Development of a first-in-class combination of DNA damage response inhibitors for the treatment of high-grade serous ovarian cancer

开发用于治疗高级别浆液性卵巢癌的一流 DNA 损伤反应抑制剂组合

• 批准号: 10603092
• 负责人: Eric J Brown
• 金额: $ 86.22万
• 依托单位: APREA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-10 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603092
• 关键词: 12 year old; BRCA mutations; BRCA1 gene; BRCA2 gene; Biological Availability; Biological Markers; Body Weight decreased; CCNE1 gene; Cancer cell line; Canis familiaris; Cell Line; Cell model; Cells; Cessation of life; Chemistry; Clinical; Combined Modality Therapy; DNA Damage; DNA Sequence Alteration; DNA replication fork; Data; Defect; Development; Disease; Dose; Drug Kinetics; Exhibits; Failure; Gene Expression; Genetic Transcription; Genomics; Growth; Half-Life; Human; Libraries; Malignant neoplasm of ovary; Medicine; Modeling; Molecular; Molecular Profiling; Mus; Oral; Ovarian Serous Adenocarcinoma; PLK1 gene; Patients; Pennsylvania; Pharmacologic Substance; Pharmacology; Phase; Phosphotransferases; Platinum; Poly(ADP-ribose) Polymerase Inhibitor; Proteomics; Publishing; Rattus; Recommendation; Reporting; Resistance; Safety; Serous; Signal Transduction; Specificity; Survival Rate; Testing; Therapeutic Index; Toxic effect; Toxicology; Treatment-related toxicity; Universities; Woman; attractin protein; brca gene; candidate marker; cell type; chemotherapy; clinical development; clinical trial protocol; efficacious treatment; first-in-human; homologous recombination; inhibitor; kinase inhibitor; manufacture; mutant; next generation; novel; overexpression; patient derived xenograft model; patient population; predicting response; predictive marker; recruit; repaired; responders and non-responders; response; success; tumor; tumor growth; tumor xenograft

PROJECT SUMMARY High-grade serous ovarian carcinoma (HGSOC) is a devastating disease responsible for the deaths of ~125,000 women worldwide each year. HGSOC has the lowest survival rates. More than 20% of HGSOCs harbor genetic mutations (e.g. BRCA1/2MUT) that cause defects in homologous recombination (HR), which causes sensitivity to PARPi. However, responses to PARPi are rarely durable and resistance is acquired rapidly. Another 50% of HGSOCs do not harbor defects in HR and instead overexpress Cyclin E (CCNE1) through amplification, copy number gain, or transcriptional means. Unlike BRCA1/BRCA2-mutant tumors, which initially respond to platinum- based chemotherapy, CCNE1-amplified tumors are associated with primary platinum failure. A recent study revealed that 1) Cyclin E (CCNE1) induction increases ATR signaling and sensitivity to WEE1 kinase inhibitor and ATR inhibitor (WEE1i-ATRi) treatment, 2) WEE1i-ATRi increases tumor regression in a CCNE1-level- dependent manner in PDXs, 3) Differential molecular effects of WEE1i and ATRi promote replication fork collapse, and 4) CCNE1 amplification is a reliable biomarker predictive of response to WEE1i-ATRi. These findings indicated that a combination of WEE1 kinase inhibitor (WEE1i) and ATR inhibitor (ATRi) is a feasible approach for the treatment of PARPi-resistant Cyclin E (CCNE1) overexpressing (CCNE1HIGH) high-grade serous ovarian cancer (HGSOC). These results provide a strong rationale for Atrin to develop a first-in-class combination of WEE1i and ATRi that can allow lower-dosing strategies to mitigate off-target toxicity for the treatment of HGSOCs. Atrin Pharmaceuticals, Inc has been in the field of DDR for over a decade and is pioneering the development of next-generation, selective ATRi. We have discovered ATRN-119 as a highly selective ATRi and have received FDA IND approval (IND #141317). In parallel, we have also discovered a highly selective WEE1 inhibitor demonstrating high potency on WEE1 kinase, superior selectivity over PLK1, and significant anti-growth activity against various cancer cell lines of NCI-60 panel with high potency. In addition, our WEE1i exhibits superior potency in OVCAR8 cells compared to AZD1775. Pharmacokinetic (PK) study in mice shows superior oral bioavailability compared to AZD1775. In an OVCAR-3 xenograft tumor model, it alone completely halts tumor growth without causing loss of body weight. Importantly, our WEE1i sensitizes the ovarian cancer cell line (OVCAR8) to ATRN-119. Given these promising results, we proposed to 1) Quantify sensitivity of HGSOC to our WEE1i and ATRN-119 alone as well the combination in PDX models of HGSOC. 2) Identify additional biomarkers to expand target patient populations, 3) Evaluate the toxicity, and 4) Obtain a GMP batch of API. The success of our Direct-to-Phase II project will further support chemistry, manufacturing, and controls (CMC) to manufacture clinical supply of our novel WEE1i and complete FDA-required IND-enabling pharmacology safety and toxicology studies. In addition, findings from this project will inform clinical trial protocols using our first-in-class combination for the treatment of HGSOC, which critically needs more efficacious treatments.

项目概要 高级别浆液性卵巢癌 (HGSOC) 是一种毁灭性疾病，导致约 125,000 人死亡 每年全世界的女性。 HGSOC 的存活率最低。超过 20% 的 HGSOC 携带遗传基因 导致同源重组 (HR) 缺陷的突变（例如 BRCA1/2MUT），从而导致敏感性 到 PARPi。然而，对 PARPi 的反应很少是持久的，并且很快就会产生耐药性。另外50% HGSOC 不存在 HR 缺陷，而是通过扩增、复制过度表达 Cyclin E (CCNE1) 数量增益，或转录手段。与 BRCA1/BRCA2 突变肿瘤不同，最初对铂类药物有反应 基于化疗，CCNE1 扩增的肿瘤与原发性铂失败相关。最近的一项研究 揭示 1) Cyclin E (CCNE1) 诱导增加 ATR 信号传导和对 WEE1 激酶抑制剂的敏感性 和 ATR 抑制剂 (WEE1i-ATRi) 治疗，2) WEE1i-ATRi 增加 CCNE1 水平的肿瘤消退 PDX 中的依赖方式，3) WEE1i 和 ATRi 促进复制叉的不同分子效应 崩溃，4) CCNE1 扩增是预测 WEE1i-ATRi 反应的可靠生物标志物。这些 研究结果表明，WEE1 激酶抑制剂 (WEE1i) 和 ATR 抑制剂 (ATRi) 的组合是可行的 治疗 PARPi 耐药性 Cyclin E (CCNE1) 过表达 (CCNE1HIGH) 高级浆液性的方法 卵巢癌（HGSOC）。这些结果为 Atrin 开发一流的组合提供了强有力的理由 WEE1i 和 ATRi 的研究可以采用较低剂量的策略来减轻治疗的脱靶毒性 HGSOC。 Atrin Pharmaceuticals, Inc 已涉足 DDR 领域十多年，并且是 开发下一代选择性 ATRi。我们发现 ATRN-119 是一种高度选择性的 ATRi， 已获得 FDA IND 批准（IND #141317）。与此同时，我们还发现了高度选择性的WEE1 该抑制剂对 WEE1 激酶具有高效力，选择性优于 PLK1，并且具有显着的抗生长作用 对 NCI-60 组的各种癌细胞系具有高效活性。此外，我们的 WEE1i 展品 与 AZD1775 相比，OVCAR8 细胞中的效力更佳。小鼠药代动力学（PK）研究显示出优越的 与 AZD1775 相比的口服生物利用度。在 OVCAR-3 异种移植肿瘤模型中，仅靠它就可以完全阻止肿瘤 生长而不引起体重减轻。重要的是，我们的 WEE1i 使卵巢癌细胞系变得敏感 (OVCAR8) 至 ATRN-119。鉴于这些有希望的结果，我们建议 1) 量化 HGSOC 对我们的敏感性 WEE1i 和 ATRN-119 单独使用，以及 HGSOC PDX 模型中的组合。 2) 识别额外的生物标志物 扩大目标患者群体，3) 评估毒性，4) 获得一批 GMP 原料药。成功 我们的直接进入第二阶段项目将进一步支持化学、制造和控制 (CMC) 的制造 我们的新型 WEE1i 的临床供应以及 FDA 要求的完整 IND 支持药理学安全性和毒理学 研究。此外，该项目的研究结果将为使用我们一流组合的临床试验方案提供信息 用于治疗 HGSOC，迫切需要更有效的治疗方法。