Volasertib

▎药明康德内容团队编辑（来源：良渚实验室） 肿瘤异质性是癌症的发生、发展以及临床治疗中的关键影响因素。高通量单细胞转录组测序（single cell RNA-seq，scRNA-seq）技术能够精确捕获单个细胞的基因表达信息，为我们深入认识肿瘤内部的异质性和发现稀有细胞类型提供了有力工具。 人工智能在癌症研究和制药创新中发挥着越来越重要的作用。它能够整合庞大的肿瘤数据集，解码肿瘤发生发展背后复杂的生物系统，深化对药物-靶点相互作用的理解，优化治疗策略，并加速新药候选物的识别进程。 图片来源：123RF 然而，目前的抗肿瘤药物筛选主要基于传统的转录组测序数据，往往会忽略肿瘤内部的异质性以及肿瘤细胞与微环境的互作关系。另外，许多研究仅聚焦于单一癌症类型，未能充分利用泛肿瘤数据中蕴含的共性特征。因此，亟需开发基于单细胞泛肿瘤图谱的药物筛选方法，在单细胞水平上实现抗肿瘤药物的高效筛选，并深入揭示药物的作用机制及潜在副作用。 近日，良渚实验室/浙江大学基础医学院郭国骥/韩晓平/夏宏光等团队合作在National Science Review上在线发表了题为A deep learning framework for in silico screening of anticancer drugs at the single-cell level的研究论文，该项工作推出了一个创新的深度学习框架“神农”（Shennong），为在单细胞水平上开展抗肿瘤药物的计算机辅助筛选提供了新途径。正如上古神农氏尝百草以明药性，今天的“神农”框架也在数字世界中“尝试”药物，预测它们对不同类型肿瘤细胞的作用效果。 泛肿瘤细胞图谱是增进对癌症生物学理解以及改善诊断和治疗的重要资源。研究人员首先使用团队自主研发的高通量单细胞测序技术平台Microwell-seq，构建了一个包含303351个细胞的泛肿瘤单细胞图谱，涵盖了中国发病率和死亡率最高的肿瘤类型。 通过该肿瘤细胞图谱，研究人员识别出了恶性细胞和癌前细胞（非恶性上皮细胞）。来源于邻近癌旁组织和肿瘤组织的癌前细胞反映了从正常到肿瘤的过渡中间状态。这些癌前细胞表现出与邻近肿瘤相关的分子改变，提示它们在肿瘤发生中发挥重要作用。癌前细胞和恶性细胞之间共享的调控通路和代谢模式强调了区分这些细胞类型的必要性——它们具有异于正常上皮细胞的特征，而这些特征在传统转录组测序中往往难以发现。 通过泛肿瘤分析，研究人员还全面表征了肿瘤相关成纤维细胞和内皮细胞。表达分析和调控模式揭示了肿瘤组织和邻近癌旁组织的基质或内皮细胞之间的相似性，证实了邻近癌旁组织和正常组织细胞的不同功能。泛肿瘤细胞图谱数据集可在交互式网站http://bis.zju.edu.cn/shennong/landscape.html进行访问。 ▲图1 泛肿瘤单细胞图谱的工作流程和细胞数据集统计（图片来源：原始论文[1]） 传统的药物筛选或药物发现方法通常耗时且成本高昂。人工智能和机器学习方法加速了药物发现和开发的进程。研究人员推出了神农框架，正是这类方法的创新典范。 神农框架以单细胞计数矩阵和预处理的细胞扰动数据为输入。通过基于变分自编码器的深度学习模型，计算每个细胞对特定药物处理的响应强度（潜在得分）和变化趋势（潜在方向）。模型包括含有4个隐藏层的编码器、相同层数但顺序相反的解码器和中间的瓶颈层。考虑到扰动数据的的庞大规模，同时某些细胞可能存在冗余的扰动特征，模型在潜在空间中采用了组套索正则化层，运用类注意力机制为每个细胞富集特征信息丰富的扰动条目。最终输出药物处理对各细胞的影响得分矩阵。 利用贝叶斯检验计算药物处理对不同细胞类型的影响，研究人员获得了富集分数矩阵，以评估不同药物对特定细胞类型的影响。这一方法不仅能预测药物的治疗效果和副作用，指导药物筛选，还能发现针对特定细胞类型的候选药物。通过分析药物处理相关基因在模型解码器中的权重，探究该基因在对应药物处理中的相对重要性，从而识别出特定药物的潜在作用靶点。 10折交叉验证结果表明，神农框架在特征提取和潜在空间的细胞聚类映射方面展现出优异的可重复性。 ▲图2 神农框架的搭建流程和应用方向（图片来源：原始论文[1]） 将神农框架应用于泛肿瘤细胞图谱后，研究人员识别出了一些具有新适应症的FDA批准药物、正在进行临床试验的候选药物以及具有抗肿瘤活性的实验性化合物。例如，FDA批准的乳腺癌治疗药物依西美坦对肺癌细胞表现出显著的抗增殖效果，同时这一发现在一期临床试验中得到证实。候选药物volasertib在多个临床试验中显示出安全性和抗肿瘤活性，能够缓解非小细胞肺癌患者的病情。细胞系实验证实了实验化合物帕苯达唑具有抗肝癌活性，其效果与晚期肝细胞癌的标准疗法（索拉非尼和瑞戈非尼）以及临床试验药物陶扎色替相当。 在药物潜在作用靶点的预测方面，神农框架的分析结果与已知研究高度吻合。例如，对候选药物volasertib的分析显示，其显著影响了多个基因的表达，包括BCL2L1、PLK1、NEK7和HMGB2，这些基因在其对应的解码器中具有极高的权重。 此外，神农框架还能评估药物引起的组织损伤效应，其预测结果与已知的毒性表现和研发停用案例高度一致。例如，框架预测维莫非尼可能损害正常胰腺上皮细胞，这与临床试验中发现的维莫非尼相关胰腺炎病例相符，该不良反应导致欧洲和加拿大更新了药品说明标签。同样，框架预测表面lopinavir可能会对来源于正常组织的肝上皮细胞和基质细胞产生显著影响，这与已报道的lopinavir相关肝损伤病例相吻合。 为了进一步验证神农框架的稳健性，研究人员比较了泛肿瘤细胞图谱和多个第三方数据集的预测结果。训练后的模型成功提取了这些数据集中来自不同组织来源的细胞的独特和共性特征。潜在空间的映射中，相同细胞谱系的细胞簇呈现出明显的聚集趋势。约有30%至45%的化合物与相应第三方数据集中的预测结果重叠。这一比较结果表明神农框架具有良好的稳健性和泛化能力。 ▲图3 第三方数据集比较（图片来源：原始论文[1]） 总的来说，本研究推出的深度学习框架“神农”（Shennong）实现了在单细胞水平上准确预测药物反应，不仅可用于筛选潜在抗肿瘤药物并探究其作用靶点，还能评估药物引起的组织损伤效应。神农框架展现出良好的稳健性和可解释性，有望显著提升药物筛选的效率和准确度，加速新药开发进程。 良渚实验室/浙江大学基础医学院郭国骥教授、浙江大学基础医学院韩晓平教授、良渚实验室/浙江大学基础医学院夏宏光教授和浙江大学医学院附属第一医院梁廷波教授为本文通讯作者。浙江大学基础医学院张霈婧博士后、浙江大学基础医学院王雪怡博士生、良渚实验室岑旭峰特聘研究员和浙江大学医学院附属第一医院章琦副教授为本文共同第一作者。良渚实验室/浙江大学基础医学院欧阳宏伟教授，良渚实验室王晶晶研究员为本研究提供了重要帮助。研究受到了国家自然科学基金委和浙江省自然科学基金委的支持。 原始论文： [1] A deep learning framework for in silico screening of anticancer drugs at the single-cell level. National Science Review, nwae451, https://doi-org.libproxy1.nus.edu.sg/10.1093/nsr/nwae451 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~

→ Kristen Mulholland will take over for the retiring Peter Fasolo as chief human resources officer at J&J on Oct. 1. “Peter has led J&J’s talent strategy for the past 16 years including remarkable leadership through the global pandemic and the separation of our consumer health business,” CEO Joaquin Duato said in a statement . “He leaves a legacy of strong leaders, deep bench strength and an inclusive, caring and patient-focused culture.” Fasolo is a Bristol Myers Squibb HR vet who left J&J to become chief talent officer for KKR , only to return in 2010. Mulholland started at J&J in 2005 and has spent nearly five years as head of human resources, global total rewards & enterprise HR functions. → Just do it: Amgen technology chief David Reese said in a LinkedIn post that the pharma giant has appointed Sean Bruich as SVP of artificial intelligence and data. Bruich moves into the pharma world after an 11-year run with Nike , where he vaulted to global VP, insights, data science & analytics. This is the second high-level AI hire by a major pharma in as many weeks — Pfizer just welcomed Berta Rodriguez-Hervas as its new chief AI and analytics officer. → In its biggest personnel news since Doug Williams ’ resignation , Sana Biotechnology has poached Dhaval Patel from UCB as the Seattle biotech awaits data readouts for its CD19-targeted allogeneic CAR-T therapy in a host of indications. Patel had a 10-year career with Novartis before he held the CSO post at UCB for nearly seven years, and he’ll have the same responsibilities at Sana under CEO Steve Harr . Sana said in its second-quarter update that the goal is to reveal data for SC291 in B cell malignancies — and such autoimmune diseases as lupus nephritis, extrarenal lupus and ANCA-associated vasculitis — sometime this year. “His expertise in immunology and autoimmune diseases make[s] him ideally suited to help advance our clinical pipeline,” Harr said in a statement . → Brian Di Donato , the CFO and head of strategy at Immunocore since May 2020 , is stepping down “at the end of the year” to take the CEO job at an unnamed San Diego biotech. Di Donato was the finance leader for Achillion when Alexion scooped it up for $930 million, and he’s also a board member at Jim Wilson joint iECURE , where ex-Achillion chief Joseph Truitt is CEO. → Telix Pharmaceuticals has separated its business into four separate entities: Telix Therapeutics , Telix Precision Medicine (diagnostics), Telix Lightpoint (medtech, from its acquisition of Lightpoint Medical ) and Telix Manufacturing Solutions . With these changes in place, Telix has tapped Richard Valeix as CEO of Telix Therapeutics, Kevin Richardson as Telix Precision Medicine’s chief executive, and Raphael Ortiz as CEO of Telix International . Christian Behrenbruch ’s title has been slightly modified to group CEO. Telix had hoped to join the Nasdaq in June with an IPO around the $200 million mark, but the Melbourne biotech made a gametime decision to pull those plans . → Cambridge, MA-based neuro player Cognito Therapeutics has promoted Christian Howell to CEO. Brent Vaughan had been running Cognito since 2020 after co-founding and leading the autism diagnostic specialist Cognoa , and he hired Howell as his chief commercial officer last October. Howell had a long career with Medtronic and then joined Aetion , where he was elevated to SVP and general manager of the emerging channels group (medical device, diagnostics, digital health, and government) in April 2023. → Elsewhere, Endo is also losing its president and CEO Blaise Coleman . Board member Scott Hirsch will serve in the interim as the company searches for a permanent successor. Hirsch joined Endo’s board in April, around the same time that the company sued the FDA over its approval of a generic version of Endo’s drug Adrenalin . Hirsch is the former CEO of Solta Medical and also held the roles of president of Ortho Dermatologics and CBO of Bausch Health / Bausch + Lomb . → Thomas Bock has handed in his resignation as CEO of Notable Labs , and CSO Joseph Wagner will take over the top spot on an interim basis. This isn’t uncharted territory for Wagner: He’s the former CEO of Oncocyte (2011-15) and Canadian I/O biotech BriaCell Therapeutics (2015-16). Notable Labs merged with VBL Therapeutics in February 2023 and will start enrolling patients in its Phase 2 study of the ex- Boehringer Ingelheim drug volasertib for acute myeloid leukemia “in the coming months,” the company said in July. → Delfi Diagnostics marked the beginning of the year with a new CEO it hired away from Illumina . Now, the competitor to Grail has brought on Thomas Russo as finance chief. Russo served in the same role at Icosavax and Assembly Biosciences . During his time at Icosavax, Russo helped with the company’s growth until its $838 million upfront acquisition by AstraZeneca . → Marea Therapeutics , the Third Rock upstart led by ex- Graphite Bio CEO Josh Lehrer , has selected Ian Clements as CFO. Clements resigned from the same post at Livmarli maker Mirum Pharmaceuticals in May 2023 after four years overall with the company, and he’s the ex-VP of investor relations for Dermira . Marea launched in June with $190 million in “combined Series A and B” funding, testing an ex-Novartis monoclonal antibody that targets ANGPTL4 in adults with metabolic dysfunction. → With ex- Synlogic CEO Aoife Brennan at the controls, a seemingly rejuvenated Eliem Therapeutics has named Brett Kaplan as COO and Nishi Rampal as SVP, clinical development. Kaplan had been president and chief financial & corporate development officer for epigenetic editing upstart Chroma Medicine , and he was also the finance chief at Prevail until Eli Lilly bought the gene therapy biotech for $1 billion. An Alexion vet, Rampal also handled the role of global development and strategy lead for the neuromyelitis optica spectrum disorder (NMOSD) treatment Uplizna as an executive director with Horizon /Amgen. Eliem’s hunt for strategic alternatives ended with the acquisition of Tenet Medicines and its anti-CD19 antibody budoprutug , once known as TNT119 . → Backed by RA Capital and Forbion , Navigator Medicines disclosed its $100 million Series A this week and the recruitment of Dana McClintock as CMO. McClintock spent six years in the same position at Alladapt Immunotherapeutics and was global head of the Office of I2O Innovation for Genentech . Navigator also said that Forbion general partner Wouter Joustra and RA Capital managing director Andrew Levin have made their way to the board of directors. → Alex Bastian has been named VP, commercial strategy at Swiss-based Memo Therapeutics , reuniting with CEO Erik van den Berg . Toward the end of van den Berg’s tenure as CEO of AM-Pharma , Bastian was the Dutch biotech’s VP, commercial & patient access. He also worked for Galapagos as VP, head of value & market access. → Structure Therapeutics , one of many biotechs developing a GLP-1 drug for obesity, has elected ex- Shire CEO Angus Russell to the board of directors. The 68-year-old Russell has chaired the board at Daxxify maker Revance Therapeutics since 2014 and has a board seat at Lineage Cell Therapeutics . → Ex- Vividion CEO Jeff Hatfield has joined the board of directors at Gate Bioscience , a California drug developer that launched last November with a $60 million Series A from several blue-chip investors. Hatfield chairs the board at Vividion and Rome Therapeutics . → Opna Bio has made room for Inozyme co-founder and former CEO Axel Bolte on the board of directors. The South San Francisco biotech also announced that it had dosed the first patient in a Phase 1 trial of its multiple myeloma candidate OPN-6602 and appointed Myeloma Investment Fund managing director Stephanie Oestreich as a board observer.