ASCL1

“早上困，中午困，下午困，晚上一拿手机就不困”“熬最长的夜，敷最贵的面膜”“三点睡五点起，阎王夸我好身体”......成了不少年轻人/打工人的真实写照。睡眠的重要性不言而喻，但随着社会飞速发展以及生活节奏加快，“拼命十三郎”们只能舍弃睡眠时间，转而投入996甚至007的“社畜”工作中。 除了繁忙的工作压缩了睡眠时间外，一个更常见的现象是“报复性熬夜”——白天被各种琐事儿缠身，只有当晚上躺在床上的那一刻，时间才开始属于自己，接着就是“无止境”的熬夜。当从手机中“缓过神”的时候，发现自己根本睡不了几个小时又要搬砖了！ 今年最新发布的《2024中国居民睡眠健康白皮书》显示，我国居民的平均睡眠时长为6.75小时，甚至有28%的人夜间睡眠时长不足6小时。睡不着、睡不深、睡不够等问题困扰着越来越多的人。 正如大家调侃得那样“晚上不睡，白天崩溃”，崩溃的不仅是精神，还有身体的方方面面——熬夜使得主要心血管不良事件的风险提升92%；增加海马体中抑制神经元活动，破坏记忆巩固；导致癌症的发生等等。早在2007年，国际癌症研究机构（IARC）就把熬夜（包括昼夜节律打乱的轮班工作）定义为2A类致癌物。 近日，来自大连医科大学的研究团队揭示了睡眠不足成为癌症“铺路石”的详细机制——具体来说，当机体睡眠不足时，脂肪酸氧化能够感知到昼夜节律的紊乱，并进一步传递到致癌代谢信号，增强癌症干性和肿瘤发生。但好消息是，有改善方法！ DOI: 10.1016/j.cmet.2024.04.018 “睡眠不足会扰乱昼夜节律”并不是新闻，睡眠不足（SD）会引发多种病理过程，包括：免疫功能紊乱、新陈代谢失调，以及过早死亡。而这种昼夜节律的紊乱同样会作用于癌症发展过程，比如：改变葡萄糖、谷氨酸、胆汁酸和脂质代谢等诸多代谢，进而刺激肿瘤生长、转移和免疫逃逸。但其中的具体机制仍不清楚，也是本次研究的焦点。 第一步，研究者定位到生物机体内感知昼夜节律的关键一环——脂肪酸氧化（FAO）。 具体来说，研究者首先发现，与对照组小鼠相比，SD组有着更长的清醒时间，以及更短的非快速动眼（NREM）和快速动眼（REM）睡眠。由此可见，睡眠不足确实会导致小鼠昼夜节律发生紊乱。 紧接着，研究者分析了野生型C57BL/6J小鼠在SD和对照组培养4周后肺组织中的转录组和代谢组的差异。RNA测序结果显示，3284个基因在SD之后失去了昼夜振荡，而这些基因与脂质代谢的生物过程高度相关，尤其是FAO。 FAO是指，利用脂肪酸转化成的乙酰辅酶A（CoA）亚基来进一步生成烟酰胺腺嘌呤二核苷酸（NADH）、乙酰-CoA和三磷酸腺苷（ATP），参与到产生能量、氧化还原平衡和生物合成反应的过程中。事实上，与FAO相关的代谢酶和代谢物表现出生物节律，以维持生理功能的平衡。 对比SD组和对照组发现，对照组的FAO基因显示出节律模式，但SD组的FAO基因则出现了明显的紊乱。同时，进一步的超高效液相色谱/质谱分析显示，SD小鼠肺组织中振荡脂质代谢物的数量明显减少，并找到了47种节律紊乱的脂质代谢物，其中游离脂肪酸（FFAs）占比最大。 由此可见，FAO能在基因表达和代谢功能水平上感知到SD诱导的生理状态节律紊乱。 FAO能感知到SD情况下的昼夜节律紊乱 第二步，找到FAO在SD促癌过程中担任的“角色”。 与对照组对比，SD明显加速了肺癌的发生和发展，包括促进肺肿瘤的形成、提高Ki-67和CD166的蛋白水平，同时还会在mRNA和蛋白水平上增加MYC、SOX2、CD166和NANOG的表达。 类似的情况也发生在患者源性异种移植模型中，SD导致肿瘤体积明显增加，降低肿瘤小鼠的存活率，并提高了肿瘤组织中干性标记物的表达。 当研究者对肺肿瘤进行RNA-seq分析后发现，SD显著上调了827个基因，而这些上调的基因主要属于脂肪酸代谢过程，尤其是FAO。同时，SD组的肿瘤组织中FAO基因表达量明显高于对照组的，并表现出了节律紊乱。 为了进一步确认FAO在整个过程中的重要作用，研究者给小鼠注射了FAO抑制剂依托莫西（ETO）。结果并不令人意外，ETO逆转了SD增强的肿瘤发生，还阻碍了肺癌中Ki-67、CD166、乙酰-CoA和ATP水平的升高，即ETO逆转了SD增加的肿瘤形成率。 总结来说，FAO感知昼夜节律紊乱是SD增强肺癌干性的基础；相反，当FAO受到抑制，肿瘤进展也会被阻碍。 FAO昼夜节律紊乱维持SD诱导的肺肿瘤病变 第三步，详细定位到FAO节律紊乱维持SD诱导肺癌干性过程中的关键分子。 对比两组情况，研究者定位到13个可能导致SD引起的致癌FAO节律紊乱的常见基因。进一步，在这13个基因中发现，Acsl1 mRNA水平在SD处理的肺肿瘤中显著升高；类似的情况还出现在患者源性异种移植模型里，ACSL1蛋白表达同样有所增加。 那么，ACSL1是不是我们要找的关键分子呢？当研究者敲除了Ascl1之后，SD促进肺癌进展的作用被阻断了，Ki-67、CD166和ACSL1的表达也趋于平常，再一次证实了ACSL1是SD增强肺肿瘤发生和发展的必要条件。 于是，研究者进一步的分析了“可能作为ACSL1底物和产物的长链FAO代谢物”。鉴于棕榈酸（PA）是最主要的饱和脂肪酸，也是长链饱和或不饱和脂肪酸的前体，研究者将目光投向了PA及其代谢产物PA-CoA。 ACSL1具有将PA转化为PA-CoA的能力，而PA-CoA将以棕榈酰肉碱的形式进一步转运到线粒体中，以促进FAO的过程。而本实验结果表明，睡眠不足会扰乱了ACSL1的节律使得更多的PA转化为PA-CoA，从而促进FAO，导致肺癌生长的加速和干性特征的维持。 除此之外，ACSL1还能感知到SD诱导的CLOCK节律失常，同样能促进肺癌的发生。 睡眠不足致癌的信号通路 当然，好消息是，研究者找到了解“癌”方案——β-内啡肽。 在14种与睡眠相关的激素中，研究者发现，注射了β-内啡肽能够显著下调肺癌细胞系中的CLOCK和ACSL1 mRNA的表达，而连续给药甚至能逆转SD诱导的肿瘤生长。 为了评估上述发现的临床价值，他们还开展了前瞻性和回顾性的临床研究，评估了血清β-内啡肽水平、睡眠质量与肺癌发展之间的临床相关性。结果令人“鼓舞”，血清β-内啡肽水平与深度睡眠和REM的比例呈正相关，而与清醒次数呈负相关，即β-内啡肽水平能够很好地预测睡眠质量。 不仅如此，对62例肺癌患者开展的回顾性分析显示，β-内啡肽水平与CLOCK、ACSL1、CD166和Ki-67评分呈负相关，呈现出抗肿瘤效果；而生存期分析结果表明，血清中的高β-内啡肽水平具有较好的预后价值。 临床试验中β-内啡肽水平与指标之间的影响 综上所述，睡眠不足会促进癌症的生长、转移和免疫逃逸，而在这个过程中，FAO的节律紊乱发挥了重要的作用。不过好消息是，补充β-内啡肽或能有效地规避这一风险。 因此，“睡眠不足，癌症来找”是有科学依据的。睡眠的重要性不言而喻，不如就从今天开始早睡计划吧！ 参考资料： [1]Peng F, Lu J, Su K, Liu X, Luo H, He B, Wang C, Zhang X, An F, Lv D, Luo Y, Su Q, Jiang T, Deng Z, He B, Xu L, Guo T, Xiang J, Gu C, Wang L, Xu G, Xu Y, Li M, Kelley KW, Cui B, Liu Q. Oncogenic fatty acid oxidation senses circadian disruption in sleep-deficiency-enhanced tumorigenesis. Cell Metab. 2024 May 14:S1550-4131(24)00138-4. doi: 10.1016/j.cmet.2024.04.018. Epub ahead of print. PMID: 38772364. 撰文 | Swagpp 编辑 | Swagpp ● 重磅！科主任训话：卫健委鼓励医护兼职创业，不是让你去摆摊、送外卖！要和医疗相关！上了热搜后，他从医院离职了！医护兼职到底能干啥？ ● 阿司匹林再添新用！JAMA最新：仅低剂量服用，能使肝脏脂肪减少10.2%、糖尿病风险降15%！ ● 热议！阳光绩效实行，医生工资升，护士工资降？护士透露：从9千多降到2千多，不怕本科护士全跑光？护士有400万缺口，不能厚此薄彼 版权说明：梅斯医学（MedSci）是国内领先的医学科研与学术服务平台，致力于医疗质量的改进，为临床实践提供智慧、精准的决策支持，让医生与患者受益。欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。 点击下方「阅读原文」 立刻下载梅斯医学APP！

*仅供医学专业人士阅读参考在我们的大脑中，不同类型的脑细胞协同工作，脑细胞主要可分为两大类：神经元和神经胶质细胞，最常见的神经胶质细胞当属星形胶质细胞，它们为神经元提供能量，也是血脑屏障的组成部分，还具有调节突触和支持免疫细胞的能力。有一小部分星形胶质细胞聚居在成年大脑的特殊区域，能够产生神经元和神经胶质细胞，它们就是神经干细胞，神经干细胞和普通星形胶质细胞的基因表达几乎没有差异，但它们的功能却如此不同，这种差异是如何产生的？此前，科学家们对此完全不清楚。然而最近，德国癌症研究中心（DKFZ）和德国海德堡大学的研究团队揭示了这个问题的答案，将最新研究成果发表在顶级期刊《自然》上[1]。他们发现，关键在于表观遗传学的差异，神经干细胞相比星形胶质细胞具有特殊的DNA甲基化模式，干细胞功能是由星形胶质细胞基因的甲基化和后来表达的干细胞基因的去甲基化介导的。他们还发现，大脑缺血会触发星形胶质细胞向神经干细胞的重编程，由DNA甲基转移酶3α（DNMT3A）介导。这为成体神经元再生研究提供了新的希望。在很长的一段时间里，学界都认为哺乳动物成年后，大脑就不会产生新的神经元了，但是后来的研究揭示，新神经元还是可以产生的，只是存在于特定的脑区中，包括齿状回和脑室-脑室下区（vSVZ）。小鼠vSVZ中的神经干细胞在激活后成为转运扩增祖细胞，经历多轮分裂并产生神经母细胞，随后迁移到嗅球，分化为神经元，整合入神经回路，也会有一小部分分化为神经胶质细胞。神经干细胞可以处于静息或激活状态，静息神经干细胞中与星形胶质细胞表型相关的基因，包括参与脂质代谢和糖酵解的基因的表达在过渡到激活状态期间逐渐下降。因此，研究人员使用单细胞核小体、甲基化组和转录组测序（scNMT-seq）同时对成年小鼠的神经干细胞的转录组、染色质可及性和DNA甲基化进行了表征。他们发现，静息与激活的神经干细胞的甲基化特征明显分离，静息状态与其他不同脑区的星形胶质细胞非常相似，但由于表达干细胞标志物TLX和TROY，可以与其他星形胶质细胞区分开来，研究人员将它们称为vSVZ星形胶质细胞。静息与激活的神经干细胞的转录组、DNA甲基化和染色质可及性通过拟合不同时间点的甲基化水平，研究人员揭示了从vSVZ星形胶质细胞到激活的神经干细胞这一转变中的甲基化和去甲基化变化，转变时，星形胶质细胞相关标志物的甲基化急剧增加。在转运扩增祖细胞阶段晚期，研究人员观察到一批主要在神经母细胞中表达的基因的去甲基化，表明这一阶段去甲基化为神经母细胞基因的后期表达提供了铺垫。vSVZ星形胶质细胞和激活的神经干细胞之间的差异化甲基化区域中，vSVZ星形胶质细胞的低甲基化出现在参与氨基酸（Slc1a2和Glul）、离子（Slc41a2）和胆固醇（Lcat）等物质转运和代谢的基因附近，激活的神经干细胞的低甲基化出现在细胞分化（Ascl1和Dlx1）和DNA结合（Nkx2-2和Pax8）调节因子附近，像Slc1a2等一些基因的甲基化水平在激活的神经干细胞中则显著升高。vSVZ星形胶质细胞和激活的神经干细胞之间的差异化甲基化基因和途径先前的研究发现，脑缺血性损伤可以增加神经母细胞的产生，以及vSVZ中的星形胶质细胞在被缺血性损伤激活后会以干扰素依赖性的方式离开静息状态，这种变化是否与甲基化重塑有关？研究人员选择了2月龄的小鼠，让它们经历了22分钟的短暂性整体脑缺血，导致了纹状体中的中等多棘神经元和白质的损伤，但没有对vSVZ造成影响。相比未处理的小鼠，缺血2天后，小鼠的vSVZ和纹状体中，神经球形成都有所增加，这是由于大多数vSVZ星形胶质细胞转化为了激活的神经干细胞，它们表现出与前述激活的神经干细胞相一致的甲基化特征，这表明脑缺血小鼠的神经发生随神经干细胞的甲基化变化增加。21天后，这种变化消失。vSVZ中，缺血后2天（2dpi）小鼠激活的神经干细胞占比显著增加，21天后变化消失第21天时检测的差异化甲基化区域与编码DNA甲基转移酶3α（DNMT3A）的Dnmt3a基因重叠，DNMT3A负责DNA的从头甲基化，研究人员发现，在Dnmt3a缺失的小鼠中，脑缺血几乎无法增加神经发生，表明DNMT3A是这一过程的重要介导因素。综上，这项研究揭示了成年的大脑中，具有干细胞特征的星形胶质细胞与激活的神经干细胞尽管转录组相近，但甲基化组差异明显，通过脑缺血等方式调控甲基化的变化，可以将它们重编程为激活的神经干细胞，促进神经发生，为通过再生医学治疗神经疾病提供了新的可能。参考文献：[1] Kremer L P M, Cerrizuela S, El-Sammak H, et al. DNA methylation controls stemness of astrocytes in health and ischaemia[J]. Nature, 2024: 1-9.本文作者丨应雨妍

Full data from the primary analysis of the positive, single-arm Phase 2 PICCOLO trial, evaluating mirvetuximab soravtansine (ELAHERE®), for high folate receptor-alpha (FRα) expressing platinum-sensitive ovarian cancer (PSOC) (mini-oral presentation). Exploratory patient reported outcomes (PROs) from the Phase 2 LUMINOSITY trial, evaluating telisotuzumab vedotin (Teliso-V), a potential first-in-class c-Met directed antibody-drug conjugate (ADC), in advanced non-small cell lung cancer (NSCLC). New safety and efficacy data in pre-treated patients with advanced NSCLC (mini-oral presentation) and gastroesophageal cancer (GEA), from a Phase 1 study of telisotuzumab adizutecan (ABBV-400), a next-generation, potential best-in-class c-Met directed ADC. NORTH CHICAGO, Ill., Sept. 9, 2024 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced that new data from its innovative antibody-drug conjugate (ADC) platform will be showcased at the upcoming European Society for Medical Oncology (ESMO) Congress 2024 (September 13-17, 2024). Presentations include data on mirvetuximab soravtansine (ELAHERE®) and c-Met targeting ADCs, telisotuzumab vedotin (Teliso-V) and telisotuzumab adizutecan (ABBV-400). AbbVie's ADCs are designed to target protein biomarkers such as folate receptor-alpha (FRα) and c-Met (MET protein) which are over expressed across various tumor types and are associated with poor prognoses.1-9 The ADCs are designed to deliver potent cancer cell-death inducing agents called 'payloads' specifically to the tumor, by utilizing these biomarkers as targets. Data from the primary analysis of the Phase 2 PICCOLO trial evaluating investigational mirvetuximab soravtansine monotherapy in heavily pre-treated patients with FRα positive, platinum-sensitive ovarian cancer (PSOC) showed that the trial met its primary endpoint with an objective response rate (ORR) of 51.9% (95% CI 40.4, 63.3), including 6 complete and 35 partial responses. Among the 79 enrolled patients, 81% had prior poly (ADP-ribose) polymerase inhibitors (PARPi) treatment; 74.7% of whom progressed while on PARPi. The median duration of response (DOR), a key secondary endpoint, was 8.3 months (95% CI 5.5, 10.8) and median progression-free survival (PFS), an additional secondary endpoint, was 6.9 months (95% CI 5.9, 9.6). The safety profile of mirvetuximab soravtansine was consistent with findings from previous studies, and no new safety concerns were identified. The most common treatment-emergent adverse events (TEAEs) (grade ≥ 3) were blurred vision (10%), dry eye (3%), nausea (1%), keratopathy (4%), and diarrhea (3%). Additional data will be presented at the meeting. "There is an urgent patient-driven unmet need to identify novel, effective and tolerable therapies for patients with platinum-sensitive ovarian cancer, including the PARPi pre-treated setting where diminished response to subsequent platinum-based chemotherapy has been reported," said Angeles Alvarez Secord, M.D., M.H.Sc., from the Duke Cancer Institute. "The response rate seen with mirvetuximab soravtansine in PICCOLO highlights the potential of mirvetuximab soravtansine for platinum-sensitive ovarian cancer patients." Mirvetuximab soravtansine is also being studied in PSOC in the Phase 3 GLORIOSA trial (NCT05445778), in combination with bevacizumab versus bevacizumab alone, in maintenance after second-line platinum-doublet therapy. Additionally, a Phase 2 study IMGN853-0420 (NCT05456685), is investigating the combination of mirvetuximab soravtansine with carboplatin as second-line treatment of PSOC with a wider range of FRα expression. Patient reported outcome (PRO) data from the Phase 2 LUMINOSITY trial of Teliso-V, in c-Met protein overexpressing, epidermal growth factor receptor (EGFR) wild type, advanced/metastatic non-squamous non-small cell lung cancer (NSCLC) patients, will be presented at the meeting. Trends in PROs observed in LUMINOSITY will be further evaluated in the ongoing Phase 3 TeliMET NSCLC-01 trial (NCT04928846). "The data at ESMO showcase the depth of our ADC pipeline and highlights the significant progress we are making across key programs in various stages of development, as we strive to deliver new and innovative medicines for patients in need," said Daejin Abidoye, M.D., vice president, head of solid tumors, oncology development, AbbVie. "A testament to these efforts is our plan to submit Teliso-V for accelerated approval as a monotherapy in patients with previously treated c-Met overexpressing, epidermal growth factor receptor (EGFR) wild-type non-squamous non-small cell lung cancer in Q3 2024." The accelerated approval submission for Teliso-V will be reviewed under FDA's real-time oncology review program with an approval decision anticipated in 2025. AbbVie announced FDA breakthrough therapy designation for Teliso-V in 2022. New safety and efficacy data from a Phase 1 study (NCT05029882) of ABBV-400, a next-generation, potential best-in-class c-Met directed ADC, highlights the potential of ABBV-400 in previously-treated NSCLC and gastroesophageal cancer (GEA) patients, and are supportive of further exploration of this novel ADC in these tumor types and other solid tumors: Preliminary data show that among 48 previously treated EGFR wild type non-squamous NSCLC patients, antitumor activity was observed with ABBV-400 when dosed at 2.4 and 3.0 mg/kg administered once every 3 weeks (n=39 and 9, respectively), with a confirmed ORR of 43.8% and clinical benefit rate of 85.4%. The most common (≥10%) TEAEs (grade ≥ 3) were anemia (25%) and neutropenia (15%). Additional endpoints (such as progression free survival), association between c-Met protein expression and treatment response, and detailed safety data will be presented at the meeting. In GEA patients, the preliminary data show that among 42 patients, antitumor activity was observed at a dose of ABBV-400 of 3.0 mg/kg administered once every 3 weeks, with confirmed ORR of 28.6%. The clinical benefit rate was 71.4%. The most common (≥20%) TEAEs (any grade) were gastrointestinal (76.2%), anemia (66.7%), nausea (47.6%), thrombocytopenia and constipation (26.2% each) and neutropenia (23.8%). Additional safety and efficacy data will be presented at the meeting. ABBV-400 is also being evaluated in a Phase 1b basket study (NCT06084481) in advanced solid tumors as a monotherapy and a Phase 2 study (NCT06107413) in second line metastatic colorectal cancer (CRC) in combination with fluorouracil, folinic acid, and bevacizumab. Teliso-V and ABBV-400 both target c-Met with the same parental antibody but have different designs and mechanisms of action.10,11 Teliso-V, AbbVie's most advanced c-Met targeted ADC in development, utilizes a microtubule polymerization inhibitor (MMAE) payload.10 ABBV-400, a next-generation c-Met targeted ADC utilizes a novel, proprietary topoisomerase 1 inhibitor (Top1i) payload.11 AbbVie will also present real-world data on the prevalence, stability, and prognostic value of c-Met protein overexpression in NSCLC from the METPRO and METEXPRESS studies at the meeting. Further information on AbbVie clinical trials is available at . Additional details on key presentations at ESMO are available below: About the PICCOLO trial PICCOLO is a single-arm Phase 2 trial evaluating the efficacy and safety of mirvetuximab soravtansine monotherapy in patients with FR-alpha high platinum-sensitive ovarian cancer who have received at least two prior lines of platinum containing therapy or have a documented platinum allergy. The primary end point is objective response rate (ORR), and the key secondary endpoint is duration of response (DOR). The PICCOLO study was designed to statistically rule out an objective response rate of 28% or lower, as excluded by the lower bound of the confidence interval, a response rate which has been observed with non-platinum, single-agent chemotherapy in platinum-sensitive disease. Patients with PSOC with multiple prior lines of platinum-based therapy or who are ineligible for platinum-based therapy, as in the population in PICCOLO, have no established benchmark standard of care, particularly after disease progression on a PARP inhibitor. AbbVie previously announced positive topline results from the study in June 2024. About the LUMINOSITY trial The LUMINOSITY trial (M14-239), is an ongoing single-arm Phase 2 study designed to identify the target NSCLC populations that overexpress c-Met best suited for Teliso-V monotherapy in the second line or third line setting, and then to expand the groups to further evaluate efficacy in the selected populations. The endpoints include overall response rate (ORR), duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS) per independent central review (ICR) as well as overall survival (OS). AbbVie previously announced positive topline results from the LUMINOSITY study in November 2023. About Mirvetuximab soravtansine Mirvetuximab soravtansine is a first-in-class ADC comprising a folate receptor-alpha binding antibody, cleavable linker, and the maytansinoid payload DM4, a potent tubulin inhibitor designed to kill the targeted cancer cells. The Marketing Authorization Application (MAA) for mirvetuximab soravtansine in Europe has been accepted by the European Medicines Agency (EMA) and regulatory submissions are also under review in multiple other countries. The safety and efficacy of mirvetuximab soravtansine has not been established for platinum-sensitive ovarian cancer. ELAHERE® (mirvetuximab soravtansine-gynx) U.S. INDICATION and IMPORTANT SAFETY INFORMATION ELAHERE® is indicated for the treatment of adult patients with folate receptor-alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Select patients for therapy based on an FDA-approved test. IMPORTANT SAFETY INFORMATION WARNING: OCULAR TOXICITY ELAHERE can cause severe ocular toxicities, including visual impairment, keratopathy, dry eye, photophobia, eye pain, and uveitis. Conduct an ophthalmic exam including visual acuity and slit lamp exam prior to initiation of ELAHERE, every other cycle for the first 8 cycles, and as clinically indicated. Administer prophylactic artificial tears and ophthalmic topical steroids. Withhold ELAHERE for ocular toxicities until improvement and resume at the same or reduced dose. Discontinue ELAHERE for Grade 4 ocular toxicities. WARNINGS and PRECAUTIONS Ocular Disorders ELAHERE can cause severe ocular adverse reactions, including visual impairment, keratopathy (corneal disorders), dry eye, photophobia, eye pain, and uveitis. Ocular adverse reactions occurred in 59% of patients with ovarian cancer treated with ELAHERE. Eleven percent (11%) of patients experienced Grade 3 ocular adverse reactions, including blurred vision, keratopathy (corneal disorders), dry eye, cataract, photophobia, and eye pain; two patients (0.3%) experienced Grade 4 events (keratopathy and cataract). The most common (≥5%) ocular adverse reactions were blurred vision (48%), keratopathy (36%), dry eye (27%), cataract (16%), photophobia (14%), and eye pain (10%). The median time to onset for first ocular adverse reaction was 5.1 weeks (range: 0.1 to 68.6). Of the patients who experienced ocular events, 53% had complete resolution; 38% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade at last follow up). Ocular adverse reactions led to permanent discontinuation of ELAHERE in 1% of patients. Premedication and use of lubricating and ophthalmic topical steroid eye drops during treatment with ELAHERE are recommended. Advise patients to avoid use of contact lenses during treatment with ELAHERE unless directed by a healthcare provider. Refer patients to an eye care professional for an ophthalmic exam including visual acuity and slit lamp exam prior to treatment initiation, every other cycle for the first 8 cycles, and as clinically indicated. Promptly refer patients to an eye care professional for any new or worsening ocular signs and symptoms. Monitor for ocular toxicity and withhold, reduce, or permanently discontinue ELAHERE based on severity and persistence of ocular adverse reactions. Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ELAHERE. Pneumonitis occurred in 10% of patients treated with ELAHERE, including 1% with Grade 3 events and 1 patient (0.1%) with a Grade 4 event. One patient (0.1%) died due to respiratory failure in the setting of pneumonitis and lung metastases. One patient (0.1%) died due to respiratory failure of unknown etiology. Pneumonitis led to permanent discontinuation of ELAHERE in 3% of patients. Monitor patients for pulmonary signs and symptoms of pneumonitis, which may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded through appropriate investigations. Withhold ELAHERE for patients who develop persistent or recurrent Grade 2 pneumonitis until symptoms resolve to ≤ Grade 1 and consider dose reduction. Permanently discontinue ELAHERE in all patients with Grade 3 or 4 pneumonitis. Patients who are asymptomatic may continue dosing of ELAHERE with close monitoring. Peripheral Neuropathy (PN) Peripheral neuropathy occurred in 36% of patients with ovarian cancer treated with ELAHERE across clinical trials; 3% of patients experienced Grade 3 peripheral neuropathy. Peripheral neuropathy adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (9%), paraesthesia (6%), neurotoxicity (3%), hypoaesthesia (1%), peripheral motor neuropathy (0.9%), polyneuropathy (0.3%), and peripheral sensorimotor neuropathy (0.1%). Monitor patients for signs and symptoms of neuropathy, such as paresthesia, tingling or a burning sensation, neuropathic pain, muscle weakness, or dysesthesia. For patients experiencing new or worsening PN, withhold dosage, dose reduce, or permanently discontinue ELAHERE based on the severity of PN. Embryo-Fetal Toxicity Based on its mechanism of action, ELAHERE can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (DM4) and affects actively dividing cells. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ELAHERE and for 7 months after the last dose. ADVERSE REACTIONS The most common (≥20 %) adverse reactions, including lab abnormalities, were increased aspartate aminotransferase, fatigue, increased alanine aminotransferase, blurred vision, nausea, increased alkaline phosphatase, diarrhea, abdominal pain, keratopathy, peripheral neuropathy, musculoskeletal pain, decreased lymphocytes, decreased platelets, decreased magnesium, decreased hemoglobin, dry eye, constipation, decreased leukocytes, vomiting, decreased albumin, decreased appetite, and decreased neutrophils. DRUG INTERACTIONS DM4 is a CYP3A4 substrate. Closely monitor patients for adverse reactions with ELAHERE when used concomitantly with strong CYP3A4 inhibitors. USE IN SPECIAL POPULATIONS Lactation Advise women not to breastfeed during treatment with ELAHERE and for 1 month after the last dose. Hepatic Impairment Avoid use of ELAHERE in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN). Please see full Prescribing Information, including BOXED WARNING About AbbVie in Oncology At AbbVie, we are committed to transforming standards of care for patients living with difficult-to-treat cancers. We are advancing a dynamic pipeline of investigational therapies across a range of cancer types in both blood cancers and solid tumors. We are focusing on creating targeted medicines that either impede the reproduction of cancer cells or enable their elimination. We achieve this through various, targeted treatment modalities including Antibody Drug Conjugates (ADCs), Immuno-Oncology, bi-specific antibody and CAR-T platforms. Our dedicated and experienced team joins forces with innovative partners to accelerate the delivery of potential breakthrough medicines. Today, our expansive oncology portfolio comprises of approved and investigational treatments for a wide range of blood and solid tumors. We are evaluating more than 20 investigational medicines in multiple clinical trials across some of the world's most widespread and debilitating cancers. As we work to have a remarkable impact on people's lives, we are committed to exploring solutions to help patients obtain access to our cancer medicines. For more information, please visit . About AbbVie AbbVie's mission is to discover and deliver innovative medicines and solutions that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people's lives across several key therapeutic areas – immunology, oncology, neuroscience, and eye care – and products and services in our Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at . Follow @abbvie on LinkedIn, Facebook, Instagram, X (formerly Twitter), and YouTube. Forward-Looking Statements Some statements in this news release are, or may be considered, forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions and uses of future or conditional verbs, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those expressed or implied in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2023 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission, as updated by its subsequent Quarterly Reports on Form 10-Q. AbbVie undertakes no obligation, and specifically declines, to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.  References: Kalli KR, Oberg AL, Keeney GL, Christianson TJ, Low PS, Knutson KL, Hartmann LC. Folate receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol Oncol. 2008 Mar;108(3):619-26. doi: 10.1016/j.ygyno.2007.11.020. Epub 2008 Jan 28. PMID: 18222534; PMCID: PMC2707764. Coleman N, Yap TA, Heymach JV, et al. Antibody-drug conjugates in lung cancer: dawn of a new era? npj Precis Oncol. 2023;7:5. doi: 10.1038/. Salgia R. 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Significance of achaete-scute complex homologue 1 (ASCL1) in pulmonary neuroendocrine carcinomas; RNA sequence analyses using small cell lung cancer cells and Ascl1-induced pulmonary neuroendocrine carcinoma cells. Histochem Cell Biol. 2020;153(6):443-456. Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein-Overexpressing Advanced Nonsquamous EGFR-Wildtype Non-Small Cell Lung Cancer in the Phase II LUMINOSITY Trial. J Clin Oncol. 2024 Jun 6:JCO2400720. doi: 10.1200/JCO.24.00720. Epub ahead of print. PMID: 38843488. Sharma M, et al. Dose escalation results from a first-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors. J Clin Oncol. 2023;41(16_suppl):3015. Doi: 10.1200/JCO.2023.41.16_suppl.3015. SOURCE AbbVie