PO.ET09.06 · 实验与分子治疗

使用新型抑制剂RPT-E-037靶向NAMPT治疗胰腺神经内分泌肿瘤

Targeting NAMPT using Novel Inhibitor RPT-E-037 in Pancreatic Neuroendocrine Tumor

编号 419 展板 22 时间 4/19 02:00–05:00 区域 Section 17 主讲 Md Hafiz Uddin, PhD

分会场 Novel Antitumor Agents 1

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作者与单位 Authors & Affiliations

Md Hafiz Uddin¹, Husain Yar Khan², Amro Aboukameel³, Sahar F. Bannoura³, Irfana Muqbil⁴, Hugo Jimenez¹, Filza Khan¹, Rafic Beydoun³, Gregory Dyson³, Yang Shi³, Mohammed N. Al Hallack³, Nitin Vaishampayan³, Ibrahim Azar³, Steve Kim³, Eliza W. Bael³, Miguel Tobon³, Khalil Choucair³, Walid Sukkari¹, Hafsa Imtiaz¹, Herbert Chen³, Muhammad W. Saif³, Anthony Frank Shields⁵, Ramzi M. Mohammad³, Philip Philip⁶, Bassel F. El Rayes⁷, Min Wu⁸, Michael Schelle⁸, Boris Pasche³, Asfar S. Azmi³

¹Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI,²Barbara Ann Karmanos Cancer Institute, Detroit, MI,³Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI,⁴Lawrence Technological University, Southfield, MI,⁵Associate Director for Clinical Research, Barbara Ann Karmanos Cancer Institute, Detroit, MI,⁶Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI,⁷University of Alabama at Birmingham, Birmingham, AL,⁸Remedy Plan Therapeutics, Gaithersburg, MD

摘要 Abstract

中文摘要

背景与目的：晚期胰腺神经内分泌肿瘤（pNET）对当前FDA批准的疗法应答不佳，凸显出寻找新型有效治疗靶点的迫切需求。烟酰胺磷酸核糖转移酶（NAMPT）是NAD生物合成途径中的关键酶，已成为pNET中一个至关重要的治疗靶点。尽管其重要性显著，但目前仍缺乏直接靶向NAMPT用于pNET治疗的特异性抑制剂。本研究旨在评估新型NAMPT抑制剂RPT-E-037在pNET临床前模型中的疗效。方法：通过MTT、集落形成和凋亡实验测定生长抑制。我们还使用细胞周期分析测定生长阻滞。基因或蛋白表达使用定量PCR和蛋白质印迹技术测定。NAMPT抑制剂RPT-E-037的影响在pNET体外培养及体内进行评估。结果：RPT-E-037在药理学相关浓度下对BON-1和QGP-1 pNET细胞系表现出生长抑制效应。在BON-1和QGP-1细胞中，半数抑制浓度（IC50）分别测定为0.3和1.2微摩尔（µM）。重要的是，RPT-E-037表现出选择性，在对肿瘤细胞有效的浓度下对正常胰岛细胞（ABC-TC4286，AcceGen）无不良影响（体现为其IC50高出40倍）。此外，烟酸（niacin）处理显著挽救了RPT-E-037对BON-1细胞的生长抑制效应。烟酸还削弱了RPT-E-037在该细胞系中的集落减少和凋亡诱导能力。新型NAMPT抑制剂RPT-E-037被证明可诱导“DNA合成（S）期”细胞周期阻滞。然而，烟酸处理将“S期”细胞周期阻滞转变为“G0/G1期”细胞周期阻滞。RPT-E-037在BON-1和QGP-1细胞系中均与pNET标准治疗的mTOR靶向药物依维莫司（everolimus）产生协同作用，导致更优的细胞死亡（CI<1）。RPT-E-037在BON-1和QGP-1细胞系来源异种移植（CDx）中的体内疗效正在进行中。结论：本研究首次揭示了新型NAMPT抑制剂RPT-E-037在临床前模型中治疗pNET的治疗潜力。RPT-E-037作为一种新型NAMPT抑制剂展现出前景，值得针对pNET进行进一步临床研究。本摘要使用了生成式AI以改善语言表达。

查看英文原文 English abstract

Background and Objective: Advanced pancreatic neuroendocrine tumors (pNETs) respond poorly to current FDA-approved therapies, emphasizing the urgent need to find new and effective treatment targets. Nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the NAD biosynthesis pathway, has emerged as a crucial therapeutic target in pNETs. Despite its importance, specific inhibitors directly targeting NAMPT for pNET treatment are currently lacking. This study aimed to evaluate the efficacy of RPT-E-037, a novel NAMPT inhibitor, in preclinical models of pNETs. Methods: Growth inhibition was determined by MTT, colony formation and apoptosis assays. We also measured growth arrest using cell cycle analysis. Expression of gene or protein was determined using quantitative PCR, and western blotting techniques. The impact of NAMPT inhibitor RPT-E-037 was evaluated in pNET in vitro cultures and in in vivo . Results: RPT-E-037 demonstrated its growth inhibitory effect in BON-1 and QGP-1 pNET cell lines at pharmacologically relevant concentrations. The inhibitory concentration-50 (IC 50 ) were determined as 0.3 and 1.2 micromolar (µM) in BON-1 and QGP-1 cells respectively. Importantly, RPT-E-037 demonstrated selectivity, showing no adverse effects on normal islet cells (ABC-TC4286, AcceGen) at concentrations effective against tumor cells (reflected by its 40-folds higher IC 50 ). In addition, growth inhibitory effect of RPT-E-037 significantly rescued by nicotinic acid (niacin) treatment in BON-1 cells. Niacin also diminishes its colony reduction and apoptotic ability of RPT-E-037 in this cell line. The novel NAMPT inhibitor RPT-E-037 was shown to induce “DNA synthesis (S) phase” cell cycle arrest. However, niacin treatment switches “S phase” cell cycle arrest to “G0/G1 phase” cell cycle arrest. RPT-E-037 synergized with pNETs standard of care mTOR targeted agent everolimus in both BON-1 and QGP-1 cell lines leading to superior cell deaths (CI<1). The in vivo efficacy of RPT-E-037 in BON-1 and QGP-1 cell line derived xenografts (CDxs) are under way. Conclusion: For the first time, this study reveals the therapeutic potential of RPT-E-037, a new NAMPT inhibitor, for pNETs in preclinical models. RPT-E-037 shows promise as a novel NAMPT inhibitor and deserves further clinical investigation for pNETs.Generative AI was used for improving the language of the abstract.

利益披露 Disclosure

M. Uddin, None.. A. Aboukameel, None.. S. F. Bannoura, None.. I. Muqbil, None.. H. Jimenez, None.. F. Khan, None.. R. Beydoun, None.. G. Dyson, None.. Y. Shi, None. M. N. Al Hallack, Ipsen Speaker. AstraZeneca Speaker. Guardant Health Speaker. Pfizer Speaker. Takeda Speaker. N. Vaishampayan, None. I. Azar, MJH Life Sciences Other, Honoraria. AstraZeneca Other, Consulting or Advisory Role. Genmab Nishant Gandhi Other, Consulting or Advisory Role. Caris Life Sciences Employment. S. Kim, None.. E. W. Bael, None.. M. Tobon, None.. K. Choucair, None.. W. Sukkari, None.. H. Imtiaz, None.. H. Chen, None. M. W. Saif, US World Meds [Oncologic Drug Advisory Committee] Other, Advisory Board. Uptodate Other, Honorarium. Amal Therapeutics ). Genentech, Inc. Other, Honorarium. IDEAYA Other, Honorarium. SpringWorks Therapeutics Other, Honorarium. Yivia Other, Honorarium. HCW Biologics Other, Honorarium. FLASCO Other, Speaker. R. M. Mohammad, None. P. Philip, Bayer Other, Honoraria. Ipsen Other, Honoraria. Incyte Other, Honoraria. Seagen Other, Honoraria. Taiho Pharmaceutical Other, Honoraria. Astellas Pharma Other, Honoraria. BioNTech SE Other, Honoraria. Novocure Other, Honoraria. TriSalus Life Sciences Other, Honoraria. SERVIER Other, Honoraria. Celgene Other, Consulting or Advisory. Ipsen Other, Consulting or Advisory. Merck Other, Consulting or Advisory. TriSalus Life Sciences Other, Consulting or Advisory. Daiichi Sankyo Other, Consulting or Advisory. SynCoreBio Other, Consulting or Advisory. Taiho Pharmaceutical Other, Consulting or Advisory. Incyte Other, Speaker. Bayer (Inst) ). Incyte (Inst) ). B. F. El Rayes, Seattle Genetics ). Exelixis Other, Advisory Board. Beigene Other, Advisory Board. AstraZeneca Other, Advisory Board. Merck ). Bristol-Myers Squibb ). Astra Zeneca ). Boehringer Ingelheim ). M. Wu, Remedy Plan, Inc. Stock Option. M. Schelle, Remedy Plan, Inc. Stock Option. Acrigen Biosciences Stock Option. B. Pasche, Merck & Co Inc ). Roche ). Novartis ). AstraZeneca ). Bristol Myers Squibb Co ). TheraBionic Inc Stock. TheraBionic GmbH Stock. A. S. Azmi, Guidepoint Other, consulting or advisory. Gerson Lehrman Group Other, consulting or advisory. Purple Biotech ). FanWave ). Colorado chromatography ). Blackstone Therapeutics ).

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