RPS6KB1

导读：作为一种染色质结合蛋白，HMGA2被广泛过表达，被认为是具有各种不确定调控机制的致癌基因。3月16日，宁波大学研究学者在期刊《Cell Death & Disease》上在线发表题为“HMGA2 alleviates ferroptosis by promoting GPX4 expression in pancreatic cancer cells”的研究论文，本研究阐明了HMGA2通过抑制铁死亡来增强胰腺癌细胞死亡抵抗力的机制。这是通过激活mTOR信号通路和随之而来的GPX4水平增加实现的。这些发现为未来克服胰腺癌化疗耐药性的治疗方法提供了潜在的靶点。https://www-nature-com.libproxy1.nus.edu.sg/articles/s41419-024-06592-y研究背景 01 胰腺癌是恶性最强的肿瘤类型之一，也是两性癌症相关死亡的第四大原因。胰腺癌通常未被发现，进展迅速，直到晚期并扩散，因此难以及时诊断。胰腺癌的临床治疗可分为手术、化疗和放疗三部分。由于胰腺癌的高放射耐药性，以及邻近器官无法耐受高剂量的辐射，因此治愈胰腺癌的唯一方法是完全切除和全身化疗相结合。然而，最近的研究表明，胰腺癌具有异质性细胞组成和冷肿瘤微环境，导致对新辅助化疗和/或放疗的耐药性。研究发现 02 在本研究中，研究人员证明了HMGA2在胰腺癌组织中高度表达，主要分布在上皮细胞中，并且代表了高上皮-间充质转化的亚型。HMGA2 的缺失通过细胞增殖、转移和体内异种移植肿瘤生长来抑制肿瘤恶性。此外，HMGA2通过抑制活性氧和促进谷胱甘肽的产生来增强细胞氧化还原状态。过表达HMGA2的细胞中铁死亡得到显著改善。相反，HMGA2缺失加剧了铁死亡。机制上，HMGA2通过转录和翻译调控激活GPX4表达。HMGA2通过增加H3K4甲基化和H3K27乙酰化来增强增强子活性，从而结合并促进GPX4基因启动子区域的顺式元件修饰。此外，HMGA2通过mTORC1-4EBP1和-S6K信号轴刺激GPX4蛋白合成。HMGA2的过表达缓解了mTORC1药理学抑制导致的GPX4蛋白水平下降。相反，与对照组相比，HMGA2缺失更强烈地降低了4EBP1和S6K的磷酸化。使用免疫组织化学染色证实了HMGA2和GPX4表达之间的强正相关。研究人员还证明，HMGA2减轻了癌细胞对铁死亡诱导剂和mTORC1抑制剂或吉西他滨联合治疗的敏感性。研究结果揭示了HMGA2协调GPX4表达的调控机制，并强调了靶向HMGA2在癌症治疗中的潜在价值。研究结论 03 综上所述，本研究阐明了HMGA2通过抑制铁死亡来增强胰腺癌细胞死亡抵抗力的机制。这是通过激活mTOR信号通路和随之而来的GPX4水平增加实现的。这些发现为未来克服胰腺癌化疗耐药性的治疗方法提供了潜在的靶点。参考资料：https://www-nature-com.libproxy1.nus.edu.sg/articles/s41419-024-06592-y识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

人口老龄化是21世纪全球重大挑战之一1。随着年龄增长，老年群体因新冠感染住院和死亡的比例远高于年轻群体，且老年性疾病如心脑血管疾病、阿尔兹海默症和癌症等的发病率与严重程度与日俱增，生活质量逐渐下降1,2。值得庆幸的是，科学研究显示，恰当的药物介入或能有效地进行抗衰老干预，提升老年人生活质量并降低疾病风险3。雷帕霉素（Rapamycin），一种过去普遍用于治疗癌症和对抗器官移植排斥的药物，因其可以在多种模式动物中稳定的延长寿命且提高老年动物的健康水平而被科学家们公认为目前最有前途的抗衰老候选药之一3。目前已知雷帕霉素通过作用于TORC1（Target of Rapamycin Complex 1）下游的自噬（Autophagy）和S6蛋白激酶（S6K）从而调控衰老进程4。尽管早在2009年已有研究证明了S6K的缺失能延长小鼠寿命5，但其具体作用机制至今依然不明确。2024年2月27日，来自德国马克斯普朗克衰老生物学研究所和英国伦敦大学学院健康衰老研究所的Linda Partridge教授课题组（张平仄博士为论文的第一作者）在Nature Aging杂志在线发表了题为Inhibition of S6K lowers age-related inflammation and increases lifespan through the endolysosomal system的研究论文。这项研究借助果蝇和小鼠为模型，揭示了S6K调控寿命和免疫系统衰老的机制，确立了内吞溶酶体系统在衰老过程中的重要作用，并指出了衰老过程中的性别差异。 研究团队首先借助果蝇模型探索了S6K延寿机制的保守性和组织特异性。研究表明，尽管在成年果蝇的神经组织、肌肉、肠道和心脏管中降低S6K水平并不能延长寿命，但在脂肪体（功能类似于哺乳动物肝脏和白色脂肪组织）中，降低S6K水平不仅延长了果蝇的寿命，且在脂肪体中过表达高活性S6K也可阻断雷帕霉素的延寿效果。这证明了成年果蝇的脂肪体是TORC1-S6K通路调控衰老的关键组织。进一步的蛋白组学研究发现，在年轻果蝇的脂肪体中S6K的活性可以影响溶酶体和自噬相关的通路。尽管共聚焦显微镜结果显示雷帕霉素能上调脂肪体内的溶酶体信号，但过表达S6K并未阻止此变化，反而导致了异常的巨型溶酶体形成。研究人员通过电子显微镜观察，发现这些巨型溶酶体是由多层溶酶体结构聚集形成的。这些多层结构溶酶体的形成机制是什么呢？在排除了自噬和溶酶体生成（Lysosome biogenesis）的可能性后，研究人员注意到蛋白组学分析中出现了内体融合（Endosomal vesical fusion）相关蛋白的富集，推测这些结构可能是由于晚期内体（Late endosome）和溶酶体的膜融合障碍造成的。随后的实验证明了与细胞膜融合相关的SNARE蛋白Syx13（Syntaxin 13）是决定S6K引起的内吞溶酶体（Endolysosome）形态改变的关键。然而，这些内吞溶酶体的改变均发生在年轻果蝇的脂肪体中，S6K是如何调控衰老的？在老年果蝇的脂肪体中，雷帕霉素和S6K敲减都影响了免疫反应（antibacterial humoral response及defense response）相关蛋白的富集，并降低了IMD通路（Immune deficiency pathway，其功能和机制类似于哺乳动物的NF-kB通路）下游分子的表达水平。研究人员发现通过抑制S6K活性，可以降低老年果蝇脂肪体中IMD通路介导的衰老相关性炎症（又名为炎症性衰老，Inflammaging）并改善因衰老引起的免疫功能降低（又名为免疫衰老，Immunosenescence）。有趣的是，通过抑制脂肪体内的炎症性衰老，可以提升老年果蝇的免疫功能并延长寿命，说明炎症性衰老是导致衰老和老年个体免疫功能下降的关键因素之一。鉴于先前的发现，即S6K能够通过影响Syx13来改变年轻果蝇脂肪体中的内吞溶酶体形态，研究人员推测雷帕霉素和S6K可能通过调控内吞溶酶体来影响免疫系统衰老和寿命。实验结果确实表明，无论是抑制初级内体（Early endosome）还是次级内体（Late endosome）的功能，都能有效阻断雷帕霉素对炎症性衰老的改善效果。研究者进一步探讨了这些内体如何调控炎症性衰老，并重点关注了与内体运输相关的免疫调控因子。IMD通路的受体PGRP-LC具有一个调控性亚型rPGRP-LC（Regulatory PGRP-LC），其在感染后可以通过初级内体的运输来抑制过度炎症反应6。由于发现rPGRP-LC和S6K诱导的巨型内吞溶酶体高度共定位，研究人员据此探索了其在炎症性衰老的作用。结果显示，在中年果蝇中，rPGRP-LC的过表达能够激活IMD通路，并在老年果蝇中抵消雷帕霉素对炎症性衰老的改善效果。此外，作为S6K的下游靶点，Syx13也对炎症性衰老、免疫衰老和寿命调控起到了关键作用，说明TORC1-S6K-Syx13信号通路通过内吞溶酶体系统调控免疫系统衰老和寿命。研究还揭示了性别在炎症性衰老中的差异，发现在雌性果蝇中，炎症性衰老比雄性更加严重，而且雷帕霉素喂养或S6K敲减并未在雄性中显著降低炎症水平，提示未来的衰老研究中需要重视性别因素。此外，研究人员发现雷帕霉素喂养不仅在果蝇中显示出延长寿命的效果，也在小鼠肝脏中提高了Stx12/13（Syntaxin 12/13）的水平，并且抑制了与衰老相关的非典型NF-κB信号通路（Noncanonical NF-κB signaling）的激活，表明TORC1-S6K通路对内吞溶酶体和炎症性衰老的调控效应在进化上具有保守性。 总的来说，这项研究揭露了TORC1-S6K-Syx13信号通路在炎症性衰老、免疫衰老和寿命调控中的核心作用，这一作用在从无脊椎动物到哺乳动物的演变过程中高度保守。研究结果为雷帕霉素和S6K调控在模型生物中的寿命增益和免疫益处提供了机制性的阐释。此外，这项研究确立了内吞溶酶体系统作为一个全新的细胞机制，它介导了雷帕霉素和S6K对免疫系统衰老和寿命的调控作用，从而为我们理解衰老过程打开了新的视角，并为未来衰老相关的研究与治疗提供了新的方向。本文的第一作者为张平仄博士，原为马克斯普朗克衰老生物学研究所博士生，现为耶鲁大学博士后。本文通讯作者为马克斯普朗克衰老生物学研究所创始所长、英国皇家学会副会长、伦敦大学学院健康衰老研究所Linda Partridge教授和马克斯普朗克衰老生物学研究所资深博士后Sebastian Grönke博士。  参考文献：1 Partridge, L., Deelen, J. & Slagboom, P. E. Facing up to the global challenges of ageing. Nature 561, 45-56 (2018). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-018-0457-82 Chen, Y. et al. Aging in COVID-19: Vulnerability, immunity and intervention. Ageing Res Rev 65, 101205 (2021). https://doi-org.libproxy1.nus.edu.sg/10.1016/j.arr.2020.1012053 Partridge, L., Fuentealba, M. & Kennedy, B. K. The quest to slow ageing through drug discovery. Nat Rev Drug Discov 19, 513-532 (2020). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41573-020-0067-74 Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab 11, 35-46 (2010). https://doi-org.libproxy1.nus.edu.sg/10.1016/j.cmet.2009.11.0105 Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140-144 (2009). https://doi-org.libproxy1.nus.edu.sg/10.1126/science.11772216 Neyen, C., Runchel, C., Schupfer, F., Meier, P. & Lemaitre, B. The regulatory isoform rPGRP-LC induces immune resolution via endosomal degradation of receptors. Nat Immunol 17, 1150-1158 (2016). https://doi-org.libproxy1.nus.edu.sg/10.1038/ni.3536本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

Highlights: Monepantel displays a superior safety, tolerability to the leading FDA approved drug Relyvrio® Preliminary efficacy data shows a 58% reduction in the rate of disease progression for Cohort 2 (High Dose) using the FDA primary efficacy endpoint, ALSFRS-R Confirmation that monepantel and its active metabolite, monepantel sulfone, are both detected in cerebrospinal fluid Optimal dose identified for the pivotal Phase 2/3 clinical study, due to commence in Q3 CY2024 PERTH, Australia, Feb. 28, 2024 /PRNewswire/ -- PharmAust Limited (ASX: PAA & PAAOA) ("PharmAust" or "the Company"), a clinical-stage biotechnology company, is pleased to announce that it has met its primary safety and tolerability endpoints with monepantel (MPL) and, importantly, demonstrated a positive signal of potential efficacy. Rates of disease progression in patients with Motor Neurone Disease (MND) / Amyotrophic Lateral Sclerosis (ALS) measured by changes in ALSFRS-R may be slowed by 58% for Cohort 2, when compared to an external control cohort (PRO-ACT database). Study Design The Phase 1 MEND Study was a multicentre, open label study comprising a 24-hour escalating single-dose PK study and 4-week repeated escalating dose study to establish the safety, tolerability and pharmacokinetic (PK) parameters of MPL administered orally to patients with MND/ALS. Twelve participants were enrolled in cohorts of 6 patients across 2 sites. Cohort 1 was administered 2 and 6 mg/kg/day dose levels, and Cohort 2 was administered 4 and 10 mg/kg/day dose levels. Participants continued to receive MPL treatment until they were offered dose escalation or until the end of treatment. Safety and Tolerability Endpoints The safety and tolerability profile of MPL included no treatment‑related deaths, with all 12 patients successfully completing the study, and no dose limiting toxicities experienced. A total of 56 treatment‑emergent Adverse Events (AEs) were reported. Only 3 AEs, graded mild, were considered possibly related to the study drug. Patients have remained on daily treatment of MPL for 10 to 16 months. Upon completing the study, all participants continued receiving MPL via a special access scheme and opted to enrol on a 12-month open-label extension (OLE) study. Exploratory Efficacy Endpoints The study's exploratory clinical efficacy markers included the ALS Functional Rating Scale-Revised ("ALSFRS-R"), ALSSQOL-R Quality of Life Questionnaire, Edinburgh Cognitive and Behavioural ALS Screen ("ECAS") and Slow Vital Capacity ("SVC"), a measure of respiratory function. ALSFRS-R is the accepted FDA primary efficacy measure to determine ALS disease progression. It assesses for changes in a person's physical abilities over time of 12 specific functions including speech, walking, climbing stairs, dressing/hygiene, handwriting, turning in bed, cutting food, salivation, swallowing and breathing. There were no significant differences in ALSFRS-R scores between pre-dose and end of treatment for all 12 patients (p=0.78), Cohort 1 (p=0.41), and Cohort 2 (p=0.88) suggesting that treatment with monepantel over 8 – 12 months slowed the rate of disease progression. A more thorough comparative analysis of the rate of decline in ALSFRS-R scores performed by Berry Consultants against 30 matched controls from the PRO-ACT database for ALSFRS-R decline has highlighted the potential for MPL to tackle disease burden and slow disease progression. The PRO-ACT database is the largest publicly available repository of merged ALS clinical study data. Clinical study data were pooled from 16 completed Phase 2/3 ALS/MND clinical studies and one observational study. Over 8 million de-identified longitudinally collected data points from more than 8,600 persons with ALS were standardised across studies and merged to create the PRO-ACT database. This database includes demographics, family histories, and longitudinal clinical and laboratory data. Matching is a procedure that finds treatment and control subjects with similar baseline characteristics to enable treatment effect estimation. For all 12 patients, the estimated rate of decline was -0.74 (p=0.08) in ALSFRS-R points per month or a 39% slowing in ALSFRS-R decline. For Cohort 1 the estimated rate of decline was -0.83 (p=0.40) in ALSFRS-R points per month or a 23% slowing in ALSFRS-R decline. For Cohort 2 the estimated rate of decline was -0.60 (p=0.11) in ALSFRS-R points per month or a 58% slowing in ALSFRS-R decline indicating a dose response. Using the prognostic predictor model described in Elamin et al., 2015, [1]depending on the current severity of the disease, a 0.48 slope change as calculated for all 12 patients could provide patients with an additional 13.5- 56.5 months in median survival. Currently approved treatments for ALS/MND provide approximately 2 – 9 months in additional life expectancy. * Berry Consultants analysis. ** Duration is dependent upon disease severity at baseline. The results of the additional exploratory efficacy measures of ALSSQOL-R (p=0.11), ECAS (p=0.21), and SVC (p=0.93) further supported slowing in disease progression. In addition, the analysis of biomarkers provided supplemental supporting evidence that MPL slows disease progression with a large reduction in cerebrospinal fluid neurofilament light chain (NfL), which is a measure of neuronal damage, amongst consenting patients (n=3). Pharmacokinetics Concentrations of MPL sulfone, the active metabolite of MPL, increased proportionally with the higher doses of MPL. MPLS was found in the cerebrospinal fluid indicating that both MPL and MPLS have the ability to cross the blood brain barrier. Target Engagement (mTOR Pathway) Target engagement of the mTOR pathway (p-EIF4EBP1 and p-RPS6KB1) in the peripheral mononuclear blood cells was confirmed at all dose levels. MEND participant, S-W, commented: "The Monepantel phase 1 study has been a very positive experience for me with no ill effects at all. At Calvary I have been treated with the most kind, caring and considerate doctors, nursing & administration staff and I know I am receiving the best care possible. I am more than happy to participate in this trial with the knowledge that MND patients may be helped in the future." MEND participant, L-G, commented: "I feel that the Monepantel may have slowed my neurological deterioration. Increasing dosage from 3 per day to 4 may also have been beneficial. My dosage was increased to 6 several days ago. There appears to be no side effects with it." Associate Professor Susan Mathers commented: "This study has shown oral Monepantel to be safe and well tolerated by people with MND. Given the promising findings on preliminary efficacy markers, I look forward to progressing a phase 2 study as soon as possible" PharmAust Chief Executive Officer Dr Michael Thurn commented: "The release of the top-line Phase 1 MEND study results is an exciting milestone for PharmAust as we take a significant step towards helping people diagnosed with this rare and incurable disease. The 58% slowing in ALSFRS-R decline amongst Cohort 2 participants clearly demonstrates the potential to provide meaningful clinical benefit to people living with MND/ALS. To know that we have potentially prolonged the lives of 12 patients is extremely satisfying and humbling. We now look forward to advancing discussions with strategic partners who share our vision for monepantel. I want to thank the trial participants, their caregivers, and families, as well as the sites' principal investigators, Associate Professor Susan Mathers and Professor Dominic Rowe, and their study coordinators for their tremendous ongoing contribution to the MEND study." PharmAust acknowledges the support of FightMND and its donors, in particular the patients, their families and friends and their support network. About FightMND Founded in 2014, FightMND was established in Australia with the purpose of finding effective treatments and ultimately a cure for Motor Neuron Disease (MND), also referred to as ALS or Lou Gehrig's Disease. FightMND, with its vision of a world without MND, is one of the largest independent funders of MND research in the world. Since 2014, FightMND has investment more than $98 million into MND research and care equipment to improve the lives of those fighting the disease. FightMND is determined to help facilitate the translation of the growing body of new knowledge about the disease into a cure for MND patients in Australia and abroad. For more information about FightMND, visit the website at About Berry Consultants Berry Consultants is a statistical consulting company based in Austin, Texas USA, specialising in innovative clinical trial design, analysis, execution, and software solutions for the pharmaceutical and medical device industry. Berry Consultants employs world-renowned experts in Bayesian statistics and strives to set the standard for adaptive clinical trial design and analysis across all medical disciplines. The Board authorises this announcement. Enquiries: Dr Michael Thurn Chief Executive Officer [email protected] Media: Matthew Wright NWR Communications [email protected] 0451 896 420 P +61 (8) 9202 6814 F +61 (8) 9467 6111 About PharmAust Limited: PharmAust Limited is listed on the Australian Securities Exchange (ASX Code: PAA). PAA is a clinical-stage biotechnology company developing therapeutics for human and animal health applications. The company is focused on repurposing monepantel (MPL) for human neurodegenerative diseases and treating cancer in dogs. MPL is a potent and safe inhibitor of the mTOR pathway. This pathway plays a central role in cell growth and proliferation of cancer cells and degenerating neurons. The mTOR pathway regulates the cellular "cleaning process", where toxic protein is broken down into macromolecules to be reused. This autophagic process is disrupted in most neurodegenerative diseases, including motor neurone disease (MND/ALS). PAA's lead MPL program is for the treatment of MND/ALS, a rare, incurable disease. The company is currently completing a Phase 1 study in patients with MND/ALS. Top-line results are expected to be announced in Q1 CY2024. PAA anticipates starting an adaptive Phase 2/3 clinical study in H2 CY 2024 that could lead to accelerated approval with the US Food and Drug Administration in 2026. PAA is preparing to start a pivotal field trial in dogs with B-Cell Lymphoma to enable product registration in the US in 2025. PAA has previously successfully completed a Phase 1 oncology clinical study of monepantel in humans and pilot studies in canine cancer. SOURCE PharmAust Limited