FOXC1

A newly developed 'GPS nanoparticle' injected intravenously can home in on cancer cells to deliver a genetic punch to the protein implicated in tumor growth and spread, according to researchers. They tested their approach in human cell lines and in mice to effectively knock down a cancer-causing gene, reporting that the technique may potentially offer a more precise and effective treatment for notoriously hard-to-treat basal-like breast cancers. A newly developed "GPS nanoparticle" injected intravenously can home in on cancer cells to deliver a genetic punch to the protein implicated in tumor growth and spread, according to researchers from Penn State. They tested their approach in human cell lines and in mice to effectively knock down a cancer-causing gene, reporting that the technique may potentially offer a more precise and effective treatment for notoriously hard-to-treat basal-like breast cancers. They published their work today (March 11) in ACS Nano. They also filed a provisional application to patent the technology described in this study. "We developed a GPS nanoparticle that can find the site where it is needed," said corresponding author Dipanjan Pan, the Dorothy Foehr Huck & J. Lloyd Huck Chair Professor in Nanomedicine and professor of nuclear engineering and of materials science and engineering at Penn State. "Once there -- and only there -- it can deliver gene editing proteins to prevent the cancer cells from spreading. It was a difficult task, but we showed that the system works for basal-like breast cancers." Similar to triple-negative breast cancers, basal-like breast cancers may be less prevalent than other breast cancers, but they can be far more challenging to treat, largely because they lack the three therapeutic targets found in other breast cancers. They also tend to be aggressive, quickly growing tumors and shedding cells that spread elsewhere in the body. Those cells can seed additional tumors, a process called metastasis. "Metastasis is a huge challenge, especially with cancers like triple-negative and basal-like breast cancers," Pan said. "The cancer can be hard to detect and does not show up during a routine mammogram, and it primarily affects the younger or African American population who may not be receiving preventative care yet. The outcome can be very, very poor, so there's a clear unmet clinical need for more effective treatments when the cancer isn't caught early enough." The team fabricated a Trojan horse nanoparticle, disguising it with specially designed fatty molecules that look like naturally occurring lipids and packing it full of CRISPR-Cas9 molecules. These molecules can target the genetic material of a cell, identify a particular gene and knock it down, or render it ineffective. In this case, the system targeted human forkhead box c1 (FOXC1), which is involved in instigating metastasis. Pan described the designer lipids as "zwitterionic," meaning they have near neutral charge on the nanoparticle's shell. This prevents the body's immune system from attacking the nanoparticle -- because it is disguised as a non-threatening, normal molecule -- and can help release the payload, but only when the lipids recognize the low pH environment of the cancer cell. To ensure the lipids would only activate at that low pH, the researchers designed them to shift their charges to positive once they enter the more acidic tumor microenvironment, triggering the payload release. But the body is a vast place, so how could the researchers ensure the CRISPR-Cas9 payload made it to the correct target? To ensure that the nanoparticle would bind to the right cells, they attached an epithelial cell adhesion molecule (EpCAM), which is known to attach to basal-like breast cancer cells. "No one has ever attempted to target a basal-like breast like cancer cell with context-responsive delivery system that can genetically knockdown the gene of interest," Pan said. "We're the first to show that it can be done." Others have developed viral delivery systems, hijacking a virus particle to carry treatment to the cells, and non-viral delivery systems, using nanoparticles. The difference, Pan said, for his team's approach is the surface lipid designed to respond only in the target environment, which reduces the potential for off-target delivery and harm to healthy cells. Also, he added, since the body doesn't consider the lipids to be a threat, there's less chance for an immune response, which they validated in their experiments. The team first tested the approach in human triple-negative breast cancer cells, validating that the nanoparticle would deploy the CRISPR/Cas9 system in the correct environment. They confirmed that the nanoparticle could find its way to a tumor in a mouse model, deploy the system and successfully knock down FOXC1. Next, Pan said, the researchers plan to continue testing the nanoparticle platform with the eventual goal of applying it clinically in humans. "We are also exploring how else we might apply the platform technology," Pan said. "We can customize the molecules on the surface, the payload it carries, and use it to encourage healing in other areas. There's a lot of potential with this platform." First author Parikshit Moitra, was a research assistant professor of nuclear engineering in Pan's laboratory at Penn State at the time of the study and is now an assistant professor at the Indian Institute of Science Education and Research at Berhampur; David Skrodzki, Matthew Molinaro, Nivetha Gunaseelan, all doctoral students at Penn State; Dinabandhu Sar, University of Illinois, Urbana-Champaign; Teresa Aditya, postdoctoral researcher in nuclear engineering at Penn State; Dipendra Dahal and Priyanka Ray, both postdoctoral researchers in Pan's laboratory at his previous institution of the University of Maryland Baltimore. Penn State, the University of Maryland Baltimore School of Medicine, the Centers for Disease Control and Prevention, the U.S. National Science Foundation and the U.S. Department of Defense Congressionally Directed Medical Research Program funded this work.

本文为转化医学网原创，转载请注明出处 作者：Jerry 导读： 大量证据证明了癌症干细胞(CSC)在肿瘤发生和耐药中的关键作用。 2月27日，同济大学附属东方医院徐美东教授、陈涛教授研究团队在期刊《Cell Death Discovery》上发表了研究论文，题为“IGF-1-mediated FOXC1 overexpression induces stem-like properties through upregulating CBX7 and IGF-1R in esophageal squamous cell carcinoma”。研究显示，在食管鳞癌（ESCC）中FOXC1表达明显上调，与预后不良相关。FOXC1的下调对ESCC的肿瘤发生、增殖和对化疗药物的耐受性具有抑制作用，同时降低了干细胞相关标志物CD133和CD44的水平。进一步的研究证实FOXC1通过反激活CBX7和IGF-1R诱导ESCC干细胞。 综上，靶向IGF-1-FOXC1-IGF-1R轴成为食管鳞癌抗CSC治疗的一种有前途的方法。 https://www-nature-com.libproxy1.nus.edu.sg/articles/s41420-024-01864-0#Sec9 研究背景 01 食管癌是全球癌症相关死亡的主要原因，食管鳞状细胞癌是其主要的组织学亚型。内镜下粘膜剥离术是世界上诊断频率第6高、死亡率第4高的癌症，已成为早期食管鳞状细胞癌首选的微创治疗方法，可改善患者预后。然而，随着疾病进展，治疗出现复杂性，导致预后减少和死亡率升高。早期食管癌的存活率超过90%，但进入晚期后，存活率急剧下降到不到5%。这些统计数据强调了早期发现和治疗食管鳞状细胞癌的关键作用。因此，有必要探索食管鳞状细胞癌进展的分子机制，并确定阻碍其进展的潜在靶点。 肿瘤干细胞具有自我更新和维持干细胞状态的能力，对肿瘤的形成、维持、进展和耐药有重要作用。因此，靶向与这些癌症干细胞相关的信号通路是一种很有前途的癌症治疗策略。 研究进展 02 在本研究中，研究人员首次揭示了FOXC1参与ESCC干性调控。CD133和CD44是ESCC的典型肿瘤干性标志物。研究人员发现FOXC1的下调在蛋白和mRNA水平上显著降低了CD44和CD133的表达，随后减少了食管癌细胞系ECA-109和KYSE-150中CD44+细胞的比例。此外，在FOXC1基因敲低组中，象征自我更新的球体形成能力(CSC的关键特征之一)显著下降，与对照组相比，球体明显变小。 此外，在体外和体内，干细胞性对肿瘤细胞增殖都有影响。FOXC1敲低导致FOXC1敲低组的生长速度减慢，这从CCK8试验中可以看出，并且与对照组相比，体内肿瘤大小和体重差异也证实了这一点。 耐药是食管鳞状细胞癌治疗的关键挑战，也是肿瘤干细胞的重要特征。虽然化疗药物以肿瘤细胞为靶点，但CSCs对化疗的耐受能力强，导致肿瘤复发。顺铂作为食管鳞癌化疗的基石，正面临耐药性挑战。 FOXC1基因沉默增强了肿瘤细胞对顺铂的敏感性，提示FOXC1可能成为食管癌治疗的生物标志物和耐药靶点。 FOXC1增强ESCC细胞在体内的致瘤性 研究结论 03 总之，本研究结果表明，IGF-1介导FOXC1表达，而FOXC1上调CBX7和IGF-1R表达并诱导ESCC干性。 因此，FOXC1成为一个潜在的预后指标，而IGF-1-FOXC1-IGF-1R致癌环路成为缓解FOXC1诱导的ESCC干性的有前途的治疗途径。 参考资料： https://www-nature-com.libproxy1.nus.edu.sg/articles/s41420-024-01864-0#Sec9 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 🕓 上海｜3月01日-02日 ▶第三届长三角单细胞组学技术应用论坛暨空间组学前沿论坛将在上海召开，诚邀您的参与！ 点击对应文字 查看详情

2023年3月27日，由复旦大学附属肿瘤医院邵志敏教授团队开展的我国首个三阴性乳腺癌精准治疗“伞型”临床试验，公布了终点分析结果。这意味着三阴性乳腺癌患者精准诊疗方案获得更进一 2023年3月27日，由复旦大学附属肿瘤医院邵志敏教授团队开展的我国首个三阴性乳腺癌精准治疗“伞型”临床试验，公布了终点分析结果。这意味着三阴性乳腺癌患者精准诊疗方案获得更进一步的证据支撑，开创了该领域研究的全新模式。相关研究成果在国际顶尖学术期刊《细胞研究》（Cell Research）在线发表。 邵志敏教授表示，三阴性乳腺癌是一类缺乏雌激素受体、孕激素受体和HER2表达的乳腺癌，约占所有新发乳腺癌的10%-20%。这类乳腺癌患者容易出现内脏转移，复发风险更高，预后较差，素来被认为是“最毒、最凶险”的乳腺癌。 近年来，对三阴性乳腺癌的管理已逐步形成共识：这是一类特征庞杂的乳腺癌。能否将这类患者进一步细分？如何进行细分？细分后如何精准施治？这些问题成为三阴性乳腺癌临床研究的焦点。 为突破上述难题，邵志敏教授领衔团队历时5年研究，绘制了全球最大的三阴性乳腺癌多组学图谱，提出了三阴性乳腺癌“复旦分型”，证实基于“复旦分型”的精准治疗，有望为三阴性乳腺癌患者带来新的治疗可能。 基于前期研究成果，复旦大学附属肿瘤医院邵志敏教授和王中华教授团队开展了晚期三阴性乳腺癌FUTURE（未来）“伞形”研究。中期分析结果已在2020年发表于《细胞研究》杂志，初步论证了分子分型基础上精准治疗策略的有效性。但全部入组患者疗效怎样，预后如何，仍待完成入组后开展最终分析。 “复旦分型”标准是研究团队根据不同基因特征，通过4个临床常用免疫组化标志物（雄激素受体、CD8、FOXC1、DCLK1），将三阴性乳腺癌分为4个不同的亚型：免疫调节型（IM）、腔面雄激素受体型 (LAR)、基底样免疫抑制型 (BLIS)、间质型 (MES)，这是国际上首个基于多组学分析系统提出的三阴性乳腺癌分类，为寻找到三阴性乳腺癌的治疗靶点指明了新的方向。 在FUTURE（未来）研究的最终分析中，共纳入了141例经多线治疗失败的难治性三阴性乳腺癌患者，以“复旦分型”为基础分别进入7个不同治疗臂（治疗组），并分别接受个体化的治疗方案。 其中， ①HER2阳性的LAR型（A臂）：吡咯替尼联合卡培他滨治疗； ②HER2阴性的LAR型（B臂）：雄激素受体拮抗剂联合治疗； ③IM型（C臂）：PD-1单抗联合白蛋白紫杉醇治疗； ④BRCA1/2胚系突变阳性的BLIS型（D臂）：PARP抑制剂联合治疗； ⑤BRCA1/2胚系突变阴性的BLIS型（E臂）：抗VEGFR/VEGF靶向联合治疗； ⑥PI3K/AKT通路突变阴性的MES型（F臂）：抗VEGFR靶向联合治疗； ⑦PI3K/AKT通路突变阳性的MES型（G臂）：依维莫司联合白蛋白紫杉醇治疗。 王中华教授介绍，这些入组的难治性三阴性乳腺癌患者，绝大部分在之前接受临床常见的六大类化疗药物治疗后发生进展、既往经历过中位3线的治疗，并伴有全身3处及以上的转移灶……这些情况往往意味着患者肿瘤负荷重、处于“无药可医”的状态。 FUTURE（未来）的终期研究结果为这些“无药可医”的患者带来希望。数据显示：入组患者，疾病控制率（DCR）达到48.2%。其中，A臂的ORR更是达到75%，免疫治疗的C臂ORR达到43.5%，远远超过此前客观缓解率（ORR）仅为5%-10%的治疗效果。 此外，相对于2020年发表的中期报告，本次研究数据首度报告了FUTURE研究的生存获益，患者总生存期（简称OS，指患者从进入研究到最后死亡的时间）达到10.7个月，无进展生存期（简称PFS，指肿瘤没有发生进展，没有出现肿瘤增长、转移或新发病灶等）相比于传统化疗也得到近一倍的提升。 值得一提的是，尽管部分患者入组前病情控制不佳、既往多线治疗后疾病复发，但在分型的精准治疗下取得了很好的疗效，入组后不仅肿瘤退缩明显，而且疾病稳定控制达一年半。这些疗效获益，也更加肯定了FUTURE（未来）研究的巨大优势。 王中华教授表示，FUTURE（未来）研究代表了三阴性乳腺癌精准诊疗“研究模式”和“治疗理念”的创新，为这些患者找到最适合的、个体化的治疗策略，最终提升了疗效，改善了患者的预后。该临床试验平台还是一个抗肿瘤药物研发的重要平台。医生可以根据药物的疗效、新药研发进展、患者的入组情况，动态调整治疗策略，不断优化治疗方案。今后，该研究团队还将持续开展三阴性乳腺癌FUTURE-SUPER、FUTURE 2.0以及腔面型乳腺癌精准治疗等系列研究，不断将乳腺癌的精准治疗推向到新阶段。 文章来源：澎湃新闻