NaCT

【导读】 激活的Wnt/β-catenin通路是肝癌发生发展的关键遗传事件。溶质载体(SLC)转运体是很有前景的药物靶点。 8月30日，天津大学与夏威夷大学研究人员合作在期刊《Nature Communications》上发表了题为“SLC13A3 is a major effector downstream of activated β-catenin in liver cancer pathogenesis”的研究论文，本研究中，研究人员发现SLC13A3是肝癌中β-catenin下游可作为药物靶点的效应因子。SLC13A3在β-catenin编码基因CTNNB1 (GOF突变)的人肝癌样本中表达升高。β-catenin激活上调SLC13A3，导致内源性SLC13A3底物在细胞内蓄积。SLC13A3被鉴定为谷胱甘肽(GSH)的低亲和力转运蛋白。沉默SLC13A3通过c-MYC信号通路下调亮氨酸转运蛋白SLC7A5，导致亮氨酸消耗和mTOR失活。此外，在β-catenin激活的肝癌细胞中，沉默SLC13A3可减少GSH并诱导自噬性铁死亡。重要的是，SLC13A3基因抑制和小分子SLC13A3抑制剂均可抑制β-catenin驱动的小鼠肝癌发生。 综上所述，本研究表明，SLC13A3可能是一个有前景的治疗靶点，用于治疗具有GOF CTNNB1突变的人肝癌。 https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-024-51860-2#Abs1 背景知识 01 肝癌是全球癌症相关死亡的第三大原因，其中肝细胞癌(HCC)占所有肝癌病例的75-85%。CTNNB1是编码β-catenin的基因，在80%以上的儿童肝癌和20-40%的成人肝癌中检测到CTNNB1的功能获得性(GOF)突变。鉴于过度激活的Wnt/β-catenin信号通路在肝癌干性、进展、转移和耐药中的关键作用，各种Wnt/β-catenin抑制剂在肝癌治疗中的潜力已被研究。然而，这些抑制剂均未获得临床批准，因为它们通常靶向β-catenin复合体或β-catenin上游通路，从而不可避免地在正常细胞中导致靶毒性。因此，迫切需要对β-catenin下游可作为药物靶点的效应分子进行研究。 溶质载体(Solute carrier, SLC)转运体调节多种溶质、代谢物、离子和药物跨细胞膜的输入和流出。SLC转运蛋白是药物开发的重要靶点。在包括肝癌在内的多种癌症中，SLC转运蛋白的表达模式发生了显著变化。溶质载体家族13成员3 (SLC13A3)又称钠依赖性二羧酸转运蛋白(NaDC3)，在肝脏中高表达。研究人员通过对TCGA-LIHC数据集的综合分析，确定了三种HCC亚型(iHCC1-3)，并证明SLC13A3 mRNA在CTNNB1突变发生率高的iHCC2亚型中显著高表达。此外，研究人员报道SLC13A3在ctnnb1突变的hcc中高表达。然而，SLC13A3与β-catenin的关系以及SLC13A3在hcc中的功能有待进一步研究。 SLC13A3抑制剂ACA可抑制人肝癌细胞的生长，并阻止β-catenin驱动的小鼠肝癌发生 02 ACA已被用作SLC13A3的抑制剂以探究其功能。研究人员发现，ACA以剂量依赖的方式显著降低了HepG2和SNU398细胞的存活率和克隆形成能力。ACA剂量依赖性地降低了SLC13A3的mRNA和蛋白质水平。尽管ACA也抑制SLC13A2和SLC13A5，但值得注意的是，肝脏组织中SLC13A2的表达较低。而且，HPA分析揭示了肝癌细胞中几乎检测不到SLC13A2的表达。这表明SLC13A2不太可能是ACA抑制HCC细胞存活的靶点。尽管HepG2和Huh7细胞中SLC13A5的mRNA高度表达，但在其他HCC细胞中，包括β-连环激活的细胞中，几乎检测不到SLC13A5的表达。SLC13A5特异性抑制剂PF-06761281对HepG2细胞的存活没有影响，而SLC13A5过表达并不能逆转ACA对细胞存活的抑制作用。这表明SLC13A5也不是ACA抑制HCC细胞存活的靶点。除了SLC13A转运体外，研究人员还报道了ACA可抑制PLA2、TRPM2和AP2M1。HPA分析显示，在肝癌细胞中几乎检测不到TRPM2的表达。虽然抑制PLA2和AP2M1已被证明可抑制自噬，但ACA却在HCC细胞中诱导了自噬。此外，PLA2、TRPM2和AP2M1的过表达并未抑制ACA对HCC细胞的毒性，ACA治疗也没有改变它们的mRNA表达。尽管无法完全排除ACA的潜在“非靶向”效应，但这些发现表明，ACA至少部分通过抑制SLC13A3来抑制HCC细胞活力。 为了确定ACA是否与SLC13A3基因抑制具有相似的作用，研究人员分析了ACA介导的细胞生长抑制的潜在机制。ACA对细胞凋亡没有显著影响，ACA的生长抑制作用可以通过抑制自噬和铁死亡来缓解，但不能通过抑制坏死（NSA）或凋亡（Z-VAD-FMK）来缓解。ACA诱导的铁死亡进一步通过升高脂质ROS（C11-BODIPY荧光）得到证实。蛋白质免疫印迹实验分析显示，ACA以剂量依赖的方式诱导自噬（降低pmTOR和P62，增加ATG5和LC3B）和铁死亡（降低FTH1，增加TfR1）的生物标志物。此外，ACA与索拉非尼在HepG2和SNU398细胞的细胞存活和克隆形成方面显示出协同作用。 ACA抑制β连环蛋白激活的肝癌细胞的生长 接下来，研究人员研究了ACA在体内对小鼠的作用。在正常C57BL/6 N或裸小鼠BALB/C中，ACA未引起明显的毒性反应。ACA（30 mg/kg，每隔一天腹腔注射）在裸小鼠BALB/C中有效地抑制了皮下HepG2异种移植物的生长，与索拉非尼呈协同作用。蛋白质免疫印迹实验和IHC分析显示，ACA在HepG2异种移植物中诱导了自噬和铁死亡。为了进一步研究ACA对β-连环蛋白驱动的肝癌的影响，从注射c-Met/β-连环蛋白和AKT/β-连环蛋白质粒的第4周开始，将30 mg/kg的ACA腹腔注射给C57BL/6 N小鼠。IHC和蛋白质免疫印迹实验分析显示，ACA诱导了自噬（增加了ATG5和LC3B；降低了pmTOR和P62）和铁死亡（增加了4HNE和TfR1；降低了FTH1）。这些发现表明，ACA对β-连环蛋白激活的肝癌具有与基因抑制SLC13A3相似的作用。 研究小结 03 综上所述，本研究强调了SLC13A3在β-catenin激活的肝癌中调节铁死亡的重要性。需要澄清的是，研究人员不是在暗示只有β-catenin激活的肝癌对SLC13A3抑制敏感。相反，研究人员认为β-catenin激活的肝癌将对SLC13A3抑制表现出特异性敏感性。抑制SLC13A3是一种有前景的靶向肝癌β-catenin信号通路的策略，且不会产生明显的不良反应。 【参考资料】 https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-024-51860-2#Abs1 【关于投稿】 转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！ 转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。 热门推荐活动 点击免费报名 🕓 上海｜09月11日 ▶ 微驭万物-单细胞空间组学技术前沿与临床应用研讨会 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会 点击对应文字 查看详情

Learn How Family Testing Played a Huge Role in Transforming the Health Journey of a Newborn SAN FRANCISCO, Feb. 27, 2024 /PRNewswire/ -- BACKGROUND: Genetic testing can be a great resource to get a clearer picture of what to do next when faced with undiagnosed health conditions. It can provide you with essential health information that could improve medical outcomes as well as unlock preventative steps for your family when they get genetic testing as well. The sooner you have a confirmed diagnosis, the sooner you can take control of the healthcare journey along with your healthcare providers as partners. Experience the full interactive Multichannel News Release here: On June 4, 2021, Rowan Black was brought into the world. The hospital medical team noticed a couple of behaviors they wanted to check on, including some regular grunting, as well as occasional shaking of his arms. After being placed in intensive care for thorough monitoring and a 48-hour antibiotic treatment, the pediatrician established that Rowan was having regular seizures, providing an explanation for the grunting and shaking. His seizures were occurring just 2-4 minutes apart, and he was not responding well to medications. Toward the end of his hospital stay in early July, genetic testing results suggested that Rowan may have a rare genetic disorder called SLC13A5 citrate transporter deficiency, but it wasn't until October when his parent's own genetic testing from Invitae helped reach a definitive diagnosis for Rowan. Invitae's genetic testing for pediatric and rare diseases helps facilitate early diagnosis, access to available treatments, and next steps for patients and their families. Following the information from Invitae, Rowan's parents quickly discovered the TESS Research Foundation, a community dedicated to improving the lives of people affected by this difficult genetic disorder. Though it was a scary time, thanks to the definitive early diagnosis, Rowan is a SLC13A5 superhero and a happy two-year-old. Michael Black, Vice Chair of the Board at TESS Research Foundation and father of Rowan shares his son's medical journey, the importance of genetic testing, and how the results from genetic testing specifically benefited his family. For more information please visit: MORE ABOUT MICHAEL BLACK: Michael Black is a digital technology professional with a strong focus on the agriculture, non-profit, and charitable sectors. He has a keen ability to blend technical expertise with strategic oversight. Beyond his professional endeavors, Michael is deeply committed to volunteerism, actively contributing to various non-profit and charitable organizations. In his role at the TESS Research Foundation as Vice Chair and webmaster, Michael's personal journey intersects with his professional skills. His advocacy for genetic testing and awareness of rare disorders is driven by his son Rowan's battle with SLC13A5 Epilepsy. This experience has not only made him a champion for health-related causes but also highlights his ability to leverage technology in support of healthcare initiatives and family well-being. Michael's involvement in diverse sectors showcases his versatile skill set and his commitment to using technology as a tool for positive impact, particularly in improving lives and supporting communities through informed healthcare and active engagement in non-profit work. Produced for: Invitae (pronounced in-VEE-tay) SOURCE Invitae

The U.S. Food and Drug Administration (FDA) has granted rare pediatric disease and orphan drug designations for Taysha Gene Therapies’ AAV9-based gene treatment candidate currently in development for epilepsy caused by SLC13A5 deficiency. SLC13A5, a rate form of infantile epilepsy caused by SLC13A5 gene mutations, is an autosomal recessive disorder characterized by developmental delay as well as seizures that occur within the first few days of life. The gene therapy company’s TSHA-105 candidate is the AAV9-based gene therapy granted these designations and is poised to be the first treatment for SLC13A5-related epilepsy. There are no currently approved treatments for epilepsy caused by SLC13A5, explained Taysha’s President, Founder and CEO, RA Session II, in a statement. “We are encouraged by the early evidence of TSHA-105’s disease-modifying approach and believe these designations will help us potentially accelerate the development of this exciting program,” said Session. “We look forward to working with the FDA to make TSHA-105 available to patients as expeditiously as possible.” “We are pleased that the FDA recognizes TSHA-105’s potential as an innovative therapeutic option for SLC13A5 deficiency,” added Rachel Bailey, Ph.D., Assistant Professor in Pediatric Neurology at UT Southwestern. “This disease is a debilitating form of genetic epilepsy in children that significantly impacts movement, motor control, cognition and quality of life, and there remains a need to alter the course of this disease early in life.” The FDA granted this rare pediatric disease designation due to the disease’s severity and relatively low prevalence in the population. Only diseases and disorders that affect fewer than 200,000 people in the U.S. receive the rare disease designation. Taysha’s TSHA-105 fell under the agency’s Rare Pediatric Disease Priority Review Voucher Program, which aims to “address the challenges that drug companies face when developing treatments for these unique patient populations,” according to the company’s statement about the designations. The program allows companies to become eligible for a priority review voucher after product approval, which is contingent on whether the marketing application “submitted for the product satisfies certain conditions, including approval prior to September 30, 2026 unless changed by legislation.” Sponsors who are issued a priority review voucher for priority review may redeem this voucher for another marketing application for another candidate. Taysha Gene Therapies recently teamed up with UT Southwestern Medical Center in Dallas, Texas, to launch an innovation fund that will finance discovery and development of other AAV gene therapies for monogenic diseases involving the central nervous system. And in early January, Taysha partnered with AllStripes to develop an AAV-based gene therapy, TSHA-104, for a rare disorder called SURF1-associated Leigh Syndrome. Several epilepsy drugs are currently in development by other pharmaceutical companies and are undergoing investigation for both rare and more prevalent forms of epilepsy. Johnson & Johnson’s Actelion, in conjunction with Idorsia Pharmaceuticals, is developing ACT-709478, a selective T-type calcium channel blocker, for patients with photosensitive epilepsy. Another drug being developed by Adamas Pharmaceuticals in collaboration with the Epilepsy Foundation, ADS-4101, is being studied for its effect in focal seizures. Dravet Syndrome, a rare and drug-resistant form of epilepsy, is also under the spotlight after Epygenix Therapeutics received Orphan Drug Designation for EPX-100 and EPX-200 in 2017. Currently, EPX-100 has advanced through Phase II trials, with a Phase III trial in the works for the near future. Most Read Today