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大原因。 5年生存率<9%，预后不良部分是由于对标准的抵抗。护理治疗包括吉西他滨 (Gem) 和 Gem+白蛋白结合型紫杉醇 (n-PTX)。转录因子 HIF-1α 和 c-MYC 是产生 Gem 和 n-PTX 耐药性是关键的治疗靶点 (R,S')-4'-甲氧基-1-萘非特罗 (R,S')-。 MNF 是一种双功能抗癌剂，可作为 GPR55 的竞争性抑制剂和 PANC-1 异种移植肿瘤模型 (R,S’)-MNF 中的 β2-肾上腺素受体偏向激动剂。显着抑制肿瘤生长，约 75% (p<0.01)，并下调 HIF-1α 和 c-MYC 我们的总体假设是 (R,S')-MNF 将减少 PDAC 肿瘤的生长单一药物并与标准护理药物产生积极的协同效应。目标是确定 (R,S')-MNF 与 GEM+n-PTX 组合的治疗潜力 PDAC 模型将利用我们对 (R,S')-MNF 的了解。药代动力学和毒性以及在 PDAC 模型中使用治疗药物的经验。具体目标是：目标 1：确定 (R,S')-MNF 单独和单独使用的抗肿瘤活性 PDAC 患者衍生异种移植 (PDX) 模型中的组合：第一步是给药发现研究确定 (R,S')-MNF 单独使用和联合使用的最大耐受剂量 GEM（70 mg/kg，腹腔注射，每周一次，持续 3 周）+ n-PTX（30 mg/kg，每周一次，持续 3 周）。最佳剂量和方案将用于源自 PDAC 患者肿瘤的 2 个 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，每组 18 人。小鼠/组：载体、单独的(R,S')-MNF、GEM+n-PTX和(R,S')-MNF+GEM+n-PTX血液和。将从每组 6 只小鼠收集主要器官组织，用于目标 2 中提出的分析。将监测剩余的小鼠（12只/组）以确定对肿瘤生长和存活的影响。目标 2：识别治疗生物标志物并确定 (R,S')-MNF 生物分布：血浆治疗前后收集的样本将使用 LC-MS/MS 进行分析，以量化小溶血磷脂酰胆碱（14:0 和 16:0）和乳酸等分子以及 ELISA 检测 PDAC 生物标志物如 CA19-9 和 CYR61 代谢物和蛋白质浓度。与肿瘤生长和存活数据以及 GPR55 和 β2-AR 的相对表达进行比较。从 (R,S')-MNF 治疗组收集的主要器官将使用 LC-MS/MS 进行分析，以确定药物的生物分布。第一阶段研究的数据将支持第二阶段的 IND 研究。 II申请，将包括GLP PK/PD、代谢和毒性研究。