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.

项目摘要 高级别浆液性卵巢癌（HGSOC）是一种毁灭性的疾病，导致约125，000人死亡 全世界的女性每年。HGSOC的存活率最低。超过20%的HGSOC含有遗传性 导致同源重组（HR）缺陷的突变（例如BRCA 1/2 MUT），从而导致敏感性 到PARPi。然而，对PARPi的反应很少是持久的，并且很快就会获得抗性。另外50%的 HGSOC不具有HR缺陷，而是通过扩增、复制和表达细胞周期蛋白E（CCNE 1）。 数量增加或转录手段。与BRCA 1/BRCA 2突变型肿瘤不同，它们最初对铂有反应， 基于化疗，CCNE 1扩增的肿瘤与原发性铂失败相关。最近的一项研究 显示1）细胞周期蛋白E（CCNE 1）诱导增加ATR信号传导和对WEE 1激酶抑制剂的敏感性 和ATR抑制剂（WEE 1 i-ATRi）治疗，2）WEE 1 i-ATRi在CCNE 1水平增加肿瘤消退。 3）WEE 1 i和ATRi促进复制叉的不同分子效应 崩溃，和4）CCNE 1扩增是一个可靠的生物标志物预测响应WEE 1 i-ATRi。这些 结果表明，WEE 1激酶抑制剂（WEE 1 i）和ATR抑制剂（ATRi）的组合是可行的， 治疗PARPi耐药细胞周期蛋白E（CCNE 1）过表达（CCNE 1HIGH）高级浆液性细胞的方法 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 WEE 1 i和ATRi的组合，可以允许较低剂量的策略来减轻用于治疗 HGSOC。Atrin Pharmaceuticals，Inc.在DDR领域已有十多年的历史， 开发下一代选择性ATRi。我们已经发现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，我们还发现了一个高度选择性的WEE 1 对WEE 1激酶表现出高效力、比PLK 1具有上级选择性和显著抗生长抑制剂 对NCI-60组的各种癌细胞系具有高效力的活性。此外，我们的WEE 1 i展品 与AZD 1775相比，在OVCAR 8细胞中具有上级效力。小鼠药代动力学（PK）研究显示具有上级 与AZD 1775相比的口服生物利用度。在OVCAR-3异种移植肿瘤模型中，它单独完全停止肿瘤生长。 生长而不引起体重减轻。重要的是，我们的WEE 1 i使卵巢癌细胞系 （OVCAR 8）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 WEE 1 i和ATRN-119单独以及HGSOC的PDX模型中的组合。2)确定其他生物标志物 以扩大目标患者群体，3）评价毒性，和4）获得API的GMP批次。成功 我们的直接进入第二阶段项目的一部分将进一步支持化学、制造和控制（CMC）， 临床供应我们的新型WEE 1 i和完整的FDA要求的IND使能药理学安全性和毒理学 问题研究此外，该项目的发现将为使用我们的一流组合的临床试验方案提供信息 用于治疗HGSOC，其迫切需要更有效的治疗。