现为设计分子策略以将疗效扩展到更多患者或预测哪些患者可能从基于吉西他滨的治疗中受益最大。吉西他滨单一疗法仍然是辅助治疗中的标准治疗方法，最近在晚期患者中进行的一项积极试验已确立吉西他滨-Abraxane 作为首选的一线治疗方案。在本提案中，我们将使用多机构 III 期试验的样本建立前所未有的吉西他滨疗效预测标记，并开发适用于所有患者（局部和晚期）的生物标记测定法。此外，我们还将深入了解控制吉西他滨代谢的分子机制。在之前的一项研究中，我们证明胰腺癌细胞中的转录后基因调控在吉西他滨疗效中起着重要作用。我们证明，RNA 结合蛋白 HuR (ELAV1) 上调脱氧胞苷激酶 (dCK)，脱氧胞苷激酶 (dCK) 是一种产生 DNA 前体分子并代谢核苷类似物吉西他滨的酶。验证我们的体外研究结果，细胞质 HuR 蛋白表达增加的患者肿瘤与接受吉西他滨治疗的患者切除后生存率的提高相关。我们假设 dCK（由 HuR 稳定）有效地代谢前药吉西他滨，从而增强针对癌细胞的药物疗效。最近，我们确定 CMPK1 和 RRM2 是另外两个 HuR 靶标，它们在吉西他滨代谢中发挥核心作用。在此，我们将 1) 使用吉西他滨辅助治疗胰腺癌的多机构随机临床试验 (ESPAC3) 的手术标本，牢固地确立 HuR 作为吉西他滨治疗胰腺癌疗效的真实预测标志物； 2) 评估细胞学抽吸确定 HuR 状态的可行性和准确性（与手术标本相比），这将扩大该测试与晚期疾病患者的相关性； 3) 通过生化和细胞测定以及胰腺癌细胞中吉西他滨代谢物的光谱分析，精确确定 HuR 如何调节吉西他滨功效（作为单药和与 Abraxane 联用）。我们预计这些研究的结果将立即提高我们确定哪些患者最有可能从基于吉西他滨的疗法中受益的能力。此外，我们预计对 HuR 对吉西他滨代谢的全局控制的机制了解最终将导致增强吉西他滨反应的治疗策略。