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

项目摘要/摘要 胰腺癌是一种毁灭性的疾病，5年生存率非常低(8%)。治疗的选择是 疗效有限，而且许多都有很大的毒性。靶向给药可能会改善治疗效果 通过提高药物对癌细胞的定位，同时最大限度地减少非靶标副作用，对抗癌药物进行索引。 与健康细胞相比，Sigma-2受体(S2R)在胰腺癌和其他癌症中高表达。 Accuronix治疗公司正在开发ACXT-3102，一种具有治疗潜力的分子 位于圣路易斯的华盛顿大学医学院。ACXT-3102由S2配体组成 共价结合到铁下垂诱导分子dm-erastin。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杀伤力增加了35倍。 ACXT-3102具有巨大的潜力，可以作为胰腺和其他几种疾病的新治疗选择 癌症的类型。药物优化策略在一期STTR中进行，产生了更好的 药物合成过程中的产率，一种具有高水溶性和改善物理性能的甲磺酸盐的鉴定 适用于口服给药的性质，显示良好的口腔疗效，并发现肿瘤 缺乏苹果酸酶1(ME1)的菌株对ACXT-3102更加敏感。 对于这一第二阶段STTR计划，Accuronix Treateutics将继续与我们的研究同事合作 从WUSM准备ACXT-3102用于研究新药(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化疗方案--了解每日给药一次、两次或三次 给药改善血浆暴露和抗肿瘤疗效，同时保持安全性，即避免剂量- 限制副作用。研究还将探索我们的药物在服用后是否可以进一步提高疗效 联合吉西他滨，目前治疗胰腺癌的标准疗法。化学和新陈代谢 ACXT-3102的稳定性将通过体外试验来确定，以指导药物的储存条件和 了解哪些临床前物种最能代表人类的新陈代谢。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进行 生成药代动力学(PK)和药效学(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联系起来。同样，正式的普洛斯 毒理学研究将在大鼠和狗身上使用三种不同的剂量来确定“未观察到” 不良反应水平“(NOAEL)。这些数据将被用来模拟人类的暴露水平，并建立 用于启动我们在癌症患者中的临床试验的安全、首例人类(FIH)剂量。在阶段结束时 II STTR拨款，我们将获得IND所需的ACXT-3102的药理和安全信息 包装，并将建立用于患者的第一剂。

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.