Ceralasertib

Artios Pharma, a startup developing drugs that weaken a tumor’s ability to maintain its DNA, announced positive results in a subset of patients with advanced cancer. It’s the first big data reveal for the Cambridge, UK-based startup, which has been relatively quiet since 2021, when it struck a drug discovery partnership with Novartis and raised $153 million in Series C financing. The company’s drug, called ART0380, inhibits a DNA repair enzyme called ATR. When administered with a low dose of the chemotherapy irinotecan, the drug shrank tumors in 37% of patients whose cancer was considered “deficient” in another DNA damage response protein dubbed ATM, according to data from a Phase 1/2 study. In patients whose tumors lacked the ATM protein entirely, the response rate was 50%, with a median duration of response of 5.7 months so far. The response rate was 22% in patients with low levels of ATM. Patients with the ATM protein, however, did not respond to the therapy. “All those patients unfortunately progress quickly and unfortunately die very quickly,” Artios Chief Medical Officer Ian Smith told Endpoints News in an interview. The new data, presented Tuesday at the American Association for Cancer Research meeting, comes from 58 patients with advanced-stage and metastatic solid tumors who were treated at the dose the company plans to use in a Phase 2 study. Artios CEO Niall Martin told Endpoints that the company has funds “through 2026.” He said the startup is looking to raise another round of private funding to test its ATR inhibitor in pancreatic and colorectal cancers before pursuing bigger and broader tissue-agnostic studies. Martin said the company’s partnership with Novartis, which wasn’t focused on its ATR inhibitor, identified several targets that could potentially be paired with Novartis’ radioligand therapies, including its prostate cancer drug Pluvicto, and discussions are underway on next steps. Artios had struck a partnership with Merck KGaA in 2020 to search for drugs that target other DNA repair proteins, but Martin told Endpoints that partnership has ended. Artios was founded in 2016 to discover a new wave of drugs that target complex networks of proteins dedicated to the faithful replication and preservation of our genomes. While cancer can survive, and even thrive, with some DNA repair enzymes missing, too many missing pieces can cause the cancer to self-destruct. A class of drugs called PARP inhibitors exploit this vulnerability by blocking the eponymous DNA repair protein in tumors that have mutations in genes called BRCA1 and BRCA2, which are also important for DNA repair. Several companies have been searching for the next combination of targets that can deliver a similar double whammy to tumors, but progress has been slow. “The field hasn’t really evolved much since PARP inhibitors,” Martin said. “So we’ve been really thinking about what are the layers of DNA damage that are created in tumors that could be used as their sort of Achilles heel.” One of those layers, according to Artios, is a phenomenon called replication stress, which can occur when DNA replication, a key step for dividing cells, is blocked. ATR and ATM are two proteins that detect and clear up these blockages. Many forms of chemotherapy obstruct DNA replication. By first inducing a bit more of that stress with a low dose of chemo — but not enough to kill the cancer itself — and then blocking ATR in tumors with little to no ATM, Artios hoped to deliver a triple whammy to tumors. “There’s always been a push to get rid of chemotherapy and have targeted drugs,” Smith said.“But if you can’t get rid of chemotherapy, what you can do is really minimize it. And that’s what we’ve done here.” Smith said the company saw two complete responses, including one in a 62-year-old female who had pancreatic cancer but has been off treatment and cancer-free since August 2023. Neutropenia, a decline in white blood cells, was the most common side effect seen in 53% of patients, with grade 3 neutropenia in 45% of patients. Anemia occurred in 41% of patients. Fatigue, diarrhea, nausea and vomiting were also common side effects. Several other drugmakers have developed their own ATR inhibitors, but lackluster results have caused some pharma companies, including Bayer and Roche, to discontinue or pare back these efforts. “ATR inhibitors have been languishing,” Smith said. “The response rates are low relative to the toxicity that you tend to get.” Roche cut its partnership with Repare Therapeutics in 2024, which paused its ATR inhibitor program earlier this year after modest responses in only 19% and 17% of endometrial and ovarian cancer patients, respectively. Merck KGaA dropped its first ATR inhibitor, berzosertib, but is still testing a second one, called tuvusertib. And AstraZeneca is testing its ATR inhibitor ceralasertib in a Phase 3 study in lung cancer with its immunotherapy Imfinzi, which is expected to complete in August. Artios executives told Endpoints that other ATR inhibitors have faltered for three reasons: the drug’s half-life was too long, leading to intolerable toxicity; the drug was tested as a monotherapy, leading to low efficacy; or the drug was paired with the wrong therapies or tested in the wrong genetic subtypes of cancer. Martin said the company plans to develop a companion diagnostic to identify patients that are most likely to respond to its drug, with an initial focus on ATM. But Artios is looking for other biomarkers that may make tumors vulnerable to ATM inhibitors too. “This whole process of replication stress can be in up to 30% to 40% of tumors,” Martin said. “So there’s a huge area of biology which no one really has tapped into.”

▎药明康德内容团队编辑 编者按：胰腺癌，因其发展迅速和治疗难度极大被称为"癌症之王"。据相关研究数据统计，胰腺癌患者的5年生存率不足10%，是预后最差的恶性肿瘤之一。预计到2030年，胰腺癌将成为仅次于肺癌的第二大癌症死亡原因。目前，化疗仍是胰腺癌的主要治疗手段，但其效果较为有限。因此，开发新的治疗策略对于改善胰腺癌患者的预后至关重要。近期，一项发表在Cell & Bioscience期刊的论文发现，通过靶向TOPBP1相关信号通路，可以显著增强胰腺癌细胞对抗癌药物PARP抑制剂——奥拉帕尼（olaparib）的敏感性，诱导癌细胞的凋亡。同时，TOPBP1有望成为一种生物标志物，用于判断和筛选受益于PARP抑制剂治疗的患者群体，实现更精准的胰腺癌治疗。药明康德为研究团队提供了模拟肿瘤在体内生长的模型，赋能后续的分析验证，从而助力科学家开发胰腺癌的创新疗法。DNA损伤修复（DDR）途径在胰腺癌的发生和发展中起着关键作用。正常细胞在受到DNA损伤时，会启动一系列修复机制，以维持基因组的稳定。然而，胰腺癌细胞的DDR途径常常发生异常并促进肿瘤的发生。TOPBP1是DDR途径中的一个重要蛋白，它参与了DNA复制、DNA损伤修复和细胞周期检查点等多个细胞过程。来自上海交通大学医学院附属瑞金医院、南通大学附属肿瘤医院、南京医科大学附属泰州人民医院的联合研究团队通过对179例胰腺癌患者的临床数据分析，发现了一个令人意外的现象：TOPBP1在胰腺癌组织中的表达水平显著高于正常组织，而且表达量越高，患者的预后越差。同时，TOPBP1的高表达与肿瘤的恶性程度呈正相关。他们发现，TOPBP1表达不同的胰腺癌细胞系对奥拉帕尼的敏感度具有差异，TOPBP1表达高的细胞系对药物的敏感度更低。当研究人员用基因编辑技术降低TOPBP1表达后，癌细胞对奥拉帕尼的敏感性几乎翻倍。分析结果显示，TOPBP1高表达的癌细胞更依赖DNA损伤修复相关的ATR通路来恢复。当TOPBP1被抑制时，ATR通路会发生"瘫痪"，迫使癌细胞转而依赖另一条修复路径——ATM通路。而奥拉帕尼的作用就是制造DNA损伤，当ATM通路不堪重负时，癌细胞就会因无法修复DNA损伤而走向死亡。▲研究指出，TOPBP1是预测奥拉帕尼和AZD6738联合疗法治疗胰腺导管腺癌疗效的潜在生物标志物（图片来源：参考资料[1]）这一发现不仅解释了TOPBP1的作用机制，更提供了一个绝佳的治疗思路：如果能同时抑制ATR通路和PARP，就能对TOPBP1高表达的癌细胞造成致命打击！随后，研究团队获取了胰腺导管腺癌患者的肿瘤组织，药明康德为团队建立了用于后续分析验证的模型，用于模拟肿瘤在体内的生长和反应。研究团队测试了奥拉帕尼与ATR抑制剂AZD6738联用的效果，结果发现原代细胞0037细胞系对奥拉帕尼和AZD6738联合治疗的敏感性较高。这类细胞TOPBP1的表达水平较高，因此提升了其对联合治疗的敏感性。这种超协同效应的产生源于癌细胞DNA修复系统的"双路封锁"：AZD6738抑制ATR通路，使癌细胞丧失主要的DNA损伤修复能力；奥拉帕尼持续制造DNA损伤，迫使癌细胞依赖已受损的ATM通路，最终引起细胞凋亡。这些结果表明， TOPBP1有望成为一种新的生物标志物，帮助医生更精准地筛选可能受益于PARP抑制剂治疗的患者群体。此外，研究也提出了一种创新的联合治疗方案，有望让更多胰腺癌患者从PARP抑制剂治疗中获益。参考资料：[1] Tang, Xiao-Mei, et al. "TOPBP1 as a Potential Predictive Biomarker for Enhanced Combinatorial Efficacy of Olaparib and AZD6738 in PDAC." Cell & Bioscience, vol. 15, no. 17, 2025, doi:10.1186/s13578-025-01350-9本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。更多推荐点个“在看”再走吧~