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

项目概要/摘要 胰腺癌是一种毁灭性的疾病，5年生存率非常低（8%）。治疗选择 其功效有限且许多具有实质性毒性。靶向给药可以改善治疗效果， 通过增强药物定位于癌细胞同时最小化脱靶副作用，实现癌症药物的指数。 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-3102，一种具有治疗潜力的分子， 华盛顿大学圣路易斯医学院（WUSM）。ACXT-3102由S2配体组成 共价结合到亚铁凋亡诱导分子DM-erastin上。初步数据显示，ACXT-3102 与单独使用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具有巨大的潜力，可作为胰腺癌和其他几种疾病的新型治疗选择。 癌症的类型。在I期STTR中进行了药物优化策略， 药物合成过程中的产率，具有高水溶性和改善的物理性质的甲磺酸盐的鉴定， 适用于口服给药的性质，良好的口服功效的证明和发现， 缺乏苹果酸酶1（ME1）的人对ACXT-3102甚至更敏感。 对于这个II期STTR项目，Accuronix Therapeutics将继续与我们的研究同事合作 从WUSM准备ACXT-3102用于研究性新药（IND）提交，并最终测试 胰腺癌患者体内的化合物我们将进行一系列临床前研究，以优化剂量 小鼠胰腺癌模型中的给药方案-了解每天给药一次、两次或三次 给药改善了血浆暴露和抗肿瘤功效，同时保持了安全性，即，避免剂量- 限制副作用。研究还将探讨我们的药物的疗效是否可以进一步提高， 与吉西他滨联合治疗，吉西他滨是胰腺癌的当前护理标准。化学和代谢 将使用体外试验确定ACXT-3102的稳定性，以指导药物的储存条件， 了解哪些临床前物种最能代表人类的代谢。要获取所需的数据， IND包装的药理学和安全性章节，临床前研究将根据良好的 实验室规范（GLP）指南，以生成以下药物的药代动力学（PK）和药效学（PD）数据： 将不同物种的血浆暴露与人类的预测相关联。同样，正式GLP 将在大鼠和犬中使用三种不同剂量完成毒理学研究，以确定"未观察到 不良作用水平"（NOAEL）。这些数据将用于模拟人类的暴露水平，并建立一个 安全，首次在人类（FIH）剂量开始我们的癌症患者的临床试验。阶段结束时 II STTR授予，我们将获得IND所需的ACXT-3102的药理学和安全性信息 包装，并将建立用于患者的第一个剂量。

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.