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 高级浆液卵巢癌（HGSOC）是一种毁灭性疾病，导致死亡约125,000 全球妇女每年。 HGSOC的存活率最低。超过20％的HGSOC港口遗传 引起同源重组（HR）缺陷的突变（例如BRCA1/2MUT），引起灵敏度 到Parpi。但是，对PARPI的响应很少耐用，并且耐药性迅速获得。另外50％ HGSOC不会在HR中留下缺陷，而是通过扩增过表达细胞周期蛋白E（CCNE1），复制 数字增益或转录手段。与BRCA1/BRCA2突变肿瘤不同，该肿瘤最初对铂作出反应 基于CCNE1扩增的化学疗法与原发性铂衰竭有关。最近的研究 发现1）细胞周期蛋白E（CCNE1）诱导增加了ATR信号传导和对WEE1激酶抑制剂的敏感性 和ATR抑制剂（WEE1I-ATRI）处理，2）WEE1I-ATRI增加CCNE1级的肿瘤消退 PDX中的依赖方式，3）WEE1I和ATRI的差异分子效应促进复制叉 崩溃，4）CCNE1扩增是对WEE1I-ATRI反应的可靠生物标志物。这些 调查结果表明，WEE1激酶抑制剂（WEE1I）和ATR抑制剂（ATRI）的组合是可行的 抗parpi抗性细胞周期蛋白E（CCNE1）过表达（CCNE1高）高级浆液的方法 卵巢癌（HGSOC）。这些结果为Atrin提供了强大的理由，以发展一流的组合 WEE1I和ATRI的含量可以允许降低剂量的策略来减轻靶向毒性以治疗 HGSOCS。 Atrin Pharmaceuticals，Inc在DDR领域已有十多年了，并开创了 开发下一代，选择性Atri。我们已经发现ATRN-119是一个高度选择性的ATRI， 已获得FDA IND批准（IND＃141317）。同时，我们还发现了一个高度选择性的WEE1 抑制剂表现出对WEE1激酶的高效力，优于PLK1的较高选择性和显着的抗增长 对具有高效力的NCI-60面板的各种癌细胞系的活性。此外，我们的wee1i展品 与AZD1775相比，OVCAR8细胞的效力优势。小鼠的药代动力学（PK）研究表明 与AZD1775相比，口服生物利用度。在OVCAR-3异种移植肿瘤模型中，它完全完全停止了肿瘤 生长而不会导致体重减轻。重要的是，我们的WEE1I敏感了卵巢癌细胞系 （OVCAR8）至ATRN-119。鉴于这些有希望的结果，我们提出了1）量化HGSOC的灵敏度 WEE1I和ATRN-119也是HGSOC PDX模型中的组合。 2）确定其他生物标志物 要扩大目标患者人群，3）评估毒性，4）获得GMP批次API。成功 我们的直接阶段II项目将进一步支持化学，制造和控制措施（CMC）制造 我们的小说WEE1I的临床供应和完整的FDA要求的指定药理学安全和毒理学 研究。此外，该项目的发现将使用我们的一等组合为临床试验方案提供信息 为了治疗HGSOC，这需要更有效的治疗方法。