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

项目总结 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 世界各地的女性每年都有。HGSOC的存活率最低。超过20%的HGSOC具有遗传性 导致同源重组(HR)缺陷的突变(例如BRCA1/2MUT)，从而导致敏感性 敬帕尔皮。然而，对PARPI的反应很少是持久的，抵抗力很快就会获得。另外50%的 HGSOC在HR中不存在缺陷，而是通过扩增、复制和过度表达Cyclin E(CCNE1) 数字增长，或转录手段。与BRCA1/BRCA2突变肿瘤不同，BRCA1/BRCA2突变肿瘤最初对铂- 在化疗的基础上，CCNE1扩增的肿瘤与原发铂金衰竭有关。最近的一项研究 研究发现：1)细胞周期蛋白E(Cyclin E，CCNE1)的诱导增加了ATR信号转导和对WEE1激酶抑制剂的敏感性 和ATR抑制剂(WEE1i-ATRI)治疗，2)WEE1i-ATRI在CCNE1水平上促进肿瘤消退- PDX的依赖方式，3)WEE1i和ATRI促进复制分叉的不同分子效应 4)CCNE1扩增是预测WEE1i-ATRI反应的可靠生物标志物。这些 结果表明，WEE1激酶抑制剂(WEE1i)和ATR抑制剂(ATRI)联合应用是可行的 PARPI耐药细胞周期蛋白E过表达(CCNE1HIGH)高级别浆膜腔积液的治疗探讨 卵巢癌(HGSOC)。这些结果为阿特林开发一流的组合提供了强有力的理由 WEE1i和ATRI，可以允许较低剂量的策略来减轻用于治疗的靶外毒性 HGSOC。Atrin PharmPharmticals，Inc.在DDR领域已经有十多年的历史了，它是 开发下一代、选择性的ATRI。我们发现ATRN-119是一种高度选择性的ATRI 已获得食品和药物管理局IND批准(IND编号141317)。与此同时，我们还发现了一种高度选择性的WEE1 显示出对WEE1激酶的高效力、比PLK1更好的选择性和显著的抗生长作用的抑制剂 NCI-60面板对多种肿瘤细胞株的高效杀伤活性。此外，我们的WEE1i展品 与AZD1775相比，在OVCAR8细胞中的效力更高。小鼠体内药代动力学(PK)研究显示优势 口服生物利用度与AZD1775的比较。在OVCAR-3异种移植瘤模型中，只有它才能完全阻止肿瘤 在不导致体重下降的情况下生长。重要的是，我们的WEE1i使卵巢癌细胞系变得敏感 (OVCAR8)至ATRN-119。考虑到这些有希望的结果，我们建议1)量化HGSOC对我们的 WEE1i和ATRN-119单独以及在HGSOC的PDX模型中的组合。2)确定其他生物标志物 为了扩大目标患者群体，3)评估毒性，4)获得GMP批次的原料药。成功之路 将进一步支持化学、制造和控制(CMC)制造 临床供应我们的新型WEE1i和FDA要求的完整IND-Enabling药理学、安全性和毒理学 学习。此外，这个项目的发现将使用我们一流的组合为临床试验方案提供参考 对于HGSOC的治疗，迫切需要更有效的治疗。

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.