Preclinical development of OR-449, a novel targeted therapy for adrenocortical cancer

摘要 肾上腺皮质癌（ACC）是一种罕见的侵袭性癌症。大多数病例为转移性或局部性 诊断时进展，5年生存率<15%。唯一一种FDA批准的化疗药物 药剂米托坦具有高毒性，难以给药，并且仅适度有效。替代化疗方案 免疫检查点抑制剂提供有限的益处。迫切需要新的治疗方法。 我们建议开发一种基于一流小分子拮抗剂的ACC靶向治疗， 类固醇生成因子-1（SF-1或NR 5A 1），一种孤儿核受体和转录因子， 肾上腺的生长和发育。多项研究结果表明，SF-1在 ACC的发病机制：（i）肿瘤内SF-1表达水平较高与成人预后不良相关 （ii）SF-1是转移性ACC的诊断标志物;（iii）SF-1是染色体扩增的，并且SF-1蛋白是转移性ACC的诊断标志物。 在儿科ACC中，相对于正常肾上腺组织， 将SF-1纳入其儿科肿瘤学分子靶点列表。 Orphagen已经确定了一种高度选择性的SF-1拮抗剂，OR-449，在30 mg/kg每日口服剂量下， 抑制SJ-ACC 3的生长，SJ-ACC 3是一种最初在圣裘德儿童医院分离的儿科ACC肿瘤异种移植物。 研究医院。OR-449还阻断分离的SJ-ACC 3肿瘤细胞培养物中的DNA合成。的 SJ-ACC 3异种移植物中的剂量响应性mRNA特征支持OR-449直接接合SF 1。 此外，OR-449在小鼠、大鼠和狗中显示出优异的口服吸收和药代动力学（PK）性质 并且在为期两周的每日口服给药鼠安全性研究中100 mg/kg耐受良好。 拟议的SBIR直接进入II期项目建立在对ACC肿瘤生长的高效抑制上， OR-449的初步安全性。我们的项目目标是完成所有临床前安全性研究 要求提交ACC中SF-1拮抗剂首次临床试验的研究性新药申请。 目的是：1）在小鼠中进行OR-449的探索性（非GLP）、剂量范围探索毒性研究， 剂量高达400 mg/kg，以确定任何严重的安全性信号，并为设计1- 一个月的监管（GLP）毒理学研究; 2）优化合成化学工艺，开发分析 方法，并完成1公斤规模的OR-449合成，以提供进一步的非临床安全性研究 并准备GMP生产; 3）在犬中进行高剂量PK研究，然后进行非GLP 7天 耐受性和14天剂量范围探索安全性研究，包括组织学和心血管监测; 4） 根据FDA指南，完成小鼠和犬1个月重复给药GLP一般毒理学研究。 项目的成功完成将提供必要的数据，以选择I期研究的起始剂量。 最终，OR-449的商业化可以提供一种安全有效的 靶向治疗显著提高ACC患者的生存率。

ABSTRACT Adrenocortical carcinoma (ACC) is a rare, aggressive cancer. The majority of cases are metastatic or locally advanced at diagnosis with a dismal five-year survival of <15%. The only FDA-approved chemotherapeutic agent, mitotane, is highly toxic, difficult to dose, and only modestly effective. Alternative chemotherapy regimens and immune checkpoint inhibitors provide limited benefit. There is an urgent need for new therapies. We propose to develop a targeted therapy for ACC based on first-in-class small molecule antagonists to steroidogenic factor-1 (SF-1 or NR5A1), an orphan nuclear receptor and transcription factor that is essential for the growth and development of the adrenal gland. Multiple findings indicate that SF-1 has a crucial role in the pathogenesis of ACC: (i) Higher levels of intra-tumoral SF-1 expression correlate with poor prognosis in adult ACC, (ii) SF-1 is a diagnostic marker of metastatic ACC; (iii) SF-1 is chromosomally amplified and SF-1 protein is elevated, relative to normal adrenal tissue, in pediatric ACC. Further, the FDA, in consultation with NCI, has included SF-1 on its Pediatric Molecular Target List for oncology. Orphagen has identified a highly selective SF-1 antagonist, OR-449, that at 30 mg/kg daily oral dosing completely inhibited the growth of SJ-ACC3, a pediatric ACC tumor xenograft originally isolated at St. Jude Children’s Research Hospital. OR-449 also blocked DNA synthesis in cultures of dissociated SJ-ACC3 tumor cells. The dose-responsive mRNA signature in the SJ-ACC3 xenografts supports direct engagement of SF1 by OR-449. Further, OR-449 showed excellent oral absorption and pharmacokinetic (PK) properties in mouse, rat, and dog and was well-tolerated at 100 mg/kg in an oral, two-week daily dosing murine safety study. The proposed SBIR Direct to Phase II Project builds on the highly effective inhibition of ACC tumor growth and promising preliminary safety profile of OR-449. Our Project goal is to complete all preclinical safety studies required to file an Investigational New Drug application for the first clinical trial of an SF-1 antagonist in ACC. The Aims are: 1) Conduct an exploratory (non-GLP), dose range-finding toxicity study of OR-449 in mice at doses up to 400 mg/kg to identify any serious safety signals and to provide key dosing data for designing a 1- month regulatory (GLP) toxicology study; 2) Optimize synthetic chemistry processes, develop analytical methods, and complete a 1-kilogram scale-up synthesis of OR-449 to supply further nonclinical safety studies and prepare for GMP manufacturing; 3) Conduct high-dose PK studies in dogs followed by non-GLP 7-day toleration and 14-day dose range-finding safety studies with histology and cardiovascular monitoring; 4) Complete 1-month repeat dose GLP general toxicology studies in mouse and dog consistent with FDA guidance. Successful completion of the Project will provide the necessary data to select a starting dose for a Phase 1 clinical trial of OR-449 in ACC. Ultimately, commercialization of OR-449 could provide a safe and effective targeted therapy to significantly improve survival for ACC patients.