HTRA1

最近几年可以说是神经和精神疾病领域的不断转折之年，可以看到lecanemab的上市，但市场表现不及预期。 可以看到Amylyx Pharmaceuticals的Relyvrio（AMX0035）虽然一度上市，后又因为临床数据不佳而退市。 市场环境可以说是有期盼也有失落，不过，一些早先被认为失败的药物仍然有翻盘的机会，一些药物集中在了精神疾病的细分领域内。近期，外媒Biospace列举了今年下半年可能比较值得关注的五项临床数据，本文将对此进行简单分析。 Athira Pharma的Fosgonimeton Fosgonimeton代表着通往阿尔兹海默症的另外一种机制，旨在通过增强肝细胞生长因子(HGF)及其受体MET的活性，来影响神经退行性变和脑组织再生。 考虑到医生对于Aβ抗体类药物的抗拒心理在一定程度上来自于副作用——脑出血和脑水肿的抗拒，来自于再生机制的Fosgonimeton安全性更佳，也更有可能受到市场的偏爱。 当然，这一药物此前也并非没有经历过失败，2022年时，fosgonimeton联合标准护理乙酰胆碱酯酶抑制剂错过了II期临床研究ACT-AD的主要终点，没能在认知改善上优于安慰剂。 虽然临床终点失败，但对于亚组的分析给了这款药物继续开发下去的信心，fosgonimeton接下来着手展开LIFT-AD。 LIFT-AD就是此次备受关注的焦点，与之前失败的ACT-AD相比，LIFT-AD没把标准护理乙酰胆碱酯酶抑制剂纳入考量，想要在未使用乙酰胆碱酯酶抑制剂背景下的患者中找到突破口。 目前，Athira Pharma已被邀请在2024年10月29日于西班牙马德里举行的第17届阿尔茨海默病临床试验(CTAD)会议上进行口头介绍，讨论更完整的数据集。 可以期待10月29日公布的数据。 艾伯维/Cerevel的Emraclidine 之前的BMS花了大价钱买下的KarTx已经说明了毒蕈碱受体激动剂在精神分裂症中的潜力，而Emraclidine就需要证明自己能与BMS的KarTx拼上一拼。 从机制上来看，KarTx是M1 / M4 毒蕈碱受体激动剂，而Emraclidine则只针对M4，KarTx的机制更为复杂，是否能证明协同作用＞单M4激动需要来自竞争对手Emraclidine的证明。 艾伯维去年12月花费了87亿美元买下了Emraclidine的开发公司Cerevel，现在今年下半年是为这一份收购是否划算盖棺定论了。 目前该公司针对精神分裂症的临床2期试验是两项安慰剂对照试验EMPOWER-1和EMPOWER-2，另还有安全扩展试验EMPOWER-3。EMPOWER计划数据预计将于2024年下半年公布。 Neumora的navacaprant Neumora 同样拥有上文所述的毒蕈碱受体激动剂资产——NMRA-266，但自从3个月前，因为临床前兔子出现抽搐，该重要资产遭到了FDA的暂停，引发股价暴跌。 现在，另外一项重要资产navacaprant的临床数据将会是该公司的重要机遇，是2020年收购BlackThorn Therapeutics公司的产物。navacaprant是一种用于治疗重度抑郁症(MDD)的κ-阿片受体(KOR)拮抗剂。 Neumora目前已经启动了Navacaprant的III期关键性临床项目KOASTAL，该项目旨在评估Navacaprant作为单药疗法治疗MDD的疗效和安全性。根据公司的公告和临床试验的常规进程，KOASTAL项目的关键试验结果有望在2024年下半年发布。这些数据将直接决定Navacaprant未来是否能够成功上市。 Neumora方面似乎对数据非常有信心，这些信心来自于关键意见领袖的正面反馈，KOR机制，以及业内反映的其他抗抑郁药物的副作用过强。 AMX003的复活？ AMX003虽然在ALS上撤市了，但是在其他神经疾病中还有机会。 在撤市之后，Amylyx发现沃尔夫拉姆综合征（Wolfram syndrome）或许是AMX0035的救星。沃尔夫拉姆综合征是一种多器官疾病，通常在儿童时期发病，表现为胰岛素依赖型糖尿病和进行性视神经萎缩。 正在进行的II期HELIOS试验的初步结果显示，AMX0035能够改善患有这种罕见遗传性疾病的成年患者的胰腺功能和血糖控制。治疗导致总C肽反应增加，这是胰腺β细胞功能和血糖控制的一个公认指标，也是该试验的主要疗效指标。 Amylyx预计将在2024年下半年获得所有12名试验参与者经过24周治疗后的主要数据。 Vigil Neuroscience的Iluzanebart 成人起病的脑白质病伴轴索球样变和色素胶质细胞（ALSP）是一种罕见的神经退行性疾病，其特征是白质脑病变、轴突球体形成和色素胶质细胞增多。该病的主要致病基因为染色体5q32上的集落刺激因子1受体（CSF1R），这是一种表达于小胶质细胞表面的酪氨酸激酶受体。此外，还有其他基因如TUBB4A、EIF2B5、HTRA1等也与ALSP相关，但CSF1R基因突变是最常见的，约占所有ALSP患者的50%以上。而ALSP目前尚无有效治疗方法。 Iluzanebart本身是一种小分子TREM2激动剂。 根据Vigil的说法，Iluzanebart可以通过DAP12/SYK增加信号传导，以减轻小胶质细胞功能障碍。在临床前研究中，iluzanebart已经证明了亚纳摩尔级的效力和与TREM2的选择性靶向接合，能够通过TREM2激活下游信号的级联反应，以介导小胶质细胞的神经保护和稳态功能。 预计2024年下半年可以看到Iluzanebart的IGNITE试验和ILLUMINATE的试验的临床数据，在有效性和安全性上实现Iluzanebart的概念验证。 这对于Vigil Neuroscience的股权投资方赛诺菲来说也是一次战略眼光检验。 参考来源： https://www.biospace.com/article/5-neuro-data-readouts-to-watch-in-the-second-half-of-2024-/

This drug-free, non-invasive approach could open the doors for new developments in cancer therapy and cancer biomarker discovery SINGAPORE, May 21, 2024 /PRNewswire/ -- A team of researchers led by Associate Professor Alfredo Franco-Obregón from the NUS Institute for Health Innovation & Technology (iHealthtech) has unveiled a novel approach to stimulate muscle, by way of using brief and mild pulsed electromagnetic field exposure, to produce and release proteins possessing anticancer properties. These soluble chemical molecules can then be carried in the blood stream to all regions of the body for system-wide protection against cancer. Exercise is known to have protective effects against cancer, including reducing the risk of developing breast, prostate, and colon cancers, as well as improving the survival rate of patients with cancer. However, given the debilitating effects of cancer progression and treatment-related side effects, patients with cancer may not be able to exercise and benefit from muscle's anticancer effects. "The BICEPS lab's method of stimulating muscle cells uses a form of magnetic therapy that exhibits key commonalities with exercise. This latest study demonstrated that our non-invasive method of muscle stimulation mobilises a similar anticancer defence as exercise, bringing us a step closer towards the development of drug-free therapeutics and the discovery of cancer-related biomarkers to help patients with cancer benefit from exercise-stimulated anticancer agents while not being able to exercise," said Assoc Prof Franco-Obregón. The NUS (National University of Singapore) team published the details of this new drug-free and non-invasive approach in Cells on 5 March 2024. Anticancer properties of magnetically-stimulated muscle cells In a previous study, Assoc Prof Franco-Obregón and his team demonstrated that briefly exposing isolated muscle cells to 10 minutes of low-energy magnetic fields was capable of boosting muscle development by stimulating their release of regenerative and rejuvenating proteins into their surroundings. In the body, these same muscle factors are also known to be protective against common diseases such as diabetes and cancer. In the new study, the team explicitly investigated whether the same magnetic stimulation protocol could encourage the production and release of anticancer agents from the intact muscles in preclinical models and to identify and validate anticancer factors. The NUS team first tested their hypothesis at the cellular level and found that muscle cells that underwent magnetic therapy could inhibit breast cancer cell growth, invasion and migration, which are hallmarks of cancer progression. In addition, magnetically-stimulated muscle cells were found to be able to shrink micro-tumours as well as reduce their blood vessel formation. Next, the researchers conducted preclinical studies to validate their tissue culture findings. They demonstrated that 10-minute exposure to magnetic therapy once a week for eight weeks was sufficient to evoke similar anticancer properties - such as preventing the growth, invasion and migration of breast cancer cells - as that produced by exercising twice a week for 20 minutes per session for eight weeks. The researchers further demonstrated that a previously suspected tumour suppressor, HTRA1, was secreted from muscle cells exposed to 10 minutes of magnetic fields per week, similarly as exercising for 20 minutes twice a week. Importantly, selectively removing HTRA1 secreted by the muscle cells eliminated its anticancer potency, whereas directly applying synthetic HTRA1 to cancer cells recreated the anticancer effect of magnetic field exposure and exercise. These results demonstrate that HTRA1 is necessary and sufficient to explain the anticancer effect of muscle. Interestingly, HTRA1 is necessary for muscle development and for the build-up of muscle's anticancer protein arsenal, which contributes to our muscle being our greatest natural defence against cancer. In this respect, the researchers showed that early exposure of isolated muscle cells (in tissue culture) to HTRA1 stimulated their development and increased their anticancer potency. In other words, HTRA1 could adapt muscle cells outside the body to become better anticancer factor secretors even when not stimulated by the magnetic fields, essentially recapitulating exercise adaptations in the laboratory, which are normally seen in the body. "HTRA1 released during exercise may cause muscles to adapt to be capable of secreting HTRA1 even at rest. This helps to explain why exercise makes us more resistant to cancer. To extend the analogy even further, if muscle is our anticancer pharmacy, magnetic field therapy may be an inexpensive, yet effective, prescription," said Assoc Prof Franco-Obregón. Next steps Following up on the promising results generated from this preclinical study, the NUS team is initiating clinical trials to assess the anticancer potential of muscle-targeted magnetic therapy in humans and to corroborate the anticancer effects of HTRA1 in humans with breast and other cancers. The team also looks forward to conducting further studies to identify other anticancer biomarkers produced and released by muscle cells, which could serve as potential targets for the development of drugs and therapeutics to treat cancer. As muscle is a foundation of rejuvenating and disease fighting factors, this approach should prove quite fruitful. Read more at: SOURCE National University of Singapore

本文为转化医学网原创，转载请注明出处 作者：Jerry 导读： 化疗是治疗结直肠癌（CRC）的重要策略，但化疗耐药严重影响了其疗效，其潜在的机制尚未完全阐明。 5月13日，南方医科大学研究人员在期刊《Cell Death Discovery》上发表了题为“HTRA1 interacts with SLC7A11 to modulate colorectal cancer chemosensitivity by inhibiting ferroptosis”的研究论文，本研究表明，铁死亡在HTRA1-介导的化疗抵抗中起作用。此外，电子显微镜分析以及CRC细胞中的ROS和MDA水平也证实了HTRA1对铁死亡的影响。研究人员还验证了HTRA1可以通过其Kazal结构域与SLC7A11相互作用，并上调SLC7A11的表达，从而抑制铁死亡并导致CRC细胞对5-FU/L-OHP的化疗抵抗。 因此，研究人员提出HTRA1可能是CRC的一种潜在治疗靶点和预后指标。 https://www.nature.com/articles/s41420-024-01993-6#Sec8 研究背景 01 结直肠癌（CRC）是消化系统最常见的恶性肿瘤之一，严重影响人类健康。根据国际癌症研究机构（IARC）2020年发布的全球癌症统计数据，CRC的患病率和死亡率分别在所有恶性肿瘤中排名第三和第二。化疗不仅被用作早期CRC患者的辅助术后治疗，也被认为是中晚期CRC综合治疗的主要手段。然而，CRC细胞的化疗耐药性严重影响了治疗效果，并与CRC患者的不良预后有关。越来越多的证据表明，肿瘤细胞内活性氧自由基（ROS）失衡介导的氧化应激防御与肿瘤化疗耐药密切相关。转运体家族7成员11（SLC7A11/xCT）是Xc系统中的关键功能亚基，作为一种半胱氨酸/谷氨酸反向转运蛋白，它将细胞外的半胱氨酸转运到细胞内。促进半胱氨酸的吸收会导致其迅速转化为胱氨酸，这是谷胱甘肽（GSH）合成的重要前体。随后，谷胱甘肽过氧化物酶4（GPX4）利用GSH作为辅因子将脂质过氧化物还原为脂质醇，从而保护细胞免受脂质过氧化诱导的铁依赖性细胞死亡。SLC7A11通常在肿瘤细胞中上调，尤其是在对化疗/放疗耐药的肿瘤细胞中。通过基因敲除或抑制SLC7A11的活性可以减少GSH的合成，导致脂质过氧化产物的产生和积累，最终诱导癌细胞发生铁死亡。 研究发现 02 研究发现，调控铁死亡和调节肿瘤细胞对氧化应激耐受的不同途径之间的相互作用会影响化疗抵抗。对宫颈癌细胞应用铁螯合剂去铁胺（DFO）可增强其对奥沙利铂的敏感性。与氧化应激相关的核转录因子NRF2的激活，通过抑制肝癌细胞中的铁死亡，上调MT-1G的表达并促进索拉非尼的耐药性。抑制KEAP1-NRF2信号通路可促进铁死亡的发生并逆转顺铂的耐药性。此外，铁死亡诱导剂与化疗药物的联合应用对肿瘤具有显著的协同作用，这可能是多种肿瘤的一种潜在治疗策略。例如，铁死亡诱导剂埃拉斯汀可显著增强顺铂对卵巢癌的治疗效果。埃拉斯汀还可显著增强阿糖胞苷和阿霉素在HL60细胞中的抗癌活性，其诱导的铁死亡可逆转急性髓细胞白血病细胞的化疗抵抗。此外，一些临床药物可以诱导铁死亡，如索拉非尼、沙利度胺和阿特斯那特，已被用作肿瘤治疗的临床辅助化疗药物。 因此，进一步阐明铁死亡及其在化疗耐药中的机制可能为逆转化疗耐药创造新的机会，而靶向调节铁死亡的关键基因很可能是改善肿瘤治疗中化疗耐药的新途径。 SLC7A11在HTRA1调控的铁死亡中的介导作用 研究结论 03 总之，研究人员筛选出HTRA1作为结直肠癌（CRC）进展相关的基因，并研究了其在CRC细胞进展中的作用。研究人员还揭示了HTRA1在铁死亡依赖的情况下对化疗耐药具有促进作用，HTRA1可能是CRC治疗的潜在靶点。 参考资料： https://www.nature.com/articles/s41420-024-01993-6#Sec8 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｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 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欢迎您的参与！ 点击对应文字 查看详情