Preclinical Development of ACXT-3102 for the Treatment of Pancreatic Adenocarcinoma (PDAC)

ACXT-3102 治疗胰腺癌 (PDAC) 的临床前开发

• 批准号: 10435565
• 负责人: WILLIAM G HAWKINS
• 金额: $ 101.92万
• 依托单位: ACCURONIX THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435565
• 关键词: Anemia; Antineoplastic Agents; Biological Availability; Body Weight; Cancer Cell Growth; Cancer Etiology; Cancer Model; Cancer Patient; Canis familiaris; Cardiac; Cardiovascular system; Cell Death; Cells; Cessation of life; Chemicals; Clinical; Clinical Trials; Cystine; Data; Development; Disease; Dose; Dose-Limiting; Drug Delivery Systems; Drug Kinetics; Drug Stability; Drug Targeting; Enzymes; Fatigue; Formulation; Glutamates; Goals; Grant; Half-Life; Human; In Vitro; Incubated; Intravenous; Investigational Drugs; Life; Life Expectancy; Ligands; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mesylates; Metabolic; Metabolism; Microsomes; Modeling; Mus; No-Observed-Adverse-Effect Level; Oral; Oral Administration; Oxidative Stress; Paclitaxel; Pancreas; Pancreatic Adenocarcinoma; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacology Study; Phase; Phase I Clinical Trials; Plasma; Play; Practice Guidelines; Quality of life; Rattus; Regimen; Research; Role; Safety; Schedule; Series; Site; Small Business Technology Transfer Research; Sodium Chloride; Solid; Solubility; Survival Rate; Temperature; Testing; Therapeutic; Therapeutic Index; Time; Toxic effect; Toxicology; Treatment Efficacy; Tumor Volume; Universities; Ventricular; Washington; Work; antiporter; aqueous; base; cancer cell; cancer type; chemical stability; commercial application; cytotoxicity; design; drug synthesis; effective therapy; erastin; first-in-human; gemcitabine; good laboratory practice; improved; in vitro Assay; in vivo; malic enzyme; medical schools; molecular marker; mouse model; nerve damage; novel; overexpression; oxaliplatin; pancreatic cancer cells; pancreatic cancer model; pancreatic cancer patients; pharmacokinetics and pharmacodynamics; physical property; pre-clinical; preclinical development; preclinical study; prevent; programs; side effect; sigma-2 receptor; small molecule; standard of care; tumor; tumor growth; tumor metabolism; uptake

Project Summary/Abstract Pancreatic cancer is a devastating disease with a very low (8%) 5-year survival rate. Therapeutic options are limited in efficacy and many have substantial toxicity. Targeted drug delivery may improve the therapeutic index of cancer drugs by enhancing drug localization to the cancer cell while minimizing off-target side effects. Sigma-2 receptors (S2R) are highly expressed in pancreatic and other cancers compared to healthy cells. Accuronix Therapeutics is developing ACXT-3102, a molecule with therapeutic potential licensed from Washington University School of Medicine in St. Louis (WUSM). ACXT-3102 is comprised of a S2 ligand covalently bound to the ferroptosis-inducing molecule dm-erastin. Preliminary data show that ACXT-3102 increased the cytotoxicity against pancreatic tumor cells in vitro by 35-fold compared to dm-erastin alone. ACXT-3102 has tremendous potential as a novel treatment option for pancreatic and perhaps several other types of cancer. Drug optimization strategies were conducted in a Phase I STTR which resulted in a better yield during drug synthesis, identification of a mesylate salt with high aqueous solubility and improved physical properties suitable for oral drug administration, demonstration of good oral efficacy and discovery that tumors lacking malic enzyme 1 (ME1) are even more sensitive to ACXT-3102. For this Phase II STTR program, Accuronix Therapeutics will continue to work with our research colleagues from WUSM to prepare ACXT-3102 for Investigational New Drug (IND) submission and eventually testing the compound in pancreatic cancer patients. We will conduct a series of preclinical studies to optimize the dosing regimen in murine pancreatic cancer models – understanding if once, twice or three times per day drug administration improves plasma exposure and anti-tumor efficacy while maintaining safety, i.e., avoiding dose- limiting side effects. Studies will also explore if efficacy of our drug can be further improved when given in combination with gemcitabine, a current standard-of-care for pancreatic cancer. Chemical and metabolic stability of ACXT-3102 will be established using in vitro assays to guide storage conditions of the drug and understand which preclinical species best represents metabolism in humans. To obtain data required for the pharmacology and safety sections of the IND package, preclinical studies will be conducted according to Good Laboratory Practice (GLP) guidelines to generate pharmacokinetic (PK) and pharmacodynamic (PD) data for correlating plasma exposures in different species to what is predicted in human. Similarly, formal GLP toxicology studies will be completed using three different doses in rats and dogs to establish the “No Observed Adverse Effect Level” (NOAEL). These data will be used to model exposure levels in humans and establish a safe, first-in-human (FIH) dose for starting our clinical trials in cancer patients. At the conclusion of the Phase II STTR grant, we will have the pharmacology and safety information on ACXT-3102 required for the IND package, and will have established the first dose to be used in patients.

项目概要/摘要 胰腺癌是一种毁灭性疾病，其 5 年生存率极低 (8%)。治疗选择有 功效有限，而且许多具有显着的毒性。靶向药物输送可改善治疗效果 通过增强药物对癌细胞的定位同时最大限度地减少脱靶副作用来提高癌症药物的指数。 与健康细胞相比，Sigma-2 受体 (S2R) 在胰腺癌和其他癌症中高度表达。 Accuronix Therapeutics 正在开发 ACXT-3102，这是一种具有治疗潜力的分子，获得许可 圣路易斯华盛顿大学医学院 (WUSM)。 ACXT-3102 由 S2 配体组成 与铁死亡诱导分子 dm-erastin 共价结合。初步数据表明ACXT-3102 与单独的 dm-erastin 相比，体外对胰腺肿瘤细胞的细胞毒性增加了 35 倍。 ACXT-3102 作为胰腺癌和其他几种疾病的新型治疗选择具有巨大的潜力 癌症的类型。在第一阶段 STTR 中进行了药物优化策略，结果取得了更好的结果 药物合成过程中的收率、具有高水溶性和改善物理性能的甲磺酸盐的鉴定 适合口服给药的特性，证明良好的口服功效并发现肿瘤 缺乏苹果酸酶 1 (ME1) 的人对 ACXT-3102 更加敏感。 对于这个 II 期 STTR 项目，Accuronix Therapeutics 将继续与我们的研究同事合作 来自 WUSM 准备 ACXT-3102 用于研究性新药 (IND) 提交并最终测试 胰腺癌患者的化合物。我们将进行一系列临床前研究来优化剂量 小鼠胰腺癌模型中的治疗方案 – 了解是否每天服用一次、两次或三次药物 给药可改善血浆暴露和抗肿瘤功效，同时保持安全性，即避免剂量- 限制副作用。研究还将探讨我们的药物在给药时是否可以进一步提高疗效。 与目前治疗胰腺癌的标准疗法吉西他滨联合使用。化学和代谢 ACXT-3102 的稳定性将通过体外测定来确定，以指导药物的储存条件和 了解哪种临床前物种最能代表人类的新陈代谢。为了获取所需的数据 IND 包的药理学和安全性部分，临床前研究将根据 Good 生成药代动力学 (PK) 和药效 (PD) 数据的实验室实践 (GLP) 指南 将不同物种的血浆暴露与人类的预测相关联。同样，正式的 GLP 毒理学研究将在大鼠和狗身上使用三种不同的剂量来完成，以确定“未观察到 不良影响水平”（NOAEL）。这些数据将用于模拟人类暴露水平并建立一个 安全的首次人体 (FIH) 剂量，用于在癌症患者中启动我们的临床试验。在该阶段结束时 II STTR拨款，我们将获得IND所需的ACXT-3102药理学和安全性信息 包装，并将确定用于患者的第一个剂量。