A novel therapy for pancreatic neuroendocrine tumors

胰腺神经内分泌肿瘤的新疗法

基本信息

批准号：
10367987
负责人：
Asfar S Azmi
金额：
$ 34.66万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367987
关键词：
ATRX gene Aerobic Anabolism Biological Assay Biological Markers Biopsy Blood CRISPR/Cas technology Cancer Etiology Cellular Spheroids Clinic Clinical Clinical Research Clinical Trials DAXX gene DNA Methylation Dependence Development Disease Dose Down-Regulation Drug resistance Enzymes Excision FDA approved FRAP1 gene Failure Fluorescent in Situ Hybridization Future Genes Genomics Growth Factor Growth Factor Receptors Hereditary Disease Incidence Individual Insulin Islet Cell Tumor Ligands Link Metabolic Metabolic Pathway Metabolism Methylation Modeling Molecular Molecular Analysis Mutation Nicotinamide adenine dinucleotide Nicotinic Acids Normal Cell Normal tissue morphology Oligonucleotide Microarrays Operative Surgical Procedures Organoids Oxidation-Reduction PTK2 gene Pathway interactions Patient Selection Patients Pharmaceutical Preparations Phase Placebos Positioning Attribute Progression-Free Survivals Proteins RNA Interference Reaction Receptor Signaling Recurrence Regimen Resected Resistance Reverse Transcriptase Polymerase Chain Reaction Role SDZ RAD Signal Pathway Signal Transduction Survival Rate Therapeutic Time Tissues Toxic effect Tumor Biology Tumor Cell Line Unresectable Von Hippel-Lindau Syndrome Warburg Effect Work acquired drug resistance aerobic glycolysis analog base beta catenin cancer cell comparative genomic hybridization cytotoxicity density effective therapy in vitro activity in vivo inhibitor mTOR Inhibitor neoplastic cell nicotinamide phosphoribosyltransferase nicotinate novel novel therapeutics overexpression p21 activated kinase pancreas xenograft patient derived xenograft model patient population patient stratification patient subsets pharmacodynamic biomarker phase I trial population based potential biomarker pre-clinical preclinical evaluation preclinical study predictive marker prevent promoter resistance mechanism response biomarker rho GTP-Binding Proteins standard of care subcutaneous therapy resistant treatment response tumor tumor xenograft

项目摘要

The incidence of the pancreatic neuroendocrine tumor (PNETs) has increased over the past two decades. The principal treatment for localized PNETs is surgical resection; however, there is no effective therapy for patients with advanced unresectable or metastatic disease. The progression-free survival rate is at the best 11 months with FDA approved agent Everolimus compared to 4.6 months with the placebo. However, the majority of the patients develop drug resistance and there is a void in our understanding of the mechanisms of resistance in PNETs. Frequent mutations in MEN1 (44%), DAXX/ATRX (43%), mTOR (15%) pathway genes and Von Hippel Lindau disease (VHL) alongside several other hereditary disorders are observed in PNETs. Loss of VHL has been linked to enhanced tumor aerobic glycolysis (Warburg effect). In this scenario, cancer cells rely more heavily on Nicotinamide Adenine Dinucleotide (NAD) pool that is a crucial co-factor in the redox reactions of metabolic pathways of cancer cells with high aerobic glycolysis. This over- dependence on NAD may provide actionable therapeutic avenues within the NAD salvage pathway. Our preliminary studies in PNET cell lines and patient derived tissue demonstrate activation of VHL regulated NAD biosynthesis rate-limiting enzyme Nicotinamide Phosphoribosyltransferase (NAMPT) alongside the over- expression of the mTOR promoter p21 activated kinase 4 (PAK4). PAK4 protein by virtue of its ability to engage multiple ligands has been shown to regulate a repertoire of signaling pathways including PNET resistance molecules. Significantly, PAK4-NAMPT dual RNAi suppressed proliferation in PNET cell lines. The CRISPR/Cas9 validated PAK4-NAMPT dual inhibitor KPT-9274 (a Phase I drug) shows antitumor activity in vitro, in PNET xenograft and could synergistically enhance the cytotoxicity of Everolimus. Molecular analysis of combination treatment showed down-regulation of known Everolimus resistance promoter suppression of ATP and NAD. Normal cells can utilize Nicotinate phosphoribosyltransferase (NAPRT1, an enzyme often absent in tumors due to promoter methylation) to generate NAD through nicotinic acid. Therefore, nicotinic acid co- treatment can allow KPT-9274 dose escalation without undue toxicity to normal tissue. We hypothesize that targeting of PAK4-NAMPT signaling could become a broad and clinically viable therapeutic strategy for PNET. Aim1: Profile the PAK4 and NAMPT aberrations in PNET patient tissue. Aim 2: Demonstrate the role of PAK4- NAMPT in PNET therapy resistance. Aim 3: Demonstrate the preclinical in vivo efficacy of PAK4-NAMPT dual inhibitors in PNET xenograft and define a biomarker of therapeutic response in biopsies from an ongoing Phase I trial. Clinical impact: Our studies will enhance the fundamental understanding of PAK signaling and NAD metabolism in PNET subsistence. This work will also uncover the ideal patient population based on their NAPRT status for best treatment response. Our preclinical studies will lead to the development of a novel tailored regimen for therapy-resistant and by far incurable PNETs.

过去两年，胰腺神经内分泌肿瘤（PNET）的发病率有所上升几十年。局部 PNET 的主要治疗方法是手术切除；但目前尚无有效的治疗患有晚期不可切除或转移性疾病的患者。无进展生存率为 FDA 批准的药物依维莫司的最佳疗效为 11 个月，而安慰剂为 4.6 个月。然而，大多数患者会产生耐药性，而我们对此的理解存在空白 PNET 中的耐药机制。 MEN1 (44%)、DAXX/ATRX (43%)、mTOR (15%) 频繁突变途径基因和 Von Hippel Lindau 病 (VHL) 以及其他几种遗传性疾病在 PNET 中观察到。 VHL 的缺失与肿瘤有氧糖酵解的增强（Warburg 效应）有关。在在这种情况下，癌细胞更加依赖烟酰胺腺嘌呤二核苷酸（NAD）池，这是一个至关重要的具有高有氧糖酵解的癌细胞代谢途径氧化还原反应的辅助因子。这个过对 NAD 的依赖可能会在 NAD 挽救途径中提供可行的治疗途径。我们的 PNET 细胞系和患者来源组织的初步研究表明 VHL 调节的 NAD 激活生物合成限速酶烟酰胺磷酸核糖转移酶 (NAMPT) mTOR 启动子 p21 激活激酶 4 (PAK4) 的表达。 PAK4 蛋白凭借其能力研究表明，与多种配体结合可以调节包括 PNET 在内的一系列信号通路抵抗分子。值得注意的是，PAK4-NAMPT 双 RNAi 抑制了 PNET 细胞系的增殖。这 CRISPR/Cas9 验证的 PAK4-NAMPT 双抑制剂 KPT-9274（I 期药物）在在体外、PNET 异种移植中，可以协同增强依维莫司的细胞毒性。分子分析联合治疗显示已知的依维莫司耐药启动子对 ATP 的抑制作用下调和辅酶A。正常细胞可以利用烟酸磷酸核糖基转移酶（NAPRT1，一种在体内通常不存在的酶）肿瘤由于启动子甲基化）通过烟酸生成NAD。因此，烟酸共治疗可以允许 KPT-9274 剂量递增，而不会对正常组织造成过度毒性。我们假设 PAK4-NAMPT 信号传导的靶向可能成为 PNET 的广泛且临床可行的治疗策略。目标 1：分析 PNET 患者组织中的 PAK4 和 NAMPT 畸变。目标 2：展示 PAK4- 的作用 NAMPT 在 PNET 治疗抵抗中的作用。目标 3：展示 PAK4-NAMPT 双通道的临床前体内功效 PNET 异种移植物中的抑制剂，并定义正在进行的活检中治疗反应的生物标志物第一阶段试验。临床影响：我们的研究将增强对 PAK 信号传导的基本理解和 PNET 生存中的 NAD 代谢。这项工作还将根据他们的情况揭示理想的患者群体 NAPRT 状态以获得最佳治疗反应。我们的临床前研究将导致一种新型药物的开发针对治疗耐药且迄今为止无法治愈的 PNET 量身定制治疗方案。