PDGFA

引言 针对pMMR（错配修复功能正常）的局部进展期直肠癌患者，当前的标准治疗方案是实施新辅助放化疗后联合全直肠系膜切除术。尽管该综合疗法能够促使约20%的患者实现完全缓解，但遗憾的是，多数患者的肿瘤并未能如预期般显著退缩，尤其对于低位直肠癌患者而言，保留肛门的功能仍面临重大挑战。此外，即便经过治疗，远处转移的风险依然高达30%，这对患者的长期生存构成了严重威胁。 2024年8月1日，中山大学肿瘤防治中心徐瑞华教授作为Leading PI带领结直肠癌MDT团队在Cancer Cell在线发表了题为Effect of neoadjuvant chemoradiotherapy with or without PD-1 antibody sintilimab in pMMR locally advanced rectal cancer: A randomized clinical trial的临床研究论文。该研究是一项前瞻性、随机对照临床研究，评估了新辅助放化疗联合信迪利单抗（sintilimab）对比新辅助放化疗治疗错配修复完整（pMMR）局部进展期直肠癌患者的疗效和安全性，并对疗效相关的指标进行了探索性分析。 近年来，免疫治疗在实体瘤中获得了突破性的进展，PD-1单抗在dMMR肠癌中疗效惊艳，但是PD-1单抗单药治疗在pMMR肠癌患者中几乎无效。尽管如此，放化疗联合PD-1/PD-L1单抗在直肠癌新辅助治疗中却初步表现出令人鼓舞的效果。因此，徐瑞华教授和潘志忠教授带领结直肠癌MDT团队开展了一项前瞻性随机对照临床研究，旨在对比新辅助放化疗联合PD-1单抗与新辅助放化疗治疗pMMR局部进展期直肠癌患者的疗效和安全性，并针对疗效相关指标开展探索性研究。 (Credit: Cancer Cell) 在2020年6月至2022年7月，研究共入组了134例既往未经治疗的pMMR局部进展期直肠癌患者，1:1随机分组，67例患者接受新辅助放化疗联合PD-1单抗（信迪利单抗），67例患者接受新辅助放化疗，主要终点为新辅助治疗的完全缓解率（CR），包括病理完全缓解和临床完全缓解。新辅助放化疗联合PD-1单抗组为44.8%，新辅助放化疗组为26.9%，两组之间的CR率差异为 17.9%，疗效比为1.667，P值为0.031。 (Credit: Cancer Cell) 亚组分析显示直肠肿瘤组织PD-L1 CPS高评分患者可能获益更加显著。在CPS≥2的患者中，研究组和对照组的CR率分别为53.8%和23.7% （P=0.007）；在CPS<2分的患者中，研究组和对照组的CR率分别为28.0%和40.0% （P=0.663），CPS以2分作为分界点的Pinteraction为0.029。CPS高评分的肿瘤免疫相关通路激活更显著，包括炎性反应、IL6-JAK-STAT3、TNFa-NFKB、IL2-STAT5信号通路。 (Credit: Cancer Cell) 两组患者未达到CR患者的直肠肿瘤较达到CR的肿瘤PDGFA和IL2RG表达量相对更高，可能与肿瘤中有较多的Treg细胞浸润和内皮细胞含量较高有关，未来进一步联合针对性的药物也许能进一步提升疗效。 在安全性方面，两组新辅助放化疗的完成均达到97%以上，研究组91%的患者完成了4个周期的PD-1单抗治疗。两组治疗相关毒性发生率没有显著差异。研究组中可能与PD-1单抗治疗相关的3-4级毒性包括肝酶异常（6.0%）、血清脂肪酶上升（3.0%）、皮疹（3.0%）和心肌炎（1.5%）。新辅助放化疗联合PD-1单抗的治疗方案安全性良好。 该研究结果发现：新辅助同步放化疗联合信迪利单抗较新辅助放化疗可显著提升pMMR局部进展期直肠癌患者完全缓解率，尤其在直肠肿瘤PD-L1联合评分表达较高的患者中具有更显著的获益；同时也提示了联合治疗策略优化的方向。该研究证实了pMMR直肠癌放化疗和PD-1单抗联合增效的研究假说，为局部进展期直肠癌的新辅助治疗提供了新的潜在治疗选择。 参考文献 https://doi-org.libproxy1.nus.edu.sg/10.1016/j.ccell.2024.07.004 责编|探索君 排版|探索君 文章来源|“BioArt” End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell综述

MELBOURNE, Australia, Feb. 19, 2024 (GLOBE NEWSWIRE) -- Certa Therapeutics (Certa), a biotechnology company developing innovative precision therapies for patients with inflammatory and fibrotic diseases, today announces that the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation for its investigational therapy FT011 for the treatment of systemic sclerosis (scleroderma), having previously granted Orphan Drug Designation.[1] The Fast Track Designation was granted based on results of the previously announced Phase 2 study which indicated that treatment of scleroderma patients with FT011 for 12 weeks resulted in a clinically meaningful improvement in 60% of patients treated with FT011 400mg and 20% of patients in the FT011 200mg group compared with 10% in the placebo group.[2] The FDA’s Fast Track program is designed to facilitate the expedited development and review of new drugs that are intended to treat serious or life-threatening conditions and demonstrate the potential to address unmet medical needs.[3] FT011 is a novel, first-in-class oral therapy for the treatment of chronic fibrosis in multiple organs. It targets a previously important but undrugged membrane GPCR receptor, GPCR68, with an extensive body of data demonstrating promising efficacy in multiple models of fibrotic disease. Transcriptomic research has validated the mechanism of action and demonstrated that treatment with FT011 results in reversal in the activation of genetic markers associated with fibrosis, providing potential for a precision therapy.[4] Professor Darren Kelly, Certa Therapeutics CEO and founder said, “We are thrilled to have received Fast Track Designation which supports further acceleration of the FT011 clinical development program. It also provides validation of FT011’s potential to offer patients with scleroderma the first anti-fibrotic and disease modifying treatment of this type.” “We know that this debilitating and life-threatening disease can severely impact the lives of patients and to date existing treatments only focus on the relief and management of symptoms, whereas FT011 precisely targets the root cause of fibrosis and has the potential to offer treatment across multiple organs within these patients.” Under the Fast Track Designation, the FT011 development program for scleroderma is eligible for various expedited regulatory review processes, including generally more frequent FDA interactions, potential eligibility for rolling review of a New Drug Application (NDA) and accelerated approval and priority review of an NDA. Certa is progressing preparations toward a pivotal clinical trial of FT011 as a treatment for scleroderma. Supported by global clinical experts, the clinical trial design and associated development plans will be discussed with the FDA as soon as possible in 2024, with complementary scientific advice sought from the EMA mid-2024, with the aim of starting the pivotal study in late-2024. C Denton, W Stevens, N Kruger, M Papadimitriou, F Khong, M Bradney, D Kelly, R Lafyatis “FT011 for the Treatment of Systemic Sclerosis. Results from a Phase II Study” Arthritis Rheumatol. 2023;75(suppl 9). Abstract 2593. U.S. Food and Drug Administration. Fast Track. Available at: Accessed January 23, 2022. S Eddy, et al., “Identification of Non-Invasive Surrogates as Predictors of Response to FT011 in Kidney Disease” ASN Kidney Week 2022, abstract 3767783. Media – Australia Kirrily Davis, E: kdavis@bcpvc.com M: +61 (0)401 220228 Media - International Sue Charles, Charles Consultants E: sue.charles@charles-consultants.com M: +44 (0)7968 726585 About Systemic Sclerosis (Scleroderma) Scleroderma is an extremely debilitating, potentially life-threatening autoimmune condition characterised by inflammation and fibrosis of the skin and other organs (commonly the lungs, kidneys, and heart). This condition results in high morbidity with substantial detriment on quality of life, with patients commonly experiencing loss of mobility and function, pain, fatigue, often accompanied with a significant impact to their mental health. Scleroderma has the highest mortality among rheumatic diseases. About Certa Therapeutics Certa Therapeutics is a clinical-stage biotechnology company focused on improving lives by treating patients with debilitating diseases via novel targeted therapies. Certa Therapeutics has designed a platform of candidate drugs and validated the role of GPR68, a defined G protein-coupled receptor (GPCR) receptor which mediates signalling pathways associated with inflammation and fibrosis. GPR68 is silent in healthy tissue but activated following injury or disease. Evidence demonstrates the role of GPR68 on multiple downstream pathways causing inflammation and fibrosis. These targeted drug candidates have established proof of concept as potential treatments for multiple fibrotic diseases including serious and chronic conditions impacting the kidney, lung, eye, skin, and heart. The morbidity and mortality impact of fibrotic diseases is substantial, ultimately causing 45% of all deaths globally. Significant breakthroughs are urgently needed in this field, addressing a market worth more than US$15B annually. The company is seeking to combine its innovative therapeutics with biomarkers and genetic analysis to identify those patients most likely to benefit from treatment, providing potential for a precision therapy. FT011 is an investigational product which has not received marketing authorisation or approval by any regulatory agency, including the US Food and Drug Administration, the European Medicines Agency, or the Australian Therapeutic Goods Agency. The investigational drug products being developed by Certa Therapeutics are undergoing clinical studies to evaluate the safety and effectiveness in humans. In the company’s lead program, FT011 is being developed as a novel, first-in-class oral therapy for the treatment of systemic sclerosis (scleroderma) and has successfully completed a multi-national, double-blinded randomised controlled trial. It has been awarded Orphan Drug Designation and Fast Track by the FDA. Follow us on LinkedIn :

本文为转化医学网原创，转载请注明出处 作者：Sophia 导读： 胚胎发生需要胚胎和胚胎外组织之间的和谐协调。虽然胚胎干细胞和胚胎外干细胞已经产生，但它们是在不同的培养条件下生长的。 12月4日，得克萨斯州西南医学中心吴军、昆明理工大学谭韬、季维智及中国农业大学魏育蕾共同通讯在《Cell》发表题为“Dissecting embryonic and extraembryonic lineage crosstalk with stem cell co-culture”的研究论文，研究发现， 在同一种培养体系下可以建立小鼠和食蟹猴囊胚来源的ESCs、XENs和TSCs细胞系，通过干细胞共培养方式构建囊胚时期细胞细胞互作环境，阐明了囊胚时期胚胎组织和胚外组织之间的相互作用及其调控机制。 https://www-cell-com.libproxy1.nus.edu.sg/cell/fulltext/S0092-8674(23)01225-4 研究背景 01 单细胞受精卵如何转化为具有截然不同的细胞表型的生物体是生物学中的一个基本问题。在哺乳动物中，胚胎发生伴随着多能性的建立和丧失，多能性是一种瞬时特性，使胚胎外胚层 （EPI） 细胞能够产生成年生物体中的所有细胞。多能 EPI 细胞可以通过改变培养条件在体外维持在一系列多能干细胞 （PSC） 状态（例如，幼稚、形成和引发）中。 动态PSC状态具有独特的分子和功能特征，为探索哺乳动物早期发育提供了重要的体外模型，并为再生医学带来了巨大的希望。 尽管 PSC s很有前途，但它们只有在与体内条件明显不同的细胞培养物中才能得以维持。一个显著的区别是，在培养的PSC中，没有与胚外细胞的相互作用。因此，仅PSC模型存在多种培养伪影，这些伪影可能会限制其潜力，例如，不同步和无组织的分化以及不受限制的生长。此外， 尽管胚外组织的功能在原肠胚形成（胚胎模式化）和胎儿发育阶段（胎儿生长的营养、呼吸和排泄支持）中是众所周知的，但它们如何与原肠胚形成前EPI细胞进行交流仍然难以捉摸。 来自胚胎和胚胎外来源的干细胞需要不同的生长条件进行培养，这给研究它们在自我更新过程中的相互作用带来了挑战。为了克服这些局限性， 我们在相同条件下从小鼠和食蟹猴（简称“猴子”）囊胚的胚胎和胚外组织中提取了早期植入后和原肠胚前干细胞。 这种情况称为 FTW，可激活 FGF、TGF-β/Smad 和 WNT/β-catenin 信号通路，为形成样胚胎干细胞 （ESC）、胚胎外内胚层干细胞 （XEN） 和滋养层干细胞 （TSC） 在独立培养和共培养中自我更新创造宽松的微环境，从而为剖析它们的直接交流打开了大门。 研究进展 02 灵长类原始内胚层细胞的自我更新机制研究相对处于空白。为了更好回答这个科学问题，研究团队首先从人的多能性干细胞分化获得稳定FTW-hXENs细胞系（hXENs）。通过一种培养条件获得三个物种（小鼠、食蟹猴、人）的XENs使得团队可以更好的对小鼠、食蟹猴和人胚外内胚层细胞做跨物种比较分析。通过物种间分析， 团队找到了XENs保守调控的关键基因。 除一些已知与原始内胚层发育相关的基因（例如GATA4、GATA6、SOX17、PDGFA）外，还包含一些之前未报道过与原始内胚层发育相关基因（例如SRC、JAK2、PIK3R1、CCL2），通过这些基因的敲除实验，进一步阐明这些新发现的功能基因XEN的不同物种多能性维持中起重要作用。 研究结果 03 在这项研究中，利用激活 FGF、TGF-β 和 WNT 通路的统一培养条件，我们成功地从小鼠和食蟹猴（Macaca fascicularis）囊胚的三个基础组织中提取了胚胎干细胞（FTW-ESC）、胚胎外内胚层干细胞 （FTW-XENs）和滋养层干细胞 （FTW-TSCs）。这种方法 促进了胚胎和胚外干细胞的共培养，揭示了胚外内胚层细胞对多能细胞的生长抑制作用，部分通过细胞外基质信号传导。 此外，我们的跨物种分析确定了调节FTW-XENs的共享和独特的转录因子和途径。胚胎和胚外干细胞共培养策略为开发更忠实的胚胎模型和设计更符合发育的分化方案提供了有希望的途径。 参考资料： https://www-cell-com.libproxy1.nus.edu.sg/cell/fulltext/S0092-8674(23)01225-4 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 北京｜12月19日-20日 ▶第四届单细胞测序技术应用研讨会暨单细胞&空间组学研讨会（日程稍后公布） 点击对应文字 查看详情