更新于：2024-11-01

RB1

更新于：2024-11-01

基本信息

别名

OSRC、p105-Rb、p110-RB1

+ [7]

简介

Tumor suppressor that is a key regulator of the G1/S transition of the cell cycle (PubMed:10499802). The hypophosphorylated form binds transcription regulators of the E2F family, preventing transcription of E2F-responsive genes (PubMed:10499802). Both physically blocks E2Fs transactivating domain and recruits chromatin-modifying enzymes that actively repress transcription (PubMed:10499802). Cyclin and CDK-dependent phosphorylation of RB1 induces its dissociation from E2Fs, thereby activating transcription of E2F responsive genes and triggering entry into S phase (PubMed:10499802). RB1 also promotes the G0-G1 transition upon phosphorylation and activation by CDK3/cyclin-C (PubMed:15084261). Directly involved in heterochromatin formation by maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation. Recruits and targets histone methyltransferases SUV39H1, KMT5B and KMT5C, leading to epigenetic transcriptional repression. Controls histone H4 'Lys-20' trimethylation. Inhibits the intrinsic kinase activity of TAF1. Mediates transcriptional repression by SMARCA4/BRG1 by recruiting a histone deacetylase (HDAC) complex to the c-FOS promoter. In resting neurons, transcription of the c-FOS promoter is inhibited by BRG1-dependent recruitment of a phospho-RB1-HDAC1 repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex (By similarity). (Microbial infection) In case of viral infections, interactions with SV40 large T antigen, HPV E7 protein or adenovirus E1A protein induce the disassembly of RB1-E2F1 complex thereby disrupting RB1's activity.

关联

项与 RB1 相关的药物

AP-3-84

靶点

RB1

作用机制

RB1 inhibitors

在研机构

The Wistar Institute

原研机构

The Wistar Institute

在研适应症

成人急性髓性白血病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

CN117551697

专利挖掘

靶点

RB1

作用机制-

在研机构

上海交通大学医学院附属第九人民医院

原研机构

上海交通大学医学院附属第九人民医院

在研适应症

生殖细胞和胚胎肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

dl 922-947

靶点

RB1

作用机制

RB1 modulators

在研机构-

原研机构

Berlex Biosciences [+3]

在研适应症-

非在研适应症

间皮瘤

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

项与 RB1 相关的临床试验

NCT01517464 / Completed临床1期

A Phase I Study of Systemic Gene Therapy With SGT-94 in Patients With Solid Tumors

This is a Phase I study designed to evaluate the safety and maximum tolerated dose (MTD) of SGT-94, a novel, tumor-targeted, systemic gene therapy agent for cancer. In addition, we will look for evidence of RB94 expression within tumor tissue after systemic administration of SGT-94.

开始日期2012-01-01

申办/合作机构

SynerGene Therapeutics, Inc.

100 项与 RB1 相关的临床结果

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100 项与 RB1 相关的转化医学

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0 项与 RB1 相关的专利（医药）

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18,323

项与 RB1 相关的文献（医药）

2025-03-01·Combinatorial Chemistry & High Throughput Screening

Pharmacological Mechanisms of Kirenol against Ovarian Carcinoma: A Network Pharmacology and Experimental Validation Study In Vitro

Article

作者: Yang, Huan ; Bao, Yin ; Lin, Shixin ; Mao, Xiaoling ; Gao, Jun ; Zhu, Hong ; Zhang, Mingyue

Background:Ovarian carcinoma is an aggressive gynecological malignancy. Kirenol, a diterpene compound, has recently gained attention for its potential anticancer properties. However, its exact anti-tumor mechanism remains largely unexplored.Objective:In this study, we explored the inhibitory effects of Kirenol on ovarian cancer using network pharmacology and in vitro experiments and elucidated its underlying mechanisms.Methods:Through the utilization of molecular docking, we established a network of proteinprotein interactions (PPI), which unveiled CDK4 as an essential target. Additionally, gene enrichment and pathway analysis highlighted the significance of the PI3K/AKT pathway. The viability of ovarian cancer cells and normal ovarian epithelial cells was evaluated using CCK8 assays to determine the effect of Kirenol. Following in vitro tests, cell colony formation, wound healing, flow cytometry, and Western blotting were conducted to assess its impact on cell proliferation, metastasis, apoptosis, and the cell cycle.Results:Kirenol significantly reduced the viability of ovarian cancer cells (SKOV3 and A2780) compared to normal ovarian epithelial cells (IOSE-80). Moreover, Kirenol efficiently suppressed the growth and movement, caused a cell cycle halt, and stimulated programmed cell death in SKOV3 and A2780 cells. Through molecular analysis, it was observed that Kirenol increased the expression of Bax while decreasing the expression of MMP2, MMP9, and Bcl-2. It also attenuated the phosphorylation of PI3K, AKT, and RB and downregulated CDK4 and CCND1 expression. Notably, co-treatment with the PI3K pathway inhibitor LY294002 enhanced the inhibitory effect of Kirenol on ovarian cancer cells.Conclusion:In summary, the combined results of our network pharmacology analysis and in vitro tests emphasized that Kirenol hinders the growth of ovarian cancer cells, causes cell cycle arrest, enhances apoptosis, and hampers migration, possibly by regulating the PI3K/AKT/CDK4 signaling pathway.

2025-01-01·Modern Pathology

Histopathologic and Molecular Characterization of IDH-Mutant Prostatic Adenocarcinoma

Article

作者: Gopalan, Anuradha ; Reuter, Victor E. ; Chen, Ying-Bei ; Al-Ahmadie, Hikmat ; Fine, Samson W. ; Samueli, Benzion ; Reuter, Victor E ; Tickoo, Satish K ; Tickoo, Satish K. ; Fine, Samson W ; Chen, Jie-Fu ; Sarungbam, Judy

Gain-of-function isocitrate dehydrogenase (IDH) mutations are pathogenically significant in many tumor types and are actionable in cholangiocarcinoma, low-grade glioma, and acute myeloid leukemia. Rare IDH mutations have been described in prostatic adenocarcinoma (PCa). Recent publications have suggested that psammomatous calcifications in PCa are associated with IDH1 mutations. In this retrospective study, we queried our institutional clinical sequencing database (cohort 1), and previously published PCa data sets in cBioPortal (cohort 2). Samples were stratified based on oncogenic hotspot IDH mutations at IDH1 R132 and IDH2 R140/R172, and other nonhotspot IDH mutations. Seventeen (0.4%) cases were identified from 4033 PCa cases in cohort 1 harboring mutually exclusive oncogenic hotspot IDH1 (N = 15, 1 of which was subclonal) or IDH2 (N = 2) mutations, and 20 (0.5%) cases had nonhotspot IDH1/2 mutations. A histologic review of 13 cases with IDH1 hotspot mutations and available material showed grade group 3 or higher disease. Immunohistochemistry was performed on cases with IDH1 hotspot mutations when possible and showed AR, PSA, PSMA, and NKX3.1 positive in all the 4 cases stained. In cohort 2, 9 cases (0.3%) harboring IDH1 hotspot mutations were identified from 2749 patients, and 9 cases carried nonhotspot IDH1/2 mutations. The combined cohorts of 23 PCa cases with clonal IDH1 hotspot mutations had no ETS fusions, SPOP hotspot mutations, and somatic or germline alterations in BRCA1/2, ATM, RB1, or AR; 19 cases with successful microsatellite instability testing were all microsatellite stable. Conversely, among 29 cases with nonhotspot IDH mutations, there were 4 with TMPRSS2::ERG fusions, 6 with SPOP hotspot mutations, and 10 with AR amplifications/hotspot mutations; 8 were microsatellite instability high. Notably, two cases with IDH1 hotspot mutations had psammomatous calcifications. Our findings provide evidence that IDH1 hotspot mutations serve as driver alterations in this rare yet distinct molecular subset of PCa. Further studies are warranted to correlate response to androgen deprivation and IDH inhibitors.

2025-01-01·Combinatorial Chemistry & High Throughput Screening

Drug-containing Serum of Quyoufang Promotes Apoptosis of Ectocervical H8 Cells through an E6/p53-related Pathway

Article

作者: Huang, Shan ; Qi, Yuanjie ; Xiao, Jing ; Chen, Xiaofeng

Background:Persistent human papillomavirus (HPV) infection is a causative agent for the majority of cervical cancer cases. The traditional Chinese medicine formula Quyoufang (QYF), a herbal oral decoction therapy, has been widely applied in the treatment of various diseases caused by HPV infection, but the molecular mechanism of QYF in the treatment of HPV infection remains unclear. This study aimed to investigate the effect of drug-containing serum of QYF on the apoptosis of HPV16-positive cervical immortalized epithelial cell line H8 in vitro.Methods:Different concentrations of medicated serum were obtained by feeding QYF into the stomachs of rats. The effects of medicated serum on H8 cell proliferation and apoptosis were detected using the cell counting kit-8 assay (CCK-8) method, flow cytometry, and Hoechst 33342/PI apoptosis assays. The different expressions of E6, E7, p53, and pRb among H8 cells were detected by RT-PCR and Western Blot.Results:The results firstly indicated that the drug-containing serum of QYF induced apoptosis and suppressed the proliferation of H8 cells in a concentration-dependent manner. RT-PCR and Western Blot unveiled that in contrast to the control group, the QYF groups could markedly elevate the mRNA expression of P53 and pRb as well as promote the expression of p53 and pRb protein levels. The QYF groups suppressed the expression of E6 mRNA and inhibited the expression of E6 protein.Conclusion:The drug-containing serum of QYF could effectively inhibit the proliferation of H8 cells and induce their apoptosis, possibly through the E6/p53-related pathway

207

项与 RB1 相关的新闻（医药）

2024-10-28

·生物探索

尿路上皮癌进化的基因密码

尿路上皮癌（UC）是一种常见且致命的癌症，具有显著的遗传异质性【1】。在癌症发展过程中，突变过程和DNA修复之间不断相互作用，导致产生独特的突变特征和广泛的基因组结构变化。APOBEC3家族的胞嘧啶脱氨酶可在多种人类癌症的基因组中引起胞嘧啶向胸腺嘧啶或鸟嘌呤的替换，形成体细胞突变特征，尤其是在UC中。研究发现，APOBEC3酶家族在多种癌症中引起的突变模式与癌症的进展和耐药性密切相关【2】。尽管已有研究探讨了化疗对癌症突变的影响，初步探索了化疗耐药性晚期UC的进化动态【1】，但关于内源性突变压力（如APOBEC3）和外源性突变过程（如化疗）的相对时序、克隆性及其对UC进化的影响仍存在许多未解之谜；复杂结构变异（SV），包括染色体外DNA（ecDNA），如何影响UC的进化和药物抗性也尚未可知。毫无疑问，这些基本问题的回答将有助于对晚期癌症患者的临床发展的预测并预防化疗耐药。为了解决这些问题，近日，来自美国威尔康奈尔医学院的Bishoy M. Faltas团队在Nature上在线发表题为The interplay of mutagenesis and ecDNA shapes urothelial cancer evolution的文章，通过全基因组测序（WGS）分析了尿路上皮癌的原发性和转移性肿瘤样本，探讨了APOBEC3和化疗引起的突变特征及其在肿瘤进化中的作用，使用连接平衡分析（JaBbA）工具分析了复杂结构变异，特别是ecDNA的形成，并研究了这些变异如何影响肿瘤对治疗的抗性。此外，研究人员还利用长读长测序技术详细绘制了ecDNA的环形结构，并在实验模型中证实了CCND1 ecDNA在促进治疗抗性中的优势。这些发现揭示了驱动尿路上皮癌进化的新机制，为开发新疗法提供了潜在靶点，具有重要的治疗意义。本文研究人员首先通过WGS分析了77个UC肿瘤样本，包括28个铂类化疗前和49个化疗后的样本，发现APOBEC3胞苷脱氨酶是UC中主要的突变酶，其引起的单碱基替换（SBS2和SBS13）以及双碱基替换（DBS11）在所有突变中占有显著比例。此外，与铂类化疗相关的SBS31、SBS35和DBS5突变特征在化疗后的肿瘤样本中也有贡献。通过构建系统发育树，研究人员确定了APOBEC3引起的突变主要发生在肿瘤早期，并且具有克隆性，而化疗引起的突变则更多出现在晚期，且为亚克隆性。APOBEC3引起的突变与化疗引起的突变在时间上有明显的先后顺序，APOBEC3突变较早，化疗突变较晚（图1）。此外，化疗引起的突变速率高于APOBEC3，这表明化疗不仅是治疗手段，也是癌症进化的驱动力。研究还发现，APOBEC3引起的突变在正常尿路上皮和肿瘤之间共享，这强调了APOBEC3在UC早期发生和发展中的作用。这些结果表明早期由APOBEC3酶引起的突变推动了UC的发生，同时显示了早期克隆性的APOBEC3引起的突变与晚期亚克隆性的化疗引起的突变之间的相互作用，这两种突变共同塑造了癌症的转移性和治疗抗性表型，提示APOBEC3和化疗引起的突变在UC的发展和对治疗的抵抗性中扮演了关键角色。基因组不稳定性来自突变和复杂的大规模染色体变异之间的相互作用，为了研究这些过程，研究人员使用连接平衡分析（JaBbA）工具对威尔康奈尔医学院(WCM)-UC队列中的高阶SV进行了全面分析。研究结果发现大多数样本中存在多个复杂SV，其中模板插入链（TIC）、染色体碎裂（chromoplexy）和断裂-融合-桥接（BFB）事件最为常见。此外，研究还观察到与TP53基因突变相关的样本在基因组改变、总连接点数量和特定SV类别方面有显著增加，暗示了基因组稳定性基因突变在复杂SV形成中的重要性。癌细胞ecDNA是扩增癌基因的兆碱基规模的环状DNA亚类，研究人员进一步专注于检测形成ecDNA的SV的两个定义特征：高拷贝数的扩增子和环状结构。结果发现约35%的样本中含有可能生成ecDNA的SV事件，这突出了它们在UC中的高发病率，提示这些ecDNA形成事件可能在癌症的进化和治疗抗性中起着关键作用。与此同时，研究人员发现APOBEC3酶和化疗都能在UC中的ecDNA上引起突变。APOBEC3诱导的聚集突变（kyklonas）多发生在ecDNA形成早期，且靠近结构变异的断点，暗示其在ecDNA形成中扮演关键角色，APOBEC3诱导的突变和ecDNA的生物发生在空间和时间上是重叠的。相比之下，化疗诱导的突变主要出现在晚期，且变异等位基因频率（VAF）较低，表明它们在肿瘤发展中出现较晚。随后，研究人员探讨了UC中由ecDNA驱动的癌基因扩增现象。利用FishHook工具分析复发性结构变异，研究人员发现其中55%的变异发生在与癌症相关的基因附近，特别是CCND1基因，它在大多数样本中通过ecDNA形成结构变异而扩增。此外，研究人员还观察到，与CCND1扩增相关的肿瘤样本中，CDKN2A基因（编码抑制CDK4/6的肿瘤抑制因子p16）的纯合缺失更为常见，提示ecDNA介导的CCND1扩增的UC肿瘤激活了p16–cyclin D1–CDK4/6–RB1通路，促进了细胞周期的进程。与此同时，研究人员分析了在系统治疗下CCND1 ecDNA形成SV的动态变化，结果发现在系统治疗后，UC中CCND1 ecDNA形成的结构变异事件变得更加复杂，拷贝数增加，提示ecDNA在选择性治疗压力下可能作为适应性储备，促进了耐药性的产生。进一步地，通过高级的ONT（Oxford Nanopore Technologies）长读长全基因组测序技术，研究人员详细描绘了UC中CCND1基因所在的ecDNA形成结构变异的环形结构，发现每个ecDNA扩增子在结构上都是独特的，并且会获取不同癌基因的启动子、增强子和超级增强子。这些ecDNA扩增子通常包含癌基因FGF3、FGF4和FGF19的扩增，并保留了CCND1局部启动子和调控元件。最后，研究人员通过实验模型，利用非整合性慢病毒载体在膀胱癌细胞中模拟了CCND1 ecDNA，并在顺铂化疗下进行了竞争实验，发现携带CCND1 ecDNA的细胞显示出更高的适应性。单细胞RNA测序分析揭示了这些细胞中E2F信号通路和其他与化疗抗性相关的通路的激活。此外，通过敲低依赖CCND1 ecDNA的癌细胞中的CCND1，研究人员观察到细胞适应性的降低。这些结果表明CCND1 ecDNA的获得显著增强了肿瘤细胞对化疗的适应性。综上所述，本研究对晚期UC患者的不同解剖区域和连续时间点收集的配对样本进行了WGS，分析揭示了两种关键致突变因素——APOBEC3胞嘧啶脱氨酶和基于铂的化疗——在UC进展中的活动时间线，全面绘制了晚期UC中的复杂SV，阐明了驱动UC进化的基本机制，为未来的研究以及开发旨在阻断尿路上皮癌变和治疗抗性的创新治疗策略带来了希望。参考文献 1. Faltas, B. M. et al. Clonal evolution of chemotherapy-resistant urothelial carcinoma. Nat. Genet. 48, 1490–1499 (2016). 2. Swanton, C., McGranahan, N., Starrett, G. J. & Harris, R. S. APOBEC enzymes: mutagenic fuel for cancer evolution and heterogeneity. Cancer Discov. 5, 704–712 (2015). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-024-07955-3 内容来源于网络，如有侵权，请联系删除。

2024-10-28

·思路迪医药 3D Medicines

恩沃利单抗或可助力临床突破晚期肺神经内分泌癌治疗瓶颈！

编者按：神经内分泌癌(NEC)罕见的发病率、高度侵袭性及其复杂的临床表现为其治疗带来了巨大挑战，肺是NEC最常见的原发部位。晚期肺NEC治疗选择局限，本期“例例生辉”，天津市肿瘤医院医院的姜战胜教授将为我们分享一例初诊的ⅢA期肺高级别NEC常规序贯放化疗后出现进展的患者。该患者在后续使用恩沃利单抗联合靶向及化疗4周期治疗后即出现了胸水吸收，多发淋巴结缩小，达到了部分缓解（PR）的临床疗效评价。目前患者仍在这一治疗方案中持续获益。让我们一睹为快！研究背景近年来，肺癌诊疗领域进展突飞猛进，但肺NEC的整体生存状况仍待改善。肺NEC包括小细胞肺癌（SCLC）及肺大细胞神经内分泌癌（LCNEC），由于其高侵袭性和治疗应答的异质性，患者在治疗选择和预后方面仍面临重大挑战，因此亟需进一步的研究和创新疗法来改善临床结局。 III期无法切除的LCNEC，推荐化疗＋放疗联合治疗。一项纳入5797例局部晚期LCNEC患者的回顾性研究显示，根治性同步放化疗较单纯化疗疗效更佳（mOS：16.1 vs 11.9月）[1]。这一结论在其他大型回顾性研究中也得到验证。基于有限的数据，可认为含4周期EP方案（依托泊苷+顺铂）的同步放化疗，是不可切除III期LCNEC合理的选择[2]。程序性死亡受体1(PD-1)/程序性死亡受体配体1(PD-L1)抑制剂已被美国食品药品监督管理局和国家药品监督管理局批准用于多个瘤种的广泛治疗，为治疗难治性和复发性肺癌带来了新的希望。恩沃利单抗是全球首个通过皮下注射给药途径的特异性阻断PD-L1的药物，其他已获批的PD-1/PD-L1抗体均为静脉输注给药。2021年，恩沃利单抗在中国获批用于治疗不可切除或转移性微卫星高度不稳定(MSI-H)或错配修复缺陷(dMMR)的晚期实体瘤[3]。2022年CSCO大会报告了一项探索恩沃利单抗联合卡铂/顺铂和依托泊苷一线治疗广泛期小细胞肺癌(ES-SCLC)的II期临床研究[4] ,该研究中有14例(87.5% )达到部分缓解(PR) ，2例(12. 5%)疾病稳定(SD) ,客观缓解率（ORR）为87.5%,疾病控制率(DCR)高达100%，表明免疫联合化疗可为ES-SCLC患者带来临床获益。但免疫治疗在LCNEC的应用价值仍需要探索。本期通过详细描述恩沃利单抗联合治疗方案在一例(右肺)高级别神经内分泌癌患者中的应用，为免疫治疗在LCNEC&SCLC患者中的治疗价值进行了一次积极探索。具体内容如下：病例报告患者信息基本信息：患者男性，71岁。主诉：确诊右肺癌5天。既往史、家族史：无特殊。个人史：吸烟史40年，25支/天。无饮酒不良嗜好。辅助检查强化CT：提示右肺上叶肿物，考虑肺癌可能性大；纵隔淋巴结肿大；支气管炎，双肺肺气肿。 PET-CT：右肺上叶肿物向右主支气管延伸，大小约1.8x6.9x5.9cm，符合中心型肺癌伴阻塞性炎症；右肺门及双颈等多处结节，考虑淋巴结转移或增生反应，最大结节约1.6x1.1cm。头部强化MRI：左侧小脑半球异常信号，不除外微小转移。病理检查：右肺上叶活检结果为癌，形态及免疫组化倾向于高级别神经内分泌癌，小部分倾向小细胞，神经内分泌指标表达欠佳。基因检测：RB1基因p.P6Rfs*2122.44%；TP53基因p.R249S 45.97%；PIK3CA基因拷贝扩增3.4；MSS。诊断结果 T3N1M0 IIIA期（局限期）右肺癌，右肺门淋巴结转移。分子分型：RB1、TP53突变及PIK3CA扩增；MSS；PDL1（TPS<1%）。ECOG评分：1分。治疗经过图1 治疗流程图 2023年7月：患者接受3周期EP化疗（依托泊苷180mg d1-3，顺铂60mg d1-2）3周期后，复查CT显示右肺上叶支气管开口周围肿物较前缩小（6.9×5.9cm至6.8×4.1cm），疾病稳定（图2）。图2 化疗3周期后影像学评估疗效 2023年10月：患者接受放疗，放疗计划为PTV54Gy/3Gy/18f。放疗1月后复查CT显示：与2023-9-15相比，右肺上叶及右主支气管内肿物增大（6.8x4.1cm到7.2x4.2cm），周围结节增多，支气管狭窄加重；左肺下叶透亮影壁厚减轻，粟粒增多；纵隔及右肺淋巴结无显著变化（较大者短径约1.1cm），提示病情稳定（图3）。图3 放疗1月后影像学疗效评估 2023年12月22日CT表现考虑为放射性肺炎，不排除合并细菌感染。患者未再入院行抗肿瘤治疗，于当地医院口服激素治疗，具体剂不详（图4）。图4 放疗2月后影像学考虑放射性肺炎 2023年12月22日患者于当地医院复查CT提示病灶较前缩小，疗效评价PR（图5）。图5 放疗2月后影像学疗效评估 2024年2月3日患者于当地医院复查CT提示疗效维持PR（肿物大小4.0x4.3cm）（图6）。图6放疗4月后影像学疗效评估患者2024年4月活动后喘憋，2024年4月11日，患者于我院检查CT结果显示：与2023年11月14日相比，右肺上叶及右主支气管肿物缩小，但右肺上叶支气管闭塞，出现肺不张和中下叶实变；双肺胸膜下多发结节及浸润影，考虑炎性改变；纵隔淋巴结增大（最大短径约1.4cm），右侧胸腔有少量积液。与当地医院2024年2月3日CT相比肿物较前明显增大，以上提示疾病进展（图7）。图7 放疗6月后影像学疗效评估由于患者疾病进展，因此改变患者治疗方案，2024年4月11日开始接受免疫联合靶向联合化疗2周期，方案为恩沃利单抗300mg d1，安罗替尼10mg d1-14，依托泊苷胶囊50mg d1-10（周期1）/100mg d1-7（周期2）。治疗2周期后，CT显示右肺上叶肿物缩小（约5.3x4.5cm），右肺上叶复张，中下叶实变部分吸收；左肺上叶胸膜下结节缩小，新见斜裂旁及舌段结节，建议抗炎后复查；纵隔及右肺门淋巴结缩小（最大短径约0.9cm），右侧胸腔积液吸收，其余无显著变化（图8）。图8 免疫联合靶向治疗及化疗2周期后影像学疗效评估 2024年7月患者继续免疫联合靶向联合化疗2周期，方案为恩沃利单抗300mg d1，安罗替尼10mg d1-14，依托泊苷胶囊100mg d1-7。2024年8月6日患者复查CT示：右肺上叶肿物较前缩小（范围4.2x3.9cm），提示病情稳定，疗效评价PR（图9）。图9 免疫联合靶向治疗及化疗2周期后影像学疗效评估研究结论本病例报告了一例(右肺)高级别神经内分泌癌IIIA期患者在接受了3周期化疗，18次放疗，病情进展之后接受了4周期的恩沃利单抗联合靶向和化疗。在4周期治疗之后，患者右肺肿物缩小，胸水吸收，右肺复张，疗效评估达到部分缓解（PR）。提示恩沃利单抗是肺NEC患者的有效治疗选择。当然，我们需要更多的临床试验数据，来进一步支持恩沃利单抗的治疗潜力，为局部晚期的肺NEC患者提供更多的治疗策略。专家点评相较于非小细胞肺癌（NSCLC），肺NEC发病率低，但基于肺癌庞大的发病率，这部分患者人数不容忽视。同时，随着病理诊断手段及水平的不断上升，肺NENs的发病率也逐渐上升[5]。近年来，精准医疗改变了癌症的诊疗方案，尤其在NSCLC领域得到了突飞猛进的发展。肺NEC这种相对罕见的肿瘤，也在免疫治疗中迎来曙光。恩沃利单抗是全球首个可以皮下给药的PD-L1单抗药物，通过抑制肿瘤免疫逃逸机制，激活免疫系统，已经在晚期实体瘤中展现出初步的抗肿瘤疗效[6-7]。WCLC大会公布了一项前瞻性、单臂、I期研究，纳入32例既往未经治疗的广泛期小细胞肺癌（ES-SCLC）患者，接受四个周期的卡铂(AUC=5/6，D1)和依托泊苷(80-100 mg/m2，D1-3)联合恩沃利单抗(300mg，D6)的诱导治疗，随后进行恩沃利单抗300 mg维持治疗，直至出现进展或无法耐受的毒性。中位随访时间为10.6个月(95%C1,8.8-12.8)，中位PFS为6.2个月，中位OS未达到。6个月和12个月PFS率分别为52.3%和14.0%，6个月、9个月和12个月OS率分别为87.3%，79.6%和71.9%，疗效显著[8]。恩沃利单抗在晚期实体瘤二线治疗中也展示出了潜力，在CSCO指南中被推荐用于MSI-H/dMMR的胃癌、子宫内膜癌患者的二线治疗[9-10]。CN-006研究是恩沃利单抗单药治疗二线及以上MSI-H/ dMMR实体瘤的单臂、国内多中心II期研究，结果显示，恩沃利单抗单药治疗既往接受至少一线标准治疗失败的 MSI-H/ dMMR 晚期CRC患者中疗效显著[11-12]。本例患者经过一线方案治疗，无进展生存期（PFS）达到了8.5个月，之后出现疾病进展，二线使用恩沃利单抗+安罗替尼+依托泊苷治疗，最终达到部分缓解。体现出恩沃利单抗在晚期肺神经内分泌癌二线治疗中的优势。未来期待恩沃利单抗能为更多患者带来新的选择和希望。专家简介姜战胜天津市肿瘤医院中西医结合科副主任医师医学博士、硕士生导师天津市抗癌协会中西医结合肿瘤治疗专业委员会候任主委承担多项国家级、省部级课题发表中英学术论文数十篇，拥有发明专利两项、实用专利两项医生简介张曼天津市肿瘤医院空港医院中西医结合科主治医师医学博士中国抗癌协会乳腺癌专业委员会会员主要从事肿瘤内科临床工作发表多篇论文主持天津市滨海新区卫健委科技项目课题1项仅供医疗卫生专业人士阅读转载自：SIMMED 恩维达学术进展：1、2024 WCLC｜创新免疫治疗方案：恩沃利单抗联合化疗在II-IIIB期NSCLC中的潜力 2、IF 40.8 | 梁廷波教授团队恩沃利单抗联合仑伐替尼和TACE治疗中晚期肝癌研究结果见刊！ 3、2024 WCLC｜恩维达®治疗鳞状非小细胞肺癌II期临床试验于WCLC大会展示最新临床数据4、2024 ESMO｜恩维达®治疗胆道癌II期临床试验将于ESMO大会展示最新临床数据 5、戴胜教授：新辅助短程放疗序贯恩沃利单抗联合CAPEOX能够给MSS局部晚期直肠癌带来革命性的pCR结果6、2024 ASCO｜恩维达®联合仑伐替尼治疗晚期子宫内膜癌数据以壁报形式首次披露，临床潜力令人期待！7、2024 ASCO｜再创新高！恩沃利单抗9项研究获大会展示8、最新学术进展|恩维达®首次进入胃癌外科领域共识，晚期胆道癌数据将亮相APASL口头报告关于恩维达®（恩沃利单抗注射液）恩维达®（恩沃利单抗注射液）由康宁杰瑞自主研发，2016年起与思路迪医药共同开发，2020年3月30日，康宁杰瑞、思路迪医药、先声药业三方达成战略合作，康宁杰瑞作为原研方负责生产和质量，思路迪医药负责肿瘤领域的临床开发，先声药业负责产品在中国大陆的独家商业推广。基于其独特设计，恩维达®在有效性、安全性、便利性、依从性方面具有优势，患者无需进行静脉滴注，同时有望降低医疗成本。目前在中国、美国和日本针对多个肿瘤适应症同步开展临床试验，多个适应症已进入注册/Ⅲ期临床。恩维达®已被美国FDA授予晚期胆道癌孤儿药资格、软组织肉瘤孤儿药资格。2021年11月，恩维达®正式在中国率先获批上市，适用于不可切除或转移性微卫星高度不稳定(MSI-H)或错配修复基因缺陷型(dMMR)的成人晚期实体瘤患者的治疗，包括既往经过氟尿嘧啶类、奥沙利铂和伊立替康治疗后出现疾病进展的晚期结直肠癌患者以及既往治疗后出现疾病进展且无满意替代治疗方案的其他晚期实体瘤患者。关于思路迪医药（3D Medicines Inc.）思路迪医药股份有限公司（1244.HK）是一家进入商业化阶段专注肿瘤慢病化治疗领域的创新药公司，秉承“帮助肿瘤患者活得更久更好”的愿景，研发新一代抗肿瘤药物。公司产品线包括12款具有差异化临床价值或全球领先的创新药，其中8款已进入临床开发或商业化阶段，包括全球首个皮下注射PD-L1单域抗体新药恩维达®已获国家药品监督管理局批准上市销售；依托公司自有mRNA研发平台和肿瘤基因组大数据AI分析平台，研发系列mRNA产品；公司自主研发的多靶点激酶抑制剂3D011也进入了临床开发阶段，临床前品种包括国际领先的CD3xPD-L1双特异性抗体。公司建立了从药物发现、临床前研究、临床开发、申报上市及商业化能力。思路迪医药坚持以患者为中心，开发具有差异化临床价值的创新药。更多信息请访问： http://www.3d-medicines.com 思路迪医药前瞻性声明本文所作出的前瞻性陈述仅与本文作出该陈述当日的事件或资料有关。除法律规定外，于作出前瞻性陈述当日之后，无论是否出现新资料、未来事件或其他情况，我们并无责任更新或公开修改任何前瞻性陈述及预料之外的事件。请细阅本文，并理解我们的实际未来业绩或表现可能与预期有重大差异。本文内所有关于或引用的本公司及董事的陈述、观点或意愿乃本文章刊发日期作出，可能因未来发展而出现变动。

CSCO会议免疫疗法临床3期临床结果临床2期

2024-10-23

·GlobeNewswire-Health Care

Kronos Bio Data Presentation at EORTC-NCI-AACR Symposium Highlights the Importance of p300 KAT Inhibition in HPV-Driven Tumors

– Preclinical data demonstrate that inhibiting the p300 KAT domain reactivates p53 in HPV-driven tumors resulting in anti-tumor activity –SAN MATEO, Calif., and CAMBRIDGE, Mass., Oct. 23, 2024 (GLOBE NEWSWIRE) -- Kronos Bio, Inc. (Nasdaq: KRON), a company dedicated to developing small molecule therapeutics that address cancers and autoimmune diseases driven by deregulated transcription, today announced preclinical data from its p300 KAT inhibitor program for human papillomavirus (HPV)-driven tumors at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. Kronos Bio is exploring the utility of its p300 KAT inhibitor, KB-9558, for HPV-driven tumors. In the presentation, the authors show that the HPV genome preferentially integrates into transcriptionally active regions in the human genome where it becomes dependent on p300 to drive expression of its E6 and E7 oncogenes. It is widely recognized that elevated transcription of HPV E6 and E7 genes promotes degradation of tumor suppressors p53 and Rb. Importantly, inhibition of p300 KAT activity was highly selective in repressing the transcription of E6 and E7, which in turn led to restoration of the p53 and Rb pathways and drove anti-tumor effects through apoptosis and inhibition of uncontrolled tumor cell growth. "Continued expression of certain viral genes, especially E6 and E7, plays a critical role in tumor growth and progression of HPV-driven tumors, including head & neck, cervical, and other anogenital cancers. Importantly, there are no approved targeted therapies that inhibit E6 and E7,” said Charles Lin, Ph.D., chief scientific officer of Kronos Bio. "While this is early-stage research, given the ability of p300 KAT inhibition to target E6 and E7 and restore tumor suppressor pathways, we believe this p300 KAT inhibitor has the potential to be a remarkable and unique approach toward ensuring that fewer people suffer from HPV-driven cancer." In the presentation titled, "Oncogenic human papillomavirus hijacks p300 to drive viral transcription, creating a therapeutic vulnerability that can be exploited with selective p300/CBP catalytic inhibitors", the authors describe the experiments that led to the following key findings: HPV integrates into the human genome at specific locations where p300 regulates transcriptionp300 inhibition demonstrated specific and potent reduction of expression of HPV oncogenes E6 and E7, both at the RNA and protein levelLoss of E6 and E7 led to restoration of p53 and Rb tumor suppressor pathways which led to the upregulation of p53 activated genes (e.g., CDKN1A) and downregulation of Rb repressed genes (e.g., CDK1)Re-expression of E6 and E7 from an exogenous lentiviral vector where viral oncogene transcription is not mediated by p300 KAT activity reversed the effects of p300 KAT inhibition on p53 restoration and anti-tumor effectsThese findings support the potential of KB-9558, a p300 KAT inhibitor, to treat HPV-driven tumors given its potential to suppress E6 and E7 expression and restore the p53 pathway The poster presentation will take place on October 24, 2024, and is currently available under the Publications section of the Kronos Bio website. About Kronos BioKronos Bio is a clinical-stage biopharmaceutical company dedicated to developing small molecule therapeutics that address deregulated transcription, a hallmark of cancer and autoimmune disease. Our proprietary discovery engine decodes complex transcription factor regulatory networks to identify druggable cofactors. We screen for and optimize small molecules that target these cofactors in a disease-specific context. Kronos Bio has a pipeline of three drug candidates. Istisociclib (KB-0742) is currently enrolling ovarian cancer patients in a Phase 1/2 clinical trial. Preclinical candidate KB-9558 is being developed for multiple myeloma and HPV-driven tumors. KB-7898 is Kronos Bio’s first autoimmune development candidate and has a target indication of Sjögren’s disease. Kronos Bio is based in San Mateo, Calif., and has a research facility in Cambridge, Mass. For more information, visit https://www.kronosbio.com or follow the Company on LinkedIn. Forward-Looking StatementsStatements in this press release that are not statements of historical fact are forward-looking statements for purposes of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. The press release, in some cases, uses terms such as “anticipate,” “believe,” “could,” “expect,” “plan,” “will,” “may,” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Forward-looking statements include statements regarding Kronos Bio’s intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things, KB-9558’s ability to potentially treat HPV-driven tumors; the potential of Kronos Bio’s product candidates, pipeline and its proprietary discovery engine; and other statements that are not historical fact. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, including, without limitation: changes in the macroeconomic environment or competitive landscape that impact Kronos Bio’s business; whether Kronos Bio will be able to progress its preclinical pipeline on the timelines anticipated, including due to risks inherent in the development of novel therapeutics; the risk that results of preclinical studies, early clinical trials (including preliminary results) and pharmacokinetic modeling are not necessarily predictive of future results; and risks associated with the sufficiency of Kronos Bio’s cash resources and need for additional capital. These and other risks are described in greater detail in Kronos Bio’s filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in its Quarterly Report on Form 10-Q for the quarter ended June 30, 2024, filed with the SEC on August 8, 2024. Any forward-looking statements that are made in this press release speak only as of the date of this press release and are based on management’s assumptions and estimates as of such date. Except as required by law, Kronos Bio assumes no obligation to update the forward-looking statements whether as a result of new information, future events or otherwise, after the date of this press release.

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