KDM1A

Study conducted under the CRADA agreement between NCI and Oryzon Jan. 13, 2025 - Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, announced today that the first patient has been dosed in a Phase I dose-finding clinical trial of iadademstat, Oryzon’s potent and selective LSD1 inhibitor, in combination with venetoclax and azacitidine in newly diagnosed acute myeloid leukemia (AML), sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health. The trial (NCT06514261), titled “Phase 1 Trial of Iadademstat in Combination With Venetoclax and Azacitidine in Patients With Treatment Naive AML”, will evaluate the safety, tolerability, and optimal dose of iadademstat when administered together with the standard-of-care venetoclax and azacitidine in treatment-naïve AML patients. Preliminary efficacy of the triple combination will also be evaluated. This Phase I study will be conducted and sponsored by the NCI, and will be led by Principal Investigator, Dr. Natalie Galanina, from the University of Pittsburgh Cancer Institute. The trial plans to enroll 45 patients and is carried out under a Cooperative Research and Development Agreement (CRADA) that Oryzon has in place with the NCI. Dr. Carlos Buesa, Oryzon’s CEO, added: “We are excited to have the first patient dosed in this study. The trial expands on the findings from our ALICE trial, where combining iadademstat with azacitidine demonstrated robust antileukemic effects in first-line AML, producing deep and durable responses along with a manageable safety profile, including in patients with high-risk prognostic factors that respond poorly to venetoclax plus azacitidine.” In AML, iadademstat is also being evaluated in combination with venetoclax and azacitidine in newly diagnosed AML patients in an investigator-initiated Phase I clinical trial at Oregon Health & Science University (OHSU) Knight Cancer Institute (NCT06357182), and in a company-sponsored Phase Ib clinical trial in combination with gilteritinib in patients with relapsed/refractory AML harboring a FMS-like tyrosine kinase mutation (FLT3mut+) (NCT05546580). Founded in 2000 in Barcelona, Spain, Oryzon (ISIN Code: ES0167733015) is a clinical stage biopharmaceutical company and the European leader in epigenetics, with a strong focus on personalized medicine in CNS disorders and oncology. Oryzon’s team is composed of highly qualified professionals from the pharma industry located in Barcelona, Boston, and San Diego. Oryzon has an advanced clinical portfolio with two LSD1 inhibitors, vafidemstat in CNS (Phase III-ready) and iadademstat in oncology (Phase II). The company has other pipeline assets directed against other epigenetic targets like HDAC-6 where a clinical candidate ORY-4001, has been nominated for its possible development in CMT and ALS. In addition, Oryzon has a strong platform for biomarker identification and target validation for a variety of malignant and neurological diseases. For more information, visit www.oryzon.com Iadademstat (ORY-1001) is a small oral molecule, which acts as a highly selective inhibitor of the epigenetic enzyme LSD1 and has a powerful differentiating effect in hematologic cancers (see Maes et al., Cancer Cell 2018 Mar 12; 33 (3): 495-511.e12.doi: 10.1016 / j.ccell.2018.02.002.). A FiM Phase I/IIa clinical trial with iadademstat in R/R AML patients demonstrated the safety and good tolerability of the drug and preliminary signs of antileukemic activity, including a CRi (see Salamero et al, J Clin Oncol, 2020, 38(36): 4260-4273. doi: 10.1200/JCO.19.03250). Iadademstat has shown encouraging safety and strong clinical activity in combination with azacitidine in a Phase IIa trial in elder 1L AML patients (ALICE trial) (see Salamero et al., ASH 2022 oral presentation & The Lancet Haematology, 2024, 11(7):e487-e498). Iadademstat is currently being evaluated in combination with gilteritinib in the ongoing Phase Ib FRIDA trial in patients with relapsed/refractory AML with FLT3 mutations, and in combination with azacitidine and venetoclax in 1L AML in an investigator-initiated study led by OHSU and in a trial under the Cooperative Research and Development Agreement (CRADA) signed with the U.S. National Cancer Institute (NCI) to collaborate on further clinical development of iadademstat in different types of hematologic and solid cancers. Beyond hematological cancers, the inhibition of LSD1 has been proposed as a valid therapeutic approach in some solid tumors such as small cell lung cancer (SCLC), neuroendocrine tumors (NET), medulloblastoma and others. In a Phase IIa trial in combination with platinum/etoposide in second line ED-SCLC patients (CLEPSIDRA trial), preliminary activity and safety results have been reported (see Navarro et al., ESMO 2018 poster). Iadademstat is in a collaborative Phase II trial with the Fox Chase Cancer Center (FCCC) in combination with paclitaxel in R/R neuroendocrine carcinomas, and in a Phase I/II randomized trial in 1L ED-SCLC in combination with ICI sponsored by NCI and led by the Memorial Sloan Kettering Cancer Center (IND approved). Oryzon is further expanding the clinical development of iadademstat through additional investigator-initiated studies. Iadademstat has orphan drug designation for SCLC in the US and for AML in the US and EU. The content above comes from the network. if any infringement, please contact us to modify.

点击蓝字 关注我们 胃癌（Gastric Cancer，GC）作为中国恶性肿瘤中的“大户”，其发病率和死亡率均居高不下，严重威胁着人们的健康。近年来，免疫治疗为胃癌治疗带来了新的曙光，而赖氨酸特异性去甲基化酶1（Lysine-specific demethylase 1，LSD1）在肿瘤免疫微环境中扮演的角色愈发受到关注。本文将对LSD1在胃癌免疫治疗中的作用进行深入探讨，以期为胃癌治疗提供新的思路。 背景：免疫逃逸与肿瘤微环境 肿瘤微环境（TME）是多种细胞成分及其相互作用的复杂生态系统，免疫细胞在其中扮演着至关重要的角色（图1）。胃癌的时间（TIME）中，浸润性T细胞（TILs）与肿瘤的生物学行为密切相关。研究发现，高水平的CD8+ T细胞浸润与患者预后良好相关，而调节性T细胞（Tregs）的增多则与肿瘤的免疫逃逸及进展密切关联。因此，调节免疫微环境中的细胞活性被视为突破口。 图1：胃癌免疫微环境 尚未充分认识的关键因子——LSD1 赖氨酸特异性去甲基化酶1（LSD1或KDM1A）是一种组蛋白去甲基化酶，其通过去甲基化H3K4和H3K9等关键位点，抑制肿瘤抑制基因的表达，促进肿瘤细胞的增殖和转移。LSD1的过表达与胃癌的不良预后关联，且与多种免疫细胞的功能抑制密切相关。 LSD1的结构与功能特征 LSD1的结构复杂，由C端氨基氧化酶样（AOL）结构域和SWIRM结构域组成(图2）。尽管最初其功能与组蛋白的去甲基化密切相关，但近年来的研究发现LSD1还可以去甲基化多个非组蛋白底物，包括E2F1、p53等，调控细胞周期、凋亡和自噬等重要生物过程。这一发现使得LSD1除了作为肿瘤生长的促进因子外，成为调控免疫反应的重要节点。 图2：LSD1的结构和功能 LSD1在免疫细胞功能调节中的作用 LSD1在不同类型免疫细胞中的作用日益受到关注（图3）。CD8+ T细胞是肿瘤杀伤的主要效应细胞，但其功能受LSD1调控的显著影响。研究发现，LSD1的缺失能够提升CD8+ T细胞的杀伤能力并增加其浸润，抑制肿瘤生长。此外，LSD1还参与PD-1/PD-L1免疫检查点的调控，其抑制剂能够增强抗PD-1治疗的效果，为难治性胃癌提供新的治疗方向。巨噬细胞在胃癌中主要表现为促肿瘤的M2型，而LSD1的作用能够影响巨噬细胞的极化状态。通过抑制LSD1，可促使M2巨噬细胞向抗肿瘤的M1型转变，增强肿瘤的免疫反应。LSD1抑制剂可通过上调NK细胞活性相关基因的表达，提升NK细胞对胃癌细胞的杀伤力。B细胞在胃癌中的作用仍有争议。一些研究表明，B细胞的某些亚型可能抑制抗肿瘤免疫反应，而LSD1通过调控B细胞的发育与功能，对肿瘤的免疫反应产生潜在影响。 图3：LSD1抑制剂在免疫治疗中的作用 LSD1抑制剂在胃癌治疗中的前景 LSD1在胃癌细胞的增殖和转移中发挥重要作用。通过调节E-cadherin表达、沉默KLF2以及与多种lncRNA相互作用，LSD1促进胃癌细胞的增殖、迁移和侵袭。LSD1抑制剂通过降低LSD1活性，调节胃癌发生过程中的多个环节。例如，新型吖啶基LSD1抑制剂Compound 5ac可使BGC-823细胞对T细胞介导的杀伤更敏感，并降低PD-L1表达。Compound 383通过增加E-cadherin启动子处的H3K4甲基化，抑制MGC803细胞的增殖、迁移和侵袭。此外，LSD1抑制剂还可通过调节EMT过程和自噬，干扰胃癌的进展，为胃癌治疗提供了新的靶向治疗思路。 在胃癌免疫微环境中，LSD1缺失可降低外泌体PD-L1表达，恢复T细胞反应。多种LSD1抑制剂如Compound 3s、Compound 5ac和6x等（表1）可抑制LSD1表达，下调PD-L1表达，增强T细胞的细胞毒性。LSD1抑制剂处理的间充质干细胞能有效刺激CD8+ T细胞激活，发挥抗肿瘤免疫反应。这表明LSD1抑制剂主要通过增强CD8+ T细胞的活性，促进其对肿瘤细胞的杀伤作用，在胃癌免疫微环境中发挥重要作用。此外，针对LSD1的抑制还可触发细胞内双链RNA（dsRNA）应激和干扰素激活，促进抗肿瘤T细胞免疫。目前，已有多种LSD1抑制剂进入临床试验，显示出其作为强效选择性抗癌药物的潜力。 表1：LSD1抑制剂对胃癌免疫功能的影响 未来展望与结论 总之，LSD1在胃癌的免疫微环境中扮演着重要角色，其抑制剂的应用前景广阔。深入研究LSD1在免疫细胞功能中的具体机制，以及其在多种免疫疗法中的应用潜力，将有助于开发新的治疗策略，改善胃癌患者的疗效与生存质量。未来的研究应集中在LSD1抑制剂的临床试验设计、联合疗法的优化及剂量的确定，以期为胃癌患者带来切实的治疗希望和生存改善。 郑州大学附属肿瘤医院（河南省肿瘤医院）硕士研究生任永静、博士后宫亚楠以及河南中医药大学硕士研究生赵焕为该论文的共同第一作者。郑州大学附属肿瘤医院（河南省肿瘤医院）的陈小兵教授和助理研究员王赛琪担任该论文的共同通讯作者。 通讯作者 陈小兵  教授 医学肿瘤学博士、二级教授/主任医师、博士生导师、博士后合作导师 郑州大学附属肿瘤医院（河南省肿瘤医院）内科副主任、支部副书记兼消化内科二病区主任 国家健康科普专家、国务院特殊津贴专家、河南省第九批优秀专家 中国抗癌协会（CACA）九届理事会理事、河南省科协十届委员会常委 CACA食管肿瘤整合康复专委会主任委员、整合食管癌委员会副主任 CACA胃部肿瘤整合康复专委会常委、胃癌专委会委员 河南省消化道肿瘤精准治疗工程技术研究中心主任 CACA《胃癌整合诊治指南》编委和指南发布会全国精讲专家 《基于PDL1蛋白表达水平的胃癌免疫治疗专家共识(2023年版)》执笔专家 中文与科技双核心期刊《中国医学前沿杂志(电子版)》编委 中国科技核心期刊《肿瘤综合治疗电子杂志》编委 主持国家自然科学基金面上项目、省自然科学基金重点项目、省杰出青年基金等课题20余项；担任国家“十四五”重点图书《整合肿瘤学》临床卷《腹部盆腔肿瘤分册》主编，负责胃癌部分撰写（56页）；参与制定40余部国家规范、指南和专家共识；发表胃癌相关论文100余篇，SCI收录50余篇（最高IF40.8分）。 王赛琪 郑州大学附属肿瘤医院（河南省肿瘤医院）助理研究员，研究方向：消化道肿瘤耐药转移机制探索及肿瘤多药耐药逆转剂开发。主持国家自然科学基金青年项目、河南自然科学基金青年项目、河南省高层次人才国际化培养项目等科研项目8项。获河南省科技进步奖叁等奖1项、中国抗癌协会科技奖1项、河南省医学科技壹等奖4项、河南省教育厅科技成果奖壹等奖1项，发表SCI论文40余篇，其中F1000推荐论文1篇，ESI高被引论文1篇。 第一作者 任永静 郑州大学附属肿瘤医院（河南省肿瘤医院）硕士研究生在读，研究方向为消化道肿瘤基础与临床研究。 推荐阅读 ●   CJCR（IF=7）| 陈小兵教授团队解读HER2阳性胃癌：曲妥珠单抗耐药的秘密与破解之道 ●   Nature子刊｜束永前/陈晓锋/陈小兵/徐同鹏等团队发表SPACE研究成果为晚期胃癌一线治疗带来新思路 ●   JMC | 陈小兵、郑一超/代兴杰团队合作发现能够激活胃癌免疫反应的新型LSD1抑制剂 声明：本文由“肿瘤界”整理与汇编，欢迎分享转载，如需使用本文内容，请务必注明出处。 引文格式：Ren Y, Gong Y, Zhao H, You D, Li Z, Wang SQ, Chen X. Role of lysine-specific demethylase 1 in immunotherapy of gastric cancer: An update. Chin J Cancer Res. 2024;36(6):669-682. 来源：《中国癌症研究》英文杂志官网 编辑：lagertha 审核：陈小兵教授

MADRID, SPAIN and CAMBRIDGE, MA, UNITED STATES, January 13th, 2025 - Oryzon Genomics, S.A. (ISIN Code: ES0167733015, ORY), a clinical-stage biopharmaceutical company leveraging epigenetics to develop therapies in diseases with strong unmet medical need, announced today that the first patient has been dosed in a Phase I dose-finding clinical trial of iadademstat, Oryzon’s potent and selective LSD1 inhibitor, in combination with venetoclax and azacitidine in newly diagnosed acute myeloid leukemia (AML), sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health. The trial (NCT06514261), titled “Phase 1 Trial of Iadademstat in Combination With Venetoclax and Azacitidine in Patients With Treatment Naive AML”, will evaluate the safety, tolerability, and optimal dose of iadademstat when administered together with the standard-of-care venetoclax and azacitidine in treatment-naïve AML patients. Preliminary efficacy of the triple combination will also be evaluated. This Phase I study will be conducted and sponsored by the NCI, and will be led by Principal Investigator, Dr. Natalie Galanina, from the University of Pittsburgh Cancer Institute. The trial plans to enroll 45 patients and is carried out under a Cooperative Research and Development Agreement (CRADA) that Oryzon has in place with the NCI. Dr. Carlos Buesa, Oryzon’s CEO, added: “We are excited to have the first patient dosed in this study. The trial expands on the findings from our ALICE trial, where combining iadademstat with azacitidine demonstrated robust antileukemic effects in first-line AML, producing deep and durable responses along with a manageable safety profile, including in patients with high-risk prognostic factors that respond poorly to venetoclax plus azacitidine.” In AML, iadademstat is also being evaluated in combination with venetoclax and azacitidine in newly diagnosed AML patients in an investigator-initiated Phase I clinical trial at Oregon Health & Science University (OHSU) Knight Cancer Institute (NCT06357182), and in a company-sponsored Phase Ib clinical trial in combination with gilteritinib in patients with relapsed/refractory AML harboring a FMS-like tyrosine kinase mutation (FLT3mut+) (NCT05546580).