Development of (R,S')-MNF as a dual-targeted therapy for pancreatic cancer

(R,S)-MNF作为胰腺癌双靶向疗法的开发

基本信息

批准号：
10546773
负责人：
Haiyong Han
金额：
$ 38.51万
依托单位：
PAZ PHARMACEUTICALS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10546773
关键词：
ABCB1 gene ABCB6 gene Adenylate Cyclase Aftercare Agonist Anabolism Animals Antineoplastic Agents Attenuated Autophagocytosis Biodistribution Biological Biological Assay Biological Markers Blood CA-19-9 Antigen Cancer Etiology Cell Line Cells Cessation of life Cyclic AMP-Dependent Protein Kinases Data Development Dose Down-Regulation Drug Kinetics Drug Targeting Drug usage Enzyme-Linked Immunosorbent Assay Evaluation Formulation G-Protein-Coupled Receptors GPR55 receptor GTP-Binding Protein alpha Subunits, Gs Genes Genetic Transcription Glutamate Metabolism Pathway Glycolysis Goals Human Immunoblot Analysis Immunohistochemistry Knowledge Liquid Chromatography Lysophosphatidylcholines MEKs Malignant neoplasm of pancreas Mass Spectrum Analysis Maximum Tolerated Dose Metabolic Metabolism Modeling Monitor Mus Organ Oxidative Stress PI3K/AKT Paclitaxel Pancreatic Ductal Adenocarcinoma Patients Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacotherapy Phase Plasma Predictive Value Preparation Process Prognosis Proteins Protocols documentation Pyrimidine Regimen Resistance Sampling Schedule Signal Transduction Small Business Technology Transfer Research Survival Rate Techniques Therapeutic Therapeutic Agents Therapeutic Uses Tissues Toxic effect Transforming Growth Factor beta Treatment Protocols Tumor Tissue Xenograft Model attenuation base beta catenin beta-2 Adrenergic Receptors c-myc Genes cancer therapy cell growth chemotherapy experience gemcitabine glucose metabolism improved inhibitor lipid metabolism metabolomics mouse model novel therapeutics pancreatic cancer patients pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model patient derived xenograft model pharmacokinetics and pharmacodynamics phase 1 study protein biomarkers response biomarker small molecule standard of care targeted treatment therapeutic evaluation therapeutic target transcription factor transcriptomics treatment group tumor tumor growth tumor xenograft

项目摘要

Summary Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the U.S. with a 5-year survival rate of <9%. The poor prognosis is partially due to resistance to standard of care treatments including gemcitabine (Gem) and Gem+nab-paclitaxel (n-PTX). The transcription factors HIF-1α and c-MYC are at the center of the mechanisms producing Gem and n-PTX resistance and are key therapeutic targets. (R,S′)-4′-Methoxy-1-naphthylfenoterol (R,S’)- MNF is a bi-functional anti-cancer agent that acts as a competitive inhibitor of GPR55 and a biased-agonist of the β2-adrenergic receptor. In a PANC-1 xenograft tumor model (R,S’)-MNF significantly dampens tumor growth, ∼75% (p<0.01), and downregulates HIF-1α and c-MYC expression. Our overarching hypothesis is that (R,S′)-MNF will reduce PDAC tumor growth as a single agent and produce positive synergistic effects with standard of care agents. The overall goal is to determine the therapeutic potential of (R,S′)-MNF in combination with GEM+n-PTX in PDAC models. The experimental protocols will utilize our knowledge of (R,S′)-MNF pharmacokinetics and toxicity and experience with use of therapeutic agents in PDAC models. Specific aims are: Aim 1: to determine the antitumor activity of (R,S′)-MNF alone and in combination in PDAC patient derived xenograft (PDX) models: The initial step will be a dosing finding study to determine maximal tolerated dose of (R,S′)-MNF alone and in combination with GEM (70 mg/kg, i.p., once a week for 3 weeks) + n-PTX (30 mg/kg, once a week for 3 weeks). Optimal dose and schedule will be used in 2 PDX models derived from PDAC patients’ tumors expressing high levels of GPR55 and β2-AR. Each study will include 4 treatment groups of 18 mice/group: vehicle, (R,S′)-MNF alone, GEM+n-PTX, and (R,S′)-MNF + GEM+n-PTX. Blood and major organ tissues will be collected from 6 mice/group for analyses proposed in Aim 2. The remaining mice (12/group) will be monitored to determine the effect on tumor growth and survival. Aim 2: to identify treatment biomarkers and determine (R,S′)-MNF biodistributions: Plasma samples collected before and after treatment will be analyzed using LC-MS/MS to quantify small molecules such as lysophosphatidylcholines (14:0 and16:0) and lactate and ELISA assays for PDAC biomarkers such as CA19-9 and CYR61. Metabolite and protein concentrations will be compared to tumor growth and survival data and to the relative expression of GPR55 and β2-AR. Major organs collected from the (R,S′)-MNF treatment group will be analyzed using LC-MS/MS to determine drug biodistribution. Data from the Phase I study will support IND studies in a Phase II application, which will include GLP PK/PD, metabolism and toxicity studies.

概括胰腺导管腺癌（PDAC）是美国癌症死亡的第三主要原因 5年生存率<9％。不良预后部分是由于对标准的抵抗力包括吉西他滨（GEM）和GEM+NAB-PACLITAXEL（N-PTX）在内的护理治疗方法。这转录因子HIF-1α和C-MYC是产生GEM的机制的中心， N-PTX抗性，是关键的治疗靶标。（r，s'） - 4'-甲氧基-1-萘基烯醇（R，S'） - MNF是一种双功能抗癌剂，充当GPR55的竞争抑制剂和A β2-肾上腺素受体的偏置激动剂。在PANC-1 Xenographic肿瘤模型（R，S'）中 - MNF 显着抑制肿瘤的生长，约75％（p <0.01），并下调HIF-1α和C-Myc 表达。我们的总体假设是（R，S'） - MNF将减少PDAC肿瘤的生长单个代理并与护理剂标准剂产生积极的协同作用。总体目标是确定（R，S'） - MNF与GEM+N-PTX的治疗潜力 PDAC模型。实验协议将利用我们对（R，S'）-MNF的了解 PDAC模型中使用治疗剂的药代动力学和毒性和经验。具体目的是：目标1：单独和MNF的抗肿瘤活性 PDAC患者衍生异种移植（PDX）模型的组合：初始步骤将是剂量寻找研究以确定（R，S'） - 单独使用MNF并结合使用的最大耐受剂量宝石（70 mg/kg，i.p.，每周一次，持续3周） + N-PTX（30 mg/kg，每周一次，持续3周）。最佳剂量和时间表将用于来自PDAC患者肿瘤的2种PDX模型表达高水平的GPR55和β2-AR。每项研究将包括4个治疗组18个小鼠/组：车辆，（R，S'） - 单独使用MNF，GEM+N-PTX和（R，S'） - MNF+GEM+N-PTX。血和将从6只小鼠/组收集主要器官组织，以进行AIM 2中提出的分析。将监测其余小鼠（12/组），以确定对肿瘤生长和存活的影响。目标2：确定治疗生物标志物并确定（R，S'） - MNF生物分布：等离子体将使用LC-MS/MS分析治疗前后收集的样品以量化小型分子，例如溶物磷脂酰胆碱（14：0和16：0），并进行ELISA分析和ELISA分析 PDAC生物标志物，例如CA19-9和CYR61。代谢物和蛋白质浓度将是与肿瘤生长和生存数据以及GPR55和β2-AR的相对表达相比。将使用LC-MS/MS分析从（R，S'） - MNF治疗组收集的主要器官确定药物生物分布。 I阶段研究的数据将在一个阶段支持IND研究 II应用，其中包括GLP PK/PD，代谢和毒性研究。