Cilengitide

整合素αv（ITGAV，CD51）被认为是肿瘤进展多个阶段的关键成分。然而，西仑吉肽（cilengitide，一种靶向表面CD51的特异性抑制剂）的临床失败表明CD51促进肿瘤进展的未知机制的重要性。2023年8月18日，中山大学项鹏及杨扬共同通讯在Journal of Hepatology（IF=26）在线发表题为“Combined inhibition of surface CD51 and γ-secretase-mediated CD51 cleavage improves therapeutic efficacy in experimental metastatic hepatocellular carcinoma”的研究论文，该研究发现CD51可以通过γ-分泌酶的跨膜切割产生一个功能性的胞内结构域(CD51-ICD)，裂解的CD51-ICD通过促进氧化磷酸化(OXPHOS)相关基因的转录促进HCC的侵袭和转移。该研究发现癌症相关成纤维细胞(CAF)衍生的骨膜蛋白是CD51切割的主要驱动因素。最后，该研究发现，当添加γ分泌酶抑制剂LY3039478时，西伦吉肽为基础的治疗在患者来源的异种移植物(PDX)和小鼠异种移植物模型中都显示出显著的改善。综上所述，该研究揭示了CD51对HCC进展先前未被认识到的作用机制，揭示了西仑吉肽治疗失败的根本原因，并支持CD51靶向联合治疗在临床上的转化前景。肝细胞癌(HCC)是癌症相关死亡的第二大原因，在世界范围内发病率不断上升。远处转移是HCC相关死亡的主要原因。肿瘤转移是一个多步骤的过程，包括上皮-间质转化(epithelial-mesenchymal transition, EMT)、细胞内转移和转移集落形成，这需要一个复杂的包括细胞内和细胞间信号转导的通讯网络。尽管癌症研究取得了进展，但对肿瘤转移的关键调控因子仍然知之甚少，并且缺乏针对转移的治疗靶点严重影响了HCC患者的预后。超过80%的HCC病例具有纤维化或肝硬化背景，这使得人们对纤维化生态位在HCC转移中的作用进行了深入研究。有报道称，癌相关成纤维细胞(cancer-associated fibroblasts, CAFs)通过多种途径促进肿瘤转移，包括细胞外基质(extracellular matrix, ECM)快速重塑、细胞因子分泌等。值得注意的是，整合素家族通过直接与ECM组分结合并激活细胞内信号传导来传导细胞外信号。在整合素家族成员中，整合素αv(CD51)因其在肿瘤转移中的作用而备受关注。FAK是CD51的主要下游激酶，可预测HCC患者的生存结果。此外，几种CD51配体，包括骨桥蛋白(OPN)和纤连蛋白(FN)，被鉴定为转移性HCC特征的主要蛋白质，可作为肝移植后患者肿瘤复发的预测因子。针对CD51，研究人员已经开发并试验了几种选择性拮抗剂。其中，西伦吉肽在临床前研究中表现出良好的效果，并在1/2期研究中证明了其安全性。出乎意料的是，西仑吉肽在胶质母细胞瘤患者的3期临床试验中失败，原因是药代动力学特性差，如半衰期短。然而，尚不清楚是否存在潜在的机制挑战限制了西仑吉肽在临床环境中作用于CD51的能力。机理模式图（图源自Journal of Hepatology）CD51属于I型跨膜蛋白家族，该家族还包括研究最多的蛋白Notch。Notch被三重蛋白水解过程激活。值得注意的是，由γ分泌酶介导的第三跨膜切割可以产生一个自由的Notch胞内结构域(NICD)，调节下游基因的表达。类似地，CD51分别经过furin和MMP介导的前两次裂解，并产生膜结合的C端片段(CD51-CTF)。然而，CD51-CTF是否可以通过γ-分泌酶进行第三次跨膜切割，以及细胞内结构域的切割是否会导致西伦吉肽的临床失败，目前尚不清楚。该研究报告了一种新的机制，其中CD51被γ-分泌酶复合物直接切割以产生细胞内结构域(CD51-ICD)。该研究发现CD51-ICD通过增强氧化磷酸化(OXPHOS)来促进肿瘤进展，并且主要由CAFs分泌的骨膜蛋白(POSTN)可以与HCC细胞上的CD51结合并促进CD51切割。该研究表明，POSTN-CD51-ICD轴不受西仑吉肽的影响，这至少部分解释了西伦吉肽的临床失败。最后，发现西仑吉肽与选择性γ分泌酶抑制剂LY3039478联合使用可以显著抑制HCC的侵袭和转移。综上所述，该研究不仅支持联合治疗可以改善HCC患者的预后，还可以改善其他晚期实体肿瘤患者的预后。这些发现为在临床环境中重新评估西仑吉肽提供了理论基础，并强调了在未来针对CD51的临床试验中确定更精确的患者亚群的重要性。文章来源“iNture”责编|文竞择校对|文竞择End往期精选围观历史性突破！不需卵子和精子就可以合成人类胚胎热文富豪用儿子血浆“回春”科学吗？Science：血液牛磺酸缺乏驱动衰老热文世界首例！35岁的她，通过机器人操刀移植的子宫，成功诞下宝宝热文为了避免心脏骤停，53岁的他成为“第一个”植入开创性除颤器的心脏病患者热文首次披露！175家生物制药公司的薪资数据：薪资中位数达20万美元点击“阅读原文”，了解更多~

IRVINE, Calif. & LIEGE, Belgium, Jul 05, 2012 (BUSINESS WIRE) -- Regulatory News: MDxHealth SA (nyse euronext:MDXH), a leading molecular diagnostic company that develops and commercializes epigenetic tests to support cancer treatment, announced today that it has expanded its collaboration with Merck KGaA, Darmstadt, Germany. This expanded collaboration covers the development and worldwide commercialization of MDxHealth's MGMT (methylguanine-DNA methyltransferase) diagnostic test (PredictMDx(TM) for Glioblastoma), which might help to identify those glioblastoma patients who might be more likely to benefit from cilengitide-based therapies that are currently under investigation, in combination with temozolomide and radiotherapy. Cilengitide is Merck's cancer drug candidate currently in Phase III development for newly diagnosed glioblastoma, an aggressive form of brain cancer. As part of the expanded collaboration, Merck has agreed to support MDxHealth's development and regulatory activities for the MGMT test and, after regulatory approval, the coordinated launch together with cilengitide in glioblastoma. Financial details of the agreement have not been disclosed. MDxHealth's PredictMDx for Glioblastoma test has already been used for the identification and stratification of newly diagnosed glioblastoma patients enrolled in cilengitide clinical studies who may benefit from combination treatment with temozolomide, radiotherapy and cilengitide. The test assesses the methylation status of the methylguanine-DNA methyltransferase (MGMT) gene promoter. The MGMT gene is thought to contribute to cellular DNA repair; and, when the gene is methylated, it is no longer expressed in normal amounts leading to a proposed increased responsiveness of tumor cells to some chemotherapeutic regimens. "With this agreement, MDxHealth and Merck are collaborating to bring PredictMDx for Glioblastoma to the clinical community -- as a companion diagnostic in the US if approved by FDA, and as a validated assay in other regions of the world -- enabling personalized treatment of newly diagnosed glioblastoma patients. Today, we are excited to be partnering with Merck, one of the most advanced pharmaceutical companies in the field of personalized medicine," said Dr. Jan Groen, CEO of MDxHealth. "Our collaboration with MDxHealth reflects the importance of diagnostics in the field of personalizing cancer care, an approach that Merck Serono is actively investing in with the ultimate goal to identify those patients who are most likely to benefit from a certain treatment through the use of a biomarker-guided approach," said Dr. Annalisa Jenkins, Head of Global Drug Development and Medical for Merck Serono. "We are hoping that this will help to improve the future treatment of patients with glioblastoma, a disease which today has high unmet medical needs." "We are proud to expand our existing partnership with MDxHealth, sharing complementary skills and capabilities in the field of personalized medicine with the common passion to get new therapies to patients who need them," added Dr. Susan Jane Herbert, Head of Global Business Development and Strategy for Merck Serono. About the MGMT assay: PredictMDx(TM) for Glioblastoma PredictMDx for Glioblastoma, MDxHealth's most advanced product, is a test to identify patients with different prognosis when treated with current standard of care (temozolomide plus radiotherapy) for newly diagnosed glioblastoma patients. The test assesses the methylation status of the MGMT gene, which is a crucial DNA repair gene. The PredictMDx for Glioblastoma test determines the methylation status of the MGMT gene promoter in tumor tissue, and it can be used as a prognostic assay for the treatment of newly diagnosed brain cancer that utilizes standard of care. The patented epigenetic gene test PredictMDx is attractive for brain cancer drug developers since this could provide an opportunity to better target their new drugs in the interest of the patients. About Cilengitide in glioblastoma Cilengitide is currently being developed by Merck Serono, a division of Merck, Darmstadt, Germany. Cilengitide is the first in a new class of investigational anti-cancer therapies called integrin inhibitors to reach Phase III development; it is currently being investigated for the treatment of newly diagnosed glioblastoma (Phase III and Phase I/II) and non-small cell lung cancer (PhaseI/ II). About MDxHealth MDxHealth is a molecular diagnostics company that develops and commercializes advanced epigenetic tests for cancer assessment and the personalized treatment of patients. By applying patented DNA methylation platform and biomarkers, MDxHealth helps to address a large and growing unmet medical need for better cancer diagnosis and treatment information. For more information visit . Important information about forward-looking statements This press release contains forward-looking statements and estimates with respect to the anticipated future performance of MDxHealth and the market in which it operates. Such statements and estimates are based on assumptions and assessments of known and unknown risks, uncertainties and other factors, which were deemed reasonable but may not prove to be correct. Actual events are difficult to predict, may depend upon factors that are beyond the company's control, and may turn out to be materially different. MDxHealth expressly disclaims any obligation to update any such forward-looking statements in this release to reflect any change in its expectations with regard thereto or any change in events, conditions or circumstances on which any such statement is based unless required by law or regulation. SOURCE: MDxHealth