更新于：2024-11-01

mTOR

更新于：2024-11-01

基本信息

别名

dJ576K7.1 (FK506 binding protein 12-rapamycin associated protein 1)、FK506 binding protein 12-rapamycin associated protein 1、FK506 binding protein 12-rapamycin associated protein 2

+ [21]

简介

Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2) (PubMed:15268862, PubMed:15467718, PubMed:18925875, PubMed:18497260, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E) (By similarity). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4 (PubMed:12150925, PubMed:12087098, PubMed:18925875). This also includes mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3: in the presence of nutrients, mediates phosphorylation of TFEB and TFE3, promoting their cytosolic retention and inactivation (PubMed:22576015, PubMed:22343943, PubMed:22692423). Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity (PubMed:22576015, PubMed:22343943, PubMed:22692423). Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex (PubMed:23429704, PubMed:23429703). Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor (PubMed:20516213). In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1 (By similarity). To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A (By similarity). mTORC1 also negatively regulates autophagy through phosphorylation of ULK1 (By similarity). Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1 (By similarity). Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP (PubMed:20537536). Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions (PubMed:30704899). Prevents autophagy by mediating phosphorylation of AMBRA1, thereby inhibiting AMBRA1 ability to mediate ubiquitination of ULK1 and interaction between AMBRA1 and PPP2CA (PubMed:23524951, PubMed:25438055). mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor (PubMed:21659604). Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules (PubMed:12231510). As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton (PubMed:15268862, PubMed:15467718). Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1 (PubMed:15718470). mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B (PubMed:15268862). mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422' (PubMed:18925875). Regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms (By similarity). Plays an important regulatory role in the circadian clock function; regulates period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks (By similarity). Phosphorylates SQSTM1, promoting interaction between SQSTM1 and KEAP1 and subsequent inactivation of the BCR(KEAP1) complex (By similarity). Activates dormant ribosomes by mediating phosphorylation of SERBP1, leading to SERBP1 inactivation and reactivation of translation (PubMed:36691768).

关联

145

项与 mTOR 相关的药物

Sirolimus Albumin-Bound

西罗莫司(白蛋白结合型)

靶点

MUT x mTOR

作用机制

MUT刺激剂 [+3]

在研机构

Aadi Bioscience, Inc. [+5]

原研机构

Abraxis BioScience, Inc.

在研适应症

血管周围上皮样细胞肿瘤 [+19]

非在研适应症

晚期肉瘤 [+16]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2021-11-22

Zotarolimus

佐他莫司

靶点

mTOR

作用机制

mTOR抑制剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段批准上市

首次获批国家/地区

加拿大

首次获批日期2008-05-16

Umirolimus

乌米莫司

靶点

mTOR

作用机制

mTOR抑制剂

在研机构-

原研机构

Biosensors International Group Ltd.

在研适应症

冠状动脉再狭窄

非在研适应症

冠心病

最高研发阶段批准上市

首次获批国家/地区-

首次获批日期2008-04-03

1,283

项与 mTOR 相关的临床试验

NCT04199026 / Not yet recruiting早期临床1期IIT

Pilot Trial of an Implantable Microdevice for In Vivo Drug Sensitivity Testing in Patients With Sarcomas

This early phase I trial studies the side effects of implanting and removing a microdevice in patients with sarcomas that have spread to other places in the body (metastatic) or have come back (recurrent). Microdevices are rice-sized devices that are implanted into tumor tissue and are loaded with 10 different drugs that are delivered at very small doses, or "microdoses," which may only affect a very small, local area inside the tumor. The purpose of this study is to determine which drugs delivered in the microdevice affect tumor tissue in patients with sarcomas.

开始日期2025-01-31

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+1]

NCT06658093 / Not yet recruiting早期临床1期IIT

RESTOR [Rapamycin and Everolimus Study Towards Older Rejuvenation]: An Exploratory PK/PD Study of mTOR Inhibition in Older Human Subjects

As people get older, there are changes in their cells and tissues that may affect their ability to function. This can lead to increased death and age-associated disorders, like heart disease, cancer, and Alzheimer's disease. Studies in animal models have been able to identify drugs that slow the aging process, leading to a longer, healthier life. This study is focused on one such family of drugs, called mTOR inhibitors, and the investigators' goal is to test two of these drugs, Rapamycin (Sirolimus) and Everolimus (Afinitor), in healthy older adults to find a dose and dose timing that can be used to safely inhibit mTOR to the levels seen in young healthy persons. The investigators expect that the dose that works well in women may differ from the one that is best in men, so it is important to include both sexes in this research.

开始日期2025-01-01

申办/合作机构

University of Texas Health Science Center At San Antonio

[+1]

NCT04736953 / Not yet recruiting临床2期IIT

Sirolimus Treatment of Patients With Systemic Lupus Erythematosus

Phase II Double-blind, placebo-controlled, randomized treatment trial with two arms: one SIROLIMUS arm with 92 patients and one placebo arm with 92 patients. The safety and therapeutic efficacy of SIROLIMUS will be determined within a dosage range of 1 mg/day to 4 mg/day, which will be titrated to tolerance during an initial 3-month open label period, relative to placebo in SLE patients over 12 months followed by a 1-month washout. The proposed study design, known as an enriched enrollment randomized withdrawal (EERW), has major advantages that (1) only people who tolerate SIROLIMUS are randomized, potentially reducing the percentage of dropouts in the randomized phase and (2) it allows participants to use an individualized dosage of study medication, which mimics clinical practice in terms of how SIROLIMUS would be administered. Healthy subjects receive no drugs and serve as controls for in vitro studies.

开始日期2025-01-01

申办/合作机构

SUNY Upstate Medical University

100 项与 mTOR 相关的临床结果

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100 项与 mTOR 相关的转化医学

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0 项与 mTOR 相关的专利（医药）

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45,285

项与 mTOR 相关的文献（医药）

2025-12-01·Journal of Clinical Immunology

Novel Compound Heterozygous Variants in the FAS Gene Lead to Fetal Onset of Autoimmune Lymphoproliferative Syndrome (ALPS)

Article

作者: Yu, Meiping ; Wu, Bingbing ; Zhu, Li ; Chen, Yao ; Wang, Chenghao ; Li, Qifan ; Qian, Feng ; Zhou, Weitao ; Liu, Luyao ; Wu, Qi ; Hui, Xiaoying ; Hou, Jia ; Zhou, Qinhua ; Sun, Bijun ; Wang, Xiaochuan ; Wang, Ying ; Sun, Jinqiao ; Ying, Wenjing ; Wang, Wenjie

OBJECTIVEFAS gene defects lead to autoimmune lymphoproliferative syndrome (ALPS), which is often inherited in an autosomal dominant and rarely in an autosomal recessive manner. We report a case of a newborn girl with novel compound heterozygous variants in FAS and reveal the underlying mechanism.METHODSWhole-exome sequencing (WES) was used to identify pathogenic variants. Multiparametric flow cytometry analysis, phosflow analysis, and FAS-induced apoptosis assays were used to explore the effects of the variants on FAS expression, apoptosis, and immunophenotype. The HEK293T cells were used to assess the impact of the variants on protein expression and FAS-induced apoptosis.RESULTSThe patient was born with hepatosplenomegaly, anemia, and thrombocytopenia. She also experienced COVID-19, rotavirus infection, herpes simplex virus infection, and severe pneumonia. The proportion of double-negative T cells (DNTs) was significantly elevated. Novel FAS compound heterozygous variants c.310T > A (p.C104S) and c.702_704del (p.T235del) were identified. The apoptotic ability of T cells was defective, and FAS expression on the surface of T cells was deficient. The T235del variant decreased FAS expression, and the C104S protein remained in the endoplasmic reticulum (ER) and could not translocate to the cell surface. Both mutations resulted in loss-of-function in terms of FAS-induced apoptosis in HEK293T cells. The DNTs were mainly terminally differentiated T (TEMRA) and CD45RA⁺HLA-DR⁺, with high expression of CD85j, PD-1, and CD57. The percentage of Th1, Tfh, and autoreactive B cells were significantly increased in the patient. The abnormal immunophenotyping was partially attenuated by sirolimus treatment.CONCLUSIONSWe identified two variants that significantly affect FAS expression or localization, leading to early disease onset of in the fetus. Abnormalities in the mTOR pathway are associated with a favorable response to sirolimus.

2025-04-01·Neural Regeneration Research

Perfluoropentane-based oxygen-loaded nanodroplets reduce microglial activation through metabolic reprogramming

Article

作者: Li, Yingjia ; Ji, Yunxiang ; Xu, Chuanhui ; Wang, Yezhong ; Ye, Yongyi ; Luo, Wanxian ; Li, Linxi

JOURNAL/nrgr/04.03/01300535-202504000-00032/figure1/v/2024-07-06T104127Z/r/image-tiff Microglia, the primary immune cells within the brain, have gained recognition as a promising therapeutic target for managing neurodegenerative diseases within the central nervous system, including Parkinson’s disease. Nanoscale perfluorocarbon droplets have been reported to not only possess a high oxygen-carrying capacity, but also exhibit remarkable anti-inflammatory properties. However, the role of perfluoropentane in microglia-mediated central inflammatory reactions remains poorly understood. In this study, we developed perfluoropentane-based oxygen-loaded nanodroplets (PFP-OLNDs) and found that pretreatment with these droplets suppressed the lipopolysaccharide-induced activation of M1-type microglia in vitro and in vivo, and suppressed microglial activation in a mouse model of Parkinson’s disease. Microglial suppression led to a reduction in the inflammatory response, oxidative stress, and cell migration capacity in vitro. Consequently, the neurotoxic effects were mitigated, which alleviated neuronal degeneration. Additionally, ultrahigh-performance liquid chromatography–tandem mass spectrometry showed that the anti-inflammatory effects of PFP-OLNDs mainly resulted from the modulation of microglial metabolic reprogramming. We further showed that PFP-OLNDs regulated microglial metabolic reprogramming through the AKT-mTOR-HIF-1α pathway. Collectively, our findings suggest that the novel PFP-OLNDs constructed in this study alleviate microglia-mediated central inflammatory reactions through metabolic reprogramming.

2025-03-01·Biomaterials

Maintaining myoprotein and redox homeostasis via an orally recharged nanoparticulate supplement potentiates sarcopenia treatment

Article

作者: Song, Xiaoyu ; Xu, Yingxi ; Xie, Xiaochun ; Wang, Xiaoxun ; Sun, Huayi ; Yu, Yang ; Huang, Runnian ; Cao, Liu ; Ma, Chunhua ; Wang, Difei ; Sun, Chen ; Chen, Fangman ; Yuan, Xiaoyue ; Xun, Zhe ; Jiang, Xuehan ; Yu, Tianhao ; Shao, Dan ; Shi, Xuetao ; Li, Yibai ; Liu, Xu ; Liu, Xiyan

Sarcopenia is a progressive skeletal muscle disorder characterized by the accelerated loss of muscle mass and function, with no promising pharmacotherapies. Understanding the imbalance of myoprotein homeostasis within myotubes, which causes sarcopenia, may facilitate the development of novel treatments for clinical use. In this study, we found a strong correlation between low serum selenium levels and muscle function in elderly patients with sarcopenia. We hypothesized that supplementation with selenium might be beneficial for the management of sarcopenia. To verify this hypothesis, we developed diselenide-bridged mesoporous silica nanoparticles (Se-Se-MSNs) with ROS-responsive degradation and release to supplement selenium. Se-Se-MSNs outperformed free selenocysteine in alleviating sarcopenia in both dexamethasone (Dex)- and denervation-induced mouse models. Subsequently, Se-Se-MSNs were loaded with leucine (Leu@Se-Se-MSNs), another nutritional supplement used in sarcopenia management. Oral administration of Leu@Se-Se-MSNs restored myoprotein homeostasis by enhancing mTOR/S6K signaling and inactivating Akt/FoxO3a/MuRF1 signaling, thus exerting optimal therapeutic effects against sarcopenia and exhibiting a more favorable in vivo safety profile. This study provides a proof of concept for treating sarcopenia by maintaining myoprotein and redox homeostasis simultaneously and offers valuable insights into the development of multifunctional nanoparticle-based supplements for sarcopenia management.

687

项与 mTOR 相关的新闻（医药）

2024-10-26

·生物探索

Cell Metab | 李珂团队合作揭示脂肪细胞谷胱甘肽在肥胖乳腺癌进展中的关键作用

引言肥胖是多种癌症类型的一个主要的诱因【1】。在与肥胖相关的女性癌症中，乳腺癌是导致死亡的主要原因【2-4】。既往研究表明，肥胖能够诱导乳腺肿瘤微环境（TME）的代谢改变和以脂肪为主的局部修饰从而促进癌症进展【5】。然而肥胖诱导的肿瘤微环境代谢物对乳腺癌生长和转移的影响尚不清楚，因此探究肥胖与乳腺癌之间的串扰因素及机制对改善肥胖乳腺癌患者的治疗效果至关重要。 2024年10月22日，中国医学科学院&北京协和医学院医药生物技术研究所李珂团队及李卓荣团队在Cell Metabolism杂志上发表题为Adipocyte-Derived Glutathione Promotes Obesity-Related Breast Cancer by Regulating the SCARB2-ARF1-mTORC1 Complex的研究论文【6】。李珂团队长期致力于乳腺癌发生发展的分子机制探究。先前研究成果表明，FGD5通过维持肿瘤起始细胞样性状促进基底样乳腺癌发生和发展【7】。本研究发现高脂饮食（HFD）诱导脂肪细胞谷胱甘肽（GSH）分泌增多，GSH通过经典摄入转运体进入肿瘤细胞，通过溶酶体膜表面的溶酶体膜蛋白2（SCARB2）活化mTORC1信号通路，促进肥胖相关乳腺癌的进展。作者首先建立了饮食诱导肥胖（DIO）的小鼠模型研究肥胖对乳腺癌进展的影响。相较于正常膳食组（NCD），HFD组小鼠表现出更快的肿瘤生长速度，且瘤体积更大，肺部转移更为严重。于是，作者检测了NCD和HFD组小鼠的肿瘤微环境（TME）代谢产物，从中筛选出了十个差异最为显著的代谢物，并通过体外和体内实验确定了代谢物中GSH的促肿瘤作用。有趣的是，作者发现，抑制肿瘤细胞内部的GSH生成对于肥胖相关乳腺癌的进展没有显著影响，这提示肿瘤微环境中的GSH可能是肥胖促乳腺癌进展的主要因素。为了阐明GSH的来源，作者对小鼠肿瘤组织进行了多重免疫荧光染色，发现GSH在HFD小鼠肿瘤组织的脂肪细胞（脂联素阳性）中有较强的聚集。此外，作者观察到肥胖乳腺癌患者的脂肪细胞而不是肿瘤细胞表现出比非肥胖患者更高水平的谷氨酸半胱氨酸连接酶（GCLC），表明肥胖患者脂肪细胞中GSH合成的能力增强。此外，与非肥胖患者相比，肥胖乳腺癌患者的脂肪细胞和肿瘤细胞显示出更高水平的GSH。随后作者利用sgRNA敲低前脂肪细胞（3T3-L1）中GCLC的内源性表达，用以上脂肪细胞的培养上清培养乳腺癌细胞，发现脂肪细胞分泌物能够促进乳腺癌细胞的增殖和侵袭，而GCLC缺失组促乳腺癌增殖和侵袭的能力减弱。最终，作者建立了脂肪细胞特异性缺失GCLC的转基因小鼠模型，发现脂肪细胞GSH合成能力受损阻碍HFD的促乳腺癌进展作用。据此作者推测脂肪细胞在肿瘤微环境中分泌的GSH是肥胖促进相关乳腺癌进展的关键因素。随后，作者关注GSH促进乳腺癌进展的机制，发现GSH能够进入肿瘤细胞，并定位于溶酶体表面。基于质谱法（MS）的蛋白质组学分析、RNA-seq分析和生化分析，作者发现GSH与溶酶体膜表面蛋白SCARB2结合进而激活mTORC1信号通路。并探索了GSH诱导mTOR的激活机制，发现GSH干扰SCARB2蛋白的N末端与C末端相互作用，促使SCARB2的N端暴露从而与GTP酶ARF1结合，促进了ARF1和mLST8的相互作用以募集mTORC1溶酶体定位，从而活化mTORC1信号通路。模式图（Credit: Cell Metabolism）综上所述，HFD导致脂肪细胞GSH分泌增多，外源性GSH进入肿瘤细胞后，与溶酶体膜表面SCARB2结合，并通过SCARB2-ARF1复合物激活mTORC1信号通路，从而促进肥胖相关乳腺癌的进展。该研究揭示了脂肪细胞来源的GSH在肥胖加速乳腺癌进展中的作用；阐明了GSH介导mTORC1活化的全新形式；并首次提出SCARB2作为GSH的新型传感器在调节mTORC1信号通路的作用。这些发现强调了靶向GSH/SCARB2/ARF1/mTOR轴能够为肥胖乳腺癌患者的有效治疗提供潜在策略。参考文献 1. Lauby-Secretan, B., C. Scoccianti, D. Loomis, Y. Grosse, F. Bianchini, K. Straif, and G. International Agency for Research on Cancer Handbook Working. (2016). Body Fatness and Cancer--Viewpoint of the IARC Working Group. N Engl J Med. 375, 794-8. https://doi.org/10.1056/NEJMsr1606602 2. Reaves, D.K., E. Ginsburg, J.J. Bang, and J.M. Fleming. (2015). Persistent organic pollutants and obesity: are they potential mechanisms for breast cancer promotion? Endocr Relat Cancer. 22, R69-86. https://doi.org/10.1530/ERC-14-0411 3. Bray, F., J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, and A. Jemal. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68, 394-424. https://doi.org/10.3322/caac.21492 4. White, A.J., H.B. Nichols, P.T. Bradshaw, and D.P. Sandler. (2015). Overall and central adiposity and breast cancer risk in the Sister Study. Cancer. 121, 3700-8. https://doi.org/10.1002/cncr.29552 5. Sanchez-Jimenez, F., A. Perez-Perez, L. de la Cruz-Merino, and V. Sanchez-Margalet. (2019). Obesity and Breast Cancer: Role of Leptin. Front Oncol. 9, 596. https://doi.org/10.3389/fonc.2019.00596 6. Chenxi Zhao, T.Z., Si-tu Xue, Peitao Zhang, Feng Wang, Yunxuan Li, Ying Liu, Luyao Zhao, Jie Wu, Yechao Yan, Xiaoyun Mao, Yuping Chen, Jian Yuan, Zhuorong Li, and Ke Li. (2024). Adipocyte-derived glutathione promotes obesity-related breast cancer by regulating the SCARB2-ARF1- mTORC1 complex. Cell Metabolism. https://doi.org/https://doi.org/10.1016/j.cmet.2024.09.013 7. Li, K., T.T. Zhang, C.X. Zhao, F. Wang, B. Cui, Z.N. Yang, X.X. Lv, Z. Yeerjiang, Y.F. Yuan, J.M. Yu, Z.H. Wang, X.W. Zhang, J.J. Yu, S.S. Liu, S. Shang, B. Huang, F. Hua, and Z.W. Hu. (2021). Faciogenital Dysplasia 5 supports cancer stem cell traits in basal-like breast cancer by enhancing EGFR stability. Sci Transl Med. 13. https://doi.org/10.1126/scitranslmed.abb2914 https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00395-4 责编|探索君排版|探索君来源|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

临床研究

2024-10-26

·GlobeNewswire-Health Care

Kura Oncology to Present New Data Supporting Combination of KO-2806 with KRAS G12C and Pan-RAS Inhibitors

– New preclinical data to be presented at EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics – Oct. 23, 2024 -- Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer, today announced the upcoming presentation of new preclinical data supporting the combination of its next-generation farnesyl transferase inhibitor (FTI) KO-2806 with targeted therapies, including KRASG12C inhibitors and pan-RAS inhibitors, at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain. “We look forward to presenting an update to our growing body of preclinical and clinical data that demonstrate the potential of KO-2806 as a companion therapeutic to augment the antitumor activities of KRASG12C and pan-RAS inhibitors,” said Troy Wilson, Ph.D., J.D., President and Chief Executive Officer of Kura Oncology. “These findings support the promising therapeutic strategy of blunting the effects of innate and adaptive resistance to targeted agents to treat cancers driven by KRAS mutations, including KRASG12C non-small cell lung cancer (NSCLC) and KRAS-mutant colorectal cancers. If successful, we believe KO-2806 could drive enhanced antitumor activity and become a combination partner to multiple targeted therapies in large solid tumor indications.” Details for the session titles and information for the two abstracts are listed below. Copies of the presentations will be available in the Posters and Presentations section on Kura’s website following presentation at the conference. KO-2806, a next-generation farnesyl transferase inhibitor, re-sensitizes KRAS G12C NSCLC tumors to KRAS G12C mutant-specific inhibitors through mTOR signaling inhibition Session Date and Time: Friday, October 25, 2024; 9:00 AM - 3:00 PM ET Session and Location: Drug Resistance and Modifiers, Exhibition Hall Poster Number: PB376 The next-generation farnesyl transferase inhibitor KO-2806 sensitizes colorectal cancers to pan-RAS inhibition Session Date and Time: Friday, October 25, 2024; 9:00 AM - 3:00 PM ET Session and Location: Drug Resistance and Modifiers, Exhibition Hall Poster Number: PB378 KO-2806 is a next-generation inhibitor of farnesyl transferase designed to improve upon the potency, pharmacokinetic and physicochemical properties of earlier FTI drug candidates. At the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Kura presented preclinical data supporting the rationale for combining KO-2806 with distinct classes of targeted therapies, including tyrosine kinase inhibitors, KRASG12C inhibitors and KRASG12D inhibitors. Kura is evaluating KO-2806 in a Phase 1 dose-escalation trial (FIT-001) as a monotherapy, in combination with cabozantinib in clear cell renal cell carcinoma and in combination with adagrasib in KRASG12C NSCLC. Additional information about clinical trials for KO-2806 can be found at https://kuraoncology.com/clinical-trials/#farnesyl-transferase-inhibitor. Kura Oncology is a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer. The Company’s pipeline consists of small molecule drug candidates that target cancer signaling pathways. Ziftomenib, a once-daily, oral drug candidate targeting the menin-KMT2A protein-protein interaction, has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration for the treatment of relapsed/refractory (R/R) NPM1-mutant AML. Kura has completed enrollment in a Phase 2 registration-directed trial of ziftomenib in R/R NPM1-mutant AML (KOMET-001). The Company is also conducting a series of clinical trials to evaluate ziftomenib in combination with current standards of care in newly diagnosed and R/R NPM1-mutant and KMT2A-rearranged AML. Kura is evaluating KO-2806, a next-generation FTI, in a Phase 1 dose-escalation trial as a monotherapy and in combination with targeted therapies (FIT-001). Tipifarnib, a potent and selective FTI, is currently in a Phase 1/2 trial in combination with alpelisib for patients with PIK3CA-dependent head and neck squamous cell carcinoma (KURRENT-HN). For additional information, please visit Kura’s website at www.kuraoncology.com and follow us on Twitter and LinkedIn. The content above comes from the network. if any infringement, please contact us to modify.

AACR会议临床结果突破性疗法

2024-10-25

·ioncology

甘露教授：精准医疗新突破——探索HR+/HER2-晚期乳腺癌患者的未来之路

点击上方蓝字关注我们编者按：激素受体阳性/人表皮生长因子受体2阴性（HR+/HER2-）乳腺癌是乳腺癌中最常见的亚型之一，约占总体乳腺癌的70%。这类患者晚期一线治疗通常依赖于内分泌治疗联合CDK4/6抑制剂，尽管这一方案显著延长了患者的无进展生存期（PFS），但大部分患者最终会出现耐药，导致疾病进展。因此，寻找新的有效治疗策略，以延长患者的生存期并提高生活质量，成为医学界亟待解决的问题。近年来，随着分子生物学研究的深入，PAM（PI3K/AKT/mTOR）信号通路在乳腺癌发生发展中的重要性逐渐凸显，为HR+/HER2-晚期乳腺癌的治疗提供了新的靶点。肿瘤瞭望特邀重庆医科大学附属第一医院甘露教授从HR+/HER2-晚期乳腺癌的治疗现状与挑战、PAM通路的重要性、后CDK4/6抑制剂时代患者治疗新选择等方面，深入探讨HR+/HER2-晚期乳腺癌患者的未来之路。一、HR+/HER2-晚期乳腺癌的治疗现状与挑战乳腺癌是全球女性最常见的恶性肿瘤，2020年中国乳腺癌新发病例41.6万例，死亡病例约11.7万例。在每年新发乳腺癌患者中，约3%～10%的患者在确诊时即有远处转移。早期患者中约有30%可发展为晚期乳腺癌，晚期乳腺癌患者5年生存率仅为20%，中位总生存时间为2～3年[1]。HR+/HER2-乳腺癌约占总体乳腺癌的70%，内分泌治疗是其重要治疗选择[2]。PALOMA、MONARCH、MONALIEESA、DAWAN等一系列研究显示[3-7]，CDK4/6抑制剂（哌柏西利、阿贝西利、瑞波西利和达尔西利）联合内分泌治疗，能显著提高乳腺癌患者的治疗敏感性，延长患者的生存时间。目前CDK4/6抑制剂联合内分泌治疗已成为HR+/HER2-晚期乳腺癌（不合并内脏危象）患者的一线治疗优选方案。 CDK4/6抑制剂联合芳香化酶抑制剂（aromatase inhibitor, AI）的临床研究结果显示（MONALEESA-2研究、PALOMA-2研究、MONARCH-3研究和DAWNA-2），一线使用 CDK4/6抑制剂联合AI后无进展生存期（PFS）约为2年左右（各研究结果存在差异），与AI单药相比，CDK4/6抑制剂联合AI方案均显著降低疾病进展风险近50%[2]。但CDK4/6抑制剂失败后的治疗选择是临床治疗难题，国内外指南无标准治疗方案推荐，且既往多项研究显示，与PAM通路正常的乳腺癌患者相比，存在通路基因改变者肿瘤进展风险更高，DFS及OS更差。二、PAM通路的重要性磷脂酰肌醇3-激酶（phosphoinositide 3-kinase，PI3K）/蛋白激酶B（protein kinase，AKT）/哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）信号转导通路（简称PAM通路）的过度活化广泛存在于各类癌种，包括乳腺癌、肺癌、头颈部肿瘤、子宫内膜癌、前列腺癌、结直肠癌等，调节肿瘤细胞存活、增殖、分化、凋亡等多种过程，从而对肿瘤的发生、发展起到关键性作用[8-9]。PAM信号通路过度激活是内分泌治疗、化疗、靶向治疗耐药的重要机制之一，不仅使乳腺癌细胞适应雌激素剥夺，通过多药耐药相关蛋白和抗凋亡作用促进化疗耐药，还通过激活PAM信号通路相关蛋白参与CDK4/6抑制剂和抗HER2治疗耐药的发生[10]。尽管HR+/HER2-乳腺癌细胞对CDK4/6抑制剂耐药的机制多种多样，但PAM信号通路表达上调是常见的，在HR+乳腺癌中，约30%～40%的患者存在PAM信号通路被激活的现象[11]，因此，PAM信号通路可能成为逆转耐药性的重要靶点[12]。一项针对中国乳腺癌患者的研究显示，PAM通路突变率高达62.6%，高于欧美人群，其中PIK3CA突变率为45%，这些突变的数量和位置对患者的预后有显著影响[13]。三、CDK4/6抑制剂后的新选择在CDK4/6抑制剂联合内分泌治疗成为HR+/HER2-晚期乳腺癌一线治疗优选方案后，对于治疗进展后出现耐药的患者，医学界一直在探索新的治疗方案。目前，化疗仍是治疗选择之一，但仅能带来中位4～5个月的PFS[14-15]，且接受化疗的患者会出现众多不良反应，严重影响患者生活质量。针对CDK4/6抑制剂跨线治疗的探索由来已久，但目前仅有有限数据支持CDK4/6抑制剂跨线治疗，且只有postMONARCH这一项III期研究显示了PFS获益（6.0个月 vs 5.3个月）[16]。 PAM通路抑制剂的出现，为CDK4/6抑制剂耐药后的患者提供了新的治疗选择。PI3K位于PAM信号通路上游，在该通路中扮演着重要角色[17]。PIK3CA突变可以异常激活PI3K通路，促进肿瘤的增殖、转移和侵袭，因此，PI3K通路为治疗靶点成为了PIK3CA突变乳腺癌患者的重要治疗手段，这为PIK3CA突变型HR+/HER2-晚期乳腺癌患者带来新的治疗希望。多项研究显示了PI3K抑制剂可为PIK3CA突变人群带来更长的PFS获益，2024版NCCN指南推荐对于PIK3CA突变的HR+/HER2-绝经后乳腺癌患者，二线治疗首选PI3K抑制剂联合内分泌治疗（Ⅰ级推荐）。 AKT位于PAM通路的核心位置，其异常激活在乳腺癌的发生与发展中起着重要作用。AKT信号通路的激活可以通过多种机制实现，包括PIK3CA的激活突变、PTEN的失活突变以及上游信号通路的异常激活等。AKT一旦被激活，可磷酸化细胞核和细胞质中的许多靶点并激活多个具有调控细胞增殖功能的下游底物，从而促进肿瘤细胞生长、增殖和血管生成。此外，AKT通过抑制促凋亡基因Bcl-2家族成员BAD和BAX、负向调节FOXO等叉头转录因子等机制促进肿瘤细胞存活并抑制其凋亡[11]。AKT抑制剂相关研究正在大量开展中。 mTOR是PAM信号通路的关键下游效应分子，通过其两个不同的复合体mTORC1和mTORC2，调控多种细胞内过程。mTOR信号通路的异常激活在约30%的癌症中被发现,对肿瘤的发生、发展和转移起着重要的促进作用。mTOR过度激活会增加促癌蛋白的翻译，直接影响细胞生长、迁移和血管新生等过程。mTOR通过影响细胞周期、生长、存活和代谢等多个方面来促进肿瘤进展，在乳腺癌中，mTOR通路的异常在约70%的病例中被发现[18]。我国一项多中心回顾性研究数据显示，在CDK4/6抑制剂哌柏西利治疗进展后的HR/HER2-晚期乳腺癌患者中，应用内分泌治疗联合mTOR抑制剂依维莫司的患者中位PFS获益达5.1个月[19]。四、未来展望随着分子生物学研究的不断深入和精准医疗理念的逐渐普及，针对PAM通路的精准治疗为HR+/HER2-晚期乳腺癌患者带来了新的希望。通过检测PAM通路的突变状态，并结合患者的临床特征，临床医生可以为患者制定更加个体化的治疗方案。这不仅有助于延长患者的生存期，还能提高患者的生活质量。同时，NCCN、CSCO等国内外权威指南也将PI3K抑制剂、AKT抑制剂和mTOR抑制剂依维莫司纳入到了HR+/HER2-晚期乳腺癌患者的治疗药物推荐之中，但基于药物可及性及或内获批相关原因，目前在CSCO指南中对HR+晚期乳腺癌TAM治疗失败、非甾体类AI治疗失败及甾体类AI治疗失败的患者均II级推荐依维莫司联合内分泌治疗，而对于CDK4/6抑制剂治疗失败的患者，目前暂无I级推荐，在III级推荐中提及AKT抑制剂+内分泌治疗。 △2024版CSCO BC指南HR+晚期乳腺癌的解救内分泌治疗相关推荐* *指南内容涉及AZ未获批产品/适应症，阿斯利康不推荐任何未获批药品/适应症的使用。未来，随着更多针对PAM信号通路抑制剂的研发和临床应用，HR+/HER2-晚期乳腺癌的治疗将更加精准和有效。同时，也期待更多的基础研究能够揭示PAM通路在乳腺癌发生与发展中的具体机制，为新药的研发提供理论依据，为HR+/HER2-晚期乳腺癌患者带来更多新的治疗希望。甘露教授重庆医科大学附属第一医院中国抗癌协会乳腺癌专业委员会常委中国抗癌协会肿瘤临床研究管理学专委会常委中国抗癌协会肿瘤科普防治专业委员会委员中国抗癌协会肿瘤临床化疗专业委员会委员重庆市抗癌协会肿瘤心理学专业委员会副主任委员重庆市医学会乳腺病分会常委重庆市肿瘤医疗质量控制中心乳腺癌诊疗专家组成员审批编号CN-145761 过期日期 2025-10-18 *本材料由阿斯利康提供，仅供医疗卫生专业人士参考参考文献上下滑动查看更多内容 [1]、国家肿瘤质控中心乳腺癌专家委员会, 中国抗癌协会乳腺癌专业委员会, 中国抗癌协会肿瘤药物临床研究专业委员会. 中国晚期乳腺癌规范诊疗指南(2022版)[J]. 中华肿瘤杂志, 2022, 44(12):1262-1287.DOI: 10.3760/cma.j.cn112152-20221007-00680. [2]、国家肿瘤质控中心乳腺癌专家委员会, 中国抗癌协会肿瘤药物临床研究专业委员会. CDK4/6抑制剂治疗激素受体阳性人表皮生长因子受体2阴性乳腺癌临床应用专家共识(2023版)[J]. 中华肿瘤杂志, 2023, 45(12):1003-1017.lDOI: 10.3760/cma.j.cn112152-20230428-00188. [3]、Cristofanilli, Massimo et al. “Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.” The Lancet. Oncology vol. 17,4 (2016): 425-439. doi:10.1016/S1470-2045(15)00613-0 [4]、Goetz, Matthew P et al. “MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer.” Journal of clinical oncology : official journal of the American Society of Clinical Oncology vol. 35,32 (2017): 3638-3646. doi:10.1200/JCO.2017.75.6155 [5]、Slamon, Dennis J et al. “Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3.” Journal of clinical oncology : official journal of the American Society of Clinical Oncology vol. 36,24 (2018): 2465-2472. doi:10.1200/JCO.2018.78.9909 [6]、Tripathy, Debu et al. “Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial.” The Lancet. Oncology vol. 19,7 (2018): 904-915. doi:10.1016/S1470-2045(18)30292-4 [7]、Xu B, Zhang Q, Zhang P, et al. Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial. Nat Med. 2021;27(11):1904-1909. doi:10.1038/s41591-021-01562-9 [8]、Dey, Nandini et al. “PI3K-AKT-mTOR inhibitors in breast cancers: From tumor cell signaling to clinical trials.” Pharmacology & therapeutics vol. 175 (2017): 91-106. doi:10.1016/j.pharmthera.2017.02.037 [9]、Castaneda, Carlos A et al. “The phosphatidyl inositol 3-kinase/AKT signaling pathway in breast cancer.” Cancer metastasis reviews vol. 29,4 (2010): 751-9. doi:10.1007/s10555-010-9261-0 [10]、中国抗癌协会肿瘤药物临床研究专业委员会, 国家肿瘤质控中心乳腺癌专家委员会, 中国抗癌协会肿瘤病理专业委员会, 等. PI3K/AKT/mTOR信号通路抑制剂治疗乳腺癌临床应用专家共识[J]. 中华肿瘤杂志, 2022, 44(7):673-692.DOI: 10.3760/cma.j.cn112152-20220412-00251. [11]、姚荟斌，赵伟鹏，史业辉. CDK4/6抑制剂治疗晚期乳腺癌的研究进展. [J].《天津医科大学学报》2021，27（5）：549 [12]、O'Brien, Neil A et al. “Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer.” Breast cancer research : BCR vol. 22,1 89. 14 Aug. 2020, doi:10.1186/s13058-020-01320-8 [13]、Xiao, Weikai et al. “Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics.” Journal of Cancer vol. 12,14 4408-4417. 27 May. 2021, doi:10.7150/jca.52993 [14]、Kaufman, Peter A et al. “Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.” Journal of clinical oncology : official journal of the American Society of Clinical Oncology vol. 33,6 (2015): 594-601. doi:10.1200/JCO.2013.52.4892 [15]、Li, Yi et al. “A multicenter analysis of treatment patterns and clinical outcomes of subsequent therapies after progression on palbociclib in HR+/HER2- metastatic breast cancer.” Therapeutic advances in medical oncology vol. 13 17588359211022890. 11 Jun. 2021, doi:10.1177/17588359211022890 [16]、Kevin Kalinsky, et al. Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: Primary outcome of the phase 3 postMONARCH trial. 2024 ASCO abstract LBA1001. [17]、Vanhaesebroeck, Bart et al. “PI3K signalling: the path to discovery and understanding.” Nature reviews. Molecular cell biology vol. 13,3 195-203. 23 Feb. 2012, doi:10.1038/nrm3290 [18]、Marafie, Sulaiman K et al. “mTOR: Its Critical Role in Metabolic Diseases, Cancer, and the Aging Process.” International journal of molecular sciences vol. 25,11 6141. 2 Jun. 2024, doi:10.3390/ijms25116141 [19]、Mo H, et al. Real-World Outcomes of Everolimus and Exemestane for the Treatment of Metastatic Hormone Receptor-Positive Breast Cancer in Patients Previously Treated With CDK4/6 Inhibitors. Clin Breast Cancer. 2022 Feb;22(2):143-148. （来源：《肿瘤瞭望》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

临床结果