This phase III trial studies using risk factors in determining treatment for children with favorable tissue (histology) Wilms tumors (FHWT). Wilms Tumor is the most common type of kidney cancer in children, and FHWT is the most common subtype. Previous large clinical trials have established treatment plans that are likely to cure most children with FHWT, however some children still have their cancer come back (called relapse) and not all survive. Previous research has identified features of FHWT that are associated with higher or lower risks of relapse. The term "risk" refers to the chance of the cancer coming back after treatment. Using results of tumor histology tests, biology tests, and response to therapy may be able to improve treatment for children with FHWT.

开始日期2025-03-31

申办/合作机构

The Children's Oncology Group Foundation, Inc.

NCT06647953

/ Not yet recruiting临床3期IIT

Prospective Treatment of Types I, II and III Pleuropulmonary Blastoma (PPB)

This phase III trial tests how well surgery plus chemotherapy compared to surgery alone works in treating patients with type I pleuropulmonary blastoma (PPB), and tests how well surgery plus standard chemotherapy with the addition of topotecan works compared to surgery plus standard chemotherapy alone in treating patients with type II and III PPB.
Historically, most children with type I PPB had surgery and approximately 40% of children with type I PPB received chemotherapy following their surgery, usually for 22-42 weeks. There has not been a consistent standard for which children with type I PPB receive chemotherapy after surgery. For patients whose tumor has been removed completely with surgery, observation without chemotherapy may work as well as giving chemotherapy after surgery in preventing a return of the PPB tumor.
The standard chemotherapy for patients with types II or III PPB in the United States is four cycles of IVADo (ifosfamide, vincristine, dactinomycin, and doxorubicin) followed by 8 cycles of IVA (ifosfamide, vincristine and dactinomycin). Ifosfamide is in a class of medications called alkylating agents. It works by slowing or stopping the growth of tumor cells in the body. Vincristine is in a class of medications called vinca alkaloids. It works by stopping tumor cells from growing and dividing and may kill them. Dactinomycin is a type of antibiotic that is only used in cancer chemotherapy (antineoplastic antibiotic). It works by damaging the cell's deoxyribonucleic acid (DNA) and may kill tumor cells. Doxorubicin is in a class of medications called anthracyclines. Doxorubicin damages the cell's DNA and may kill tumor cells. It also blocks a certain enzyme needed for cell division and DNA repair. Topotecan is in a class of medications called topoisomerase I inhibitors. It works by interfering with tumor cell DNA which kills them. Giving topotecan in addition to standard IVADo and IVA chemotherapy regimens may shrink the cancer as well as or better than the standard therapy or could decrease the chance the tumor spreads while causing fewer side effects.

开始日期2025-03-17

申办/合作机构

The Children's Oncology Group Foundation, Inc.

NCT06020755

/ Recruiting临床2期IIT

Efficacy and Safety of Toripalimab Plus Actinomycin-D As Fist-Line Treatment in Patients with Gestational Trophoblastic Neoplasia with FIGO Score 7: a Single-Arm, Multicenter, Phase II Trial

The goal of this clinical trial is to evaluate the efficacy and safety of toripalimab plus actinomycin-D as fist-line treatment in patients with gestational trophoblastic neoplasia with FIGO score 7. The main questions it aims to answer are:
* Whether toripalimab plus actinomycin-D as fist-line treatment can achieve a high complete response rate.
* Whether an equally high cure rate can be achieved by multi-drug chemotherapy as second-line treatment in patients who have failed fist-line treatment with toripalimab plus actinomycin-D.
Participants will receive toripalimab plus actinomycin-D. Treatment will be continued until disease progression, unacceptable toxicity, or withdrawal of consent. Treatment will be completed after 4 consolidation cycles.

开始日期2024-12-01

申办/合作机构

北京协和医院

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100 项与放线菌素D 相关的专利（医药）

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23,814

项与放线菌素D 相关的文献（医药）

2025-12-01·FUNCTIONAL & INTEGRATIVE GENOMICS

Epigenetic modification mediated by PHF20/METTL14/HOXA13 signaling axis modulates osteogenic differentiation of mesenchymal stem cells

Article

作者: Chen, Ting ; Feng, Weijia

This study investigates the mechanism of PHF20 in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). BMSCs from Balb/c mouse were cultured and identified through osteogenesis, adipogenesis, and flow cytometry. After osteogenic induction, the levels of OPN and OCN in BMSCs were detected by RT-qPCR. Alizarin red staining and alkaline phosphatase (ALP) staining were used to evaluate the osteogenic differentiation ability of BMSCs. PHF20, METTL14, and HOXA13 expressions were detected by RT-qPCR and Western blot. After quantitative analysis of m6A level, RNA immunoprecipitation (RIP) was performed to measure the enrichment of IGF2BP3 or m6A on HOXA13 mRNA. HOXA13 mRNA stability was assessed after actinomycin D treatment. PHF20, METT14, and HOXA13 expressions gradually increased during osteogenic differentiation of BMSCs. Suppression of PHF20 expression repressed the osteogenic differentiation of BMSCs, mainly resulted in a decrease in OPN and OCN levels, reduced mineralization, and weakened ALP activity. Mechanistically, PHF20 elevated METTL14 expression by enhancing the enrichment of H3K4me3 on its promoter, and METTL14 strengthened HOXA13 m6A methylation to maintain HOXA13 mRNA stability through IGF2BP3. In conclusion, PHF20 elevates METTL14 expression by enhancing H3K4me3 enrichment on its promoter and enhances HOXA13 mRNA stability via IGF2BP3-mediated m6A modification, thus facilitating HOXA13 expression and eventually inducing osteogenic differentiation of BMSCs.

2025-07-01·Annals of Hepatology

The promoting effect of the POU3F2/METTL16/PFKM cascade on glycolysis and tumorigenesis of hepatocellular carcinoma

Article

作者: Yang, Yuan ; Hu, Guangsheng ; Chen, Ming ; Peng, Zhong ; Wen, Wu

INTRODUCTION AND OBJECTIVES:

Deregulation of m⁶A methylation, the most prevailing RNA modification, participates in cancer pathogenesis. METTL16, an atypical methyltransferase, functions as a pro-tumorigenic factor in hepatocellular carcinoma (HCC). Here, we explored the action of METTL16 on HCC glycolysis and the associated mechanism.

MATERIALS AND METHODS:

Expression analysis was done by quantitative PCR, immunoblotting, or immunohistochemistry. Cell sphere formation, invasiveness, apoptosis, proliferation and viability were detected by sphere formation, transwell, flow cytometry, EdU and CCK-8 assays, respectively. Xenograft studies were performed to analyze the role in vivo. Methylated RNA immunoprecipitation (MeRIP) and RIP assays were used to verify the METTL16/PFKM relationship. PFKM mRNA stability was tested by actinomycin D treatment. Chromatin immunoprecipitation (ChIP) and luciferase assays were performed to analyze the POU3F2/METTL16 relationship.

RESULTS:

In HCC, METTL16 expression was elevated, and increased levels of METTL16 transcript predicted poor HCC prognosis. METTL16 deficiency resulted in suppressed HCC cell growth, invasiveness and sphere formation. Moreover, METTL16 depletion diminished HCC cell glycolysis. Mechanistically, PFKM expression was positively associated with METTL16 expression. METTL16 mediated m6A methylation to stabilize PFKM mRNA via an IGF2BP3-dependent manner. Restored PFKM expression exerted a counteracting effect on METTL16 deficiency-mediated in vitro cell phenotype alterations and in vivo xenograft growth suppression. Furthermore, POU3F2 promoted the transcription of METTL16 in HCC cells.

CONCLUSIONS:

Our findings define the crucial role of the POU3F2/METTL16/PFKM axis in HCC pathogenesis, offering the potential opportunity to combat HCC.

2025-04-01·INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES

Comprehensive analysis of the xbp1 gene in Pacific abalone Haliotis discus hannai: Structure, expression, and role in heat stress response

Article

作者: Liu, Yue ; Pan, Mingzhu ; Li, Xinxin ; Zhang, Wenbing ; Qin, Gaochan ; Chen, Zhichu ; Mai, Kangsen ; Yu, Xiaojun ; Huang, Dong

The present study explores the x-box binding protein 1 (xbp1) gene in Haliotis discus hannai (Pacific abalone), focusing on its structure, expression, and functional role under heat stress. Southern blot revealed two copies of xbp1 in the intestine and mantle, one in the gill and muscle, and no detection in the digestive gland. mRNA expression level of xbp1 was highest in the gill, followed by the mantle, intestine, and muscle, with the digestive gland showing the lowest expression. Actinomycin D treatment demonstrated that xbp1 mRNA stability varied among tissues, with slower degradation in the gill and mantle, while rapid degradation was observed in the digestive gland. Heat stress caused a 20 bp fragment removal from xbp1 mRNA, producing spliced xbp1 (xbp1s), with a conserved inositol-requiring enzyme 1α (IRE1α) cleavage motif (5'- CAGCACCUGCUGAUCCUCUG -3'). Genome walking was used to obtain the promoter sequences of downstream genes regulated by xbp1s. Through sequence conservation analysis, the binding sites of xbp1s on these promoters were identified in Pacific abalone. Yeast one-hybrid (Y1H) assays confirmed xbp1s binding to these sites, and morpholino oligonucleotides (MO) treatment effectively suppressed xbp1s production. Western blot analysis demonstrated that heat stress induced the expression of HDEL-related proteins, while MO injection significantly reduced their expression under both basal and heat stress conditions. Immunofluorescence analysis revealed decreased endoplasmic reticulum (ER) chaperone glucose-regulated protein 78 (GRP78) levels and increased apoptosis in MO-treated abalone under heat stress, suggesting a compromised ER stress response. These findings underscore XBP1's crucial role in regulating ER stress management and apoptotic processes, providing new insights into the functional significance of xbp1 in abalone's response to thermal stress.

项与放线菌素D 相关的新闻（医药）

2025-02-28

·ioncology

SGO 2025丨最重要的研究进展：科学全体会议的报告一览

点上方蓝字“ioncology”关注我们，然后点右上角“…”菜单，选择“设为星标” SGO 2025微专辑扫描二维码可查看更多内容第56届美国妇科肿瘤学年会（SGO 2025）将于2025年3月14-17日在西雅图举办。在肿瘤学学术会议中，“Scientific Plenary”（科学全体会议）通常是指会议中最核心、最具权威性的学术环节，其内容往往代表年度研究最高水平。本文汇总2025 SGO科学全体会议的研究内容，供读者参考。科学全体会议（Scientific Plenary）摘要ID：935279 英文标题：Pembrolizumab Plus Chemoradiotherapy for High-Risk Locally Advanced Cervical Cancer: Overall Survival and Progression-Free Survival 2 Results From the Randomized, Double-Blind, Phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 Study 中文标题：帕博利珠单抗联合放化疗治疗高风险局部晚期宫颈癌：随机、双盲、III期ENGOT-cx11/GOG-3047/KEYNOTE-A18研究的总生存（OS）和第二次无进展生存（PFS2）结果汇报人：Linda Duska丨弗吉尼亚大学医学院摘要ID：864114 英文标题：Cadonilimab plus lenvatinib in patients with advanced endometrial cancer: a multicenter, single-arm, phase II trial 中文标题：卡度尼利单抗+乐伐替尼治疗晚期子宫内膜癌患者：一项多中心、单组I期试验汇报人：蓝春燕丨中山大学附属肿瘤医院摘要ID：852136 英文标题：A Phase II study of induction PD-1 blockade (nivolumab) in patients with surgically completely resectable mismatch repair deficient endometrial cancer (NIVEC) 中文标题：针对可手术完全切除的错配修复缺陷型子宫内膜癌患者进行诱导PD-1阻断（纳武利尤单抗）治疗的II期研究汇报人：Lee Yong Jae丨延世大学医学院摘要ID：812874 英文标题：Sentinel Lymph Node Biopsy versus Pelvic Lymphadenectomy in Cervical Cancer: the PHENIX-I trial 中文标题：宫颈癌前哨淋巴结活检vs盆腔淋巴结清扫术：PHENIX-I试验汇报人：刘继红丨中山大学肿瘤防治中心摘要ID：922975 英文标题：Durvalumab plus carboplatin/paclitaxel followed by durvalumab with/without olaparib in endometrial cancer: biomarkers, histological heterogeneity, baseline circulating tumor DNA levels, and efficacy in the DUO-E mismatch repair proficient subpopulation 中文标题：度伐利尤单抗+卡铂/紫杉醇序贯度伐利尤单抗±奥拉帕利治疗子宫内膜癌：生物标志物、组织学异质性、基线循环肿瘤DNA水平以及DUO-E错配修复功能健全亚组的疗效汇报人：Kathleen Moore丨俄克拉荷马大学摘要ID：815965 英文标题：Randomized Phase III Trial of Adjuvant Radiation versus Chemo-radiation in Intermediate-Risk, Early-stage Cervical Carcinoma following Radical Hysterectomy and Lymphadenectomy (Results of NRG Oncology/GOG-263) 中文标题：对比辅助放疗vs化放疗用于接受根治性子宫切除术和淋巴结清扫术后的中危早期宫颈癌患者：随机III期NRG Oncology/GOG-263试验结果汇报人：Ryu Sang Young丨韩国癌症中心医院摘要ID：808923 英文标题：Patient-reported outcomes (PROs) on a Randomized Phase III Clinical Trial of Adjuvant Radiation (RT) versus Chemoradiation (RT+CIS) in Intermediate Risk, Stage I/IIA Cervical Cancer Treated with Initial Radical Hysterectomy and Pelvic Lympha 中文标题：对比辅助放疗vs放化疗用于初始根治性子宫切除术和盆腔淋巴结清扫术治疗后的中危I/IIA期宫颈癌患者：一项随机III期临床试验的患者报告结果(PRO) 汇报人：Alexandra Smick丨加利福尼亚大学洛杉矶分校（UCLA）摘要ID：811862 英文标题：Comparing community member and provider-perceived barriers to clinical trial enrollment in rural areas: how well do we know our patients? 中文标题：比较社区成员和医疗提供方认为的农村地区临床试验的入组障碍：我们对患者的了解程度如何？汇报人：Kaylee Underkofler丨弗吉尼亚大学摘要ID：812926 英文标题：Development of an Endometrial Cancer Test for Evaluating Abnormal Uterine Bleeding 中文标题：开发用于评估异常子宫出血的子宫内膜癌检测方法汇报人：Jamie Bakkum-Gamez丨梅奥诊所摘要ID：822422 英文标题：Utility of the CA125 KELIM in for predicting the benefit of from HIPEC in patients with advanced ovarian cancer: pooled analysis of individual data from KGOG3042 and KOV-HIPEC01 中文标题：使用CA125 KELIM预测晚期卵巢癌患者接受HIPEC治疗获益：KGOG3042和KOV-HIPEC01个体数据的汇总分析汇报人：Cho Hyun-Woong丨高丽大学教师医院摘要ID：843870 英文标题：An Open-Label Randomized Active-Controlled Phase II Clinical Study to Assess the Efficacy and Safety of Afuresertib Plus Paclitaxel Versus Paclitaxel in Patients with Platinum-Resistant Ovarian Cancer (GOG 3044) 中文标题：开放标签随机阳性对照II期临床研究（GOG 3044）：评估Afuresertib+紫杉醇vs紫杉醇治疗铂耐药卵巢癌患者的疗效和安全汇报人：Thomas Herzog丨辛辛那提大学癌症中心摘要ID：812768 英文标题：DB-1305/BNT325 (a novel TROP-2 ADC) in patients with ovarian cancer: Efficacy and safety data from a phase 1/2 study 中文标题：DB-1305/BNT325（新型TROP-2 ADC）在卵巢癌患者中的应用：I/II期研究的疗效和安全性数据汇报人：Maria Rubinstein丨纪念斯隆凯特琳癌症中心摘要ID：814654 英文标题：Cyclin E1 is a Predictive Biomarker of Azenosertib Benefit in Platinum-Resistant Ovarian Cancer (PROC): Outcomes from Part 1b of the DENALI Study (GOG-3066) 中文标题：细胞周期蛋白E1是Azenosertib治疗铂耐药卵巢癌获益的预测性生物标志物：DENALI研究（GOG-3066）Ib部分的结果汇报人：Fiona Simpkins丨宾夕法尼亚大学摘要ID：933087 英文标题：Safety and preliminary efficacy of puxitatug samrotecan (P-Sam, AZD8205) in patients (pts) with endometrial cancer (EC): a first-in-human Phase 1/2a study 中文标题：puxitatug samrotecan（P-Sam, AZD8205）治疗子宫内膜癌患者的安全性和初步疗效：一项首次人体I/IIa期研究汇报人：Stephanie Gaillard丨约翰霍普金斯大学西德尼·金梅尔癌症中心摘要ID：926320 英文标题：Early salpingectomy with delayed oophorectomy as alternative for risk-reducing salpingo-oophorectomy - the first 2000 participants in the ongoing international TUBA-WISP II study 中文标题：早期输卵管切除术和延迟卵巢切除术作为降低风险的输卵管卵巢切除术的替代方案：正在进行的国际II期TUBA-WISP研究的前2000名受试者汇报人：Tamar Gootzen丨拉德堡德医学中心摘要ID：927707 英文标题：Comparing Efficacy and Safety of Biweekly Single-Dose Actinomycin D versus Multiday Methotrexate Therapy in Low-Risk Gestational Trophoblastic Neoplasia: A Prospective Multicentre Randomized Trial 中文标题：比较每两周一次放线菌素D vs多日甲氨蝶呤治疗低风险妊娠滋养细胞肿瘤的疗效和安全性：一项前瞻性多中心随机试验汇报人：蒋芳丨北京协和医院摘要ID：938179 英文标题：Phase 2 study of letrozole, abemaciclib and metformin in estrogen receptor (ER) positive recurrent endometrial cancer (EC) 中文标题：来曲唑、阿贝西利和二甲双胍治疗雌激素受体（ER）阳性复发性子宫内膜癌的II期研究汇报人：Panagiotis Konstantinopoulos丨丹娜—法伯癌症研究所摘要ID：922978 英文标题：Efficacy and safety of luveltamab tazevibulin in patients with recurrent platinum-resistant ovarian cancer: results from the dose-optimization stage of the REFRalphaME-O1 (GOG-3086, ENGOT-79OV, and APGOT-OV9) phase 2/3 study 中文标题：Luveltamab tazevibulin治疗复发性铂耐药卵巢癌的疗效和安全性：II/III期REFRaME-O1（GOG-3086、ENGOT-79OV和APGOT-OV9）临床试验剂量优化阶段的结果汇报人：Lee Jung-Yun丨延世大学世福兰斯医院摘要ID：953906 英文标题：Chemotherapy with or without pembrolizumab followed by maintenance with olaparib or placebo for first-line treatment of advanced BRCA non-mutated epithelial ovarian cancer: Results from the randomized phase 3 ENGOT-OV43/GOG-30 中文标题：化疗±帕博利珠单抗序贯奥拉帕利或安慰剂维持治疗作为晚期BRCA非突变上皮性卵巢癌的一线治疗：随机III期ENGOT-OV43/GOG-30试验结果汇报人：Matthew Powell丨华盛顿大学医学院摘要ID：939696 英文标题：Final overall survival analysis among patients with FRalpha;-positive, platinum-resistant ovarian cancer (PROC) treated with mirvetuximab soravtansine (MIRV) vs. investigator's choice chemotherapy (ICC) in the Phase 3 MIRASOL (GOG 304) 中文标题：索米妥昔单抗(MIRV) vs 研究者选择的化疗治疗FRα阳性、铂耐药卵巢癌：III期MIRASOL（GOG 304）试验的最终OS分析汇报人：Toon Van Gorp丨鲁汶大学医院摘要ID：822484 英文标题：Phase 2 study of Maintenance of Niraparib rechallenge plus Bevacizumab in Patients with Platinum-Sensitive, Recurrent Ovarian Cancer Previously Treated with a PARP inhibitor (KGOG 3056/NIRVANA-R) 中文标题：PARP抑制剂经治的铂敏感复发性卵巢癌患者接受尼拉帕利再使用+贝伐珠单抗维持治疗的II期临床研究 (KGOG 3056/NIRVANA-R) 汇报人：Hyun-Woong Cho丨高丽大学九老医院摘要ID：938651 英文标题：Trends in Gynecologic Cancers across the United States from 2001-2019: Impact of Social Determinants of Health on Stage at Diagnosis 中文标题：2001-2019年美国妇科癌症趋势：“健康的社会决定因素”对诊断分期的影响汇报人：Michael Desjardins丨约翰霍普金斯大学彭博公共卫生学院摘要ID：812404 英文标题：Measuring Contemporary Symptoms in a Diverse Population of Endometrial Cancer Patients: Development and Initial Validation of a Brief Symptom Index from the PROMOTE Study 中文标题：评估不同子宫内膜癌患者群体的当前症状：PROMOTE研究中简明症状指数的开发和初步验证汇报人：Chelsea McKinney丨加州大学欧文分校摘要ID：842468 英文标题：Impact of treatment-emergent ocular events on health-related quality of life in patients with FRalpha;-positive platinum-resistant ovarian cancer treated with mirvetuximab soravtansine: results from the phase 3 MIRASOL study 中文标题：治疗中出现的眼部不良事件对接受索米妥昔单抗治疗的FRa阳性铂耐药卵巢癌患者健康相关生活质量的影响：来自III期MIRASOL研究的结果汇报人：Tashanna Myers丨贝斯特医疗中心摘要ID：808773 英文标题：Clinician Nudge to Gynecologic Oncology Referral at Suspected Ovarian Cancer Diagnosis: A Pilot Study 中文标题：临床医生推动疑似卵巢癌的患者向妇科肿瘤科转诊：一项试点研究汇报人：Anna Jo Smith丨宾夕法尼亚大学（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2期临床结果

2025-02-27

·ioncology

SGO 2025丨美国妇科肿瘤学年会上的中国好声音

点上方蓝字“ioncology”关注我们，然后点右上角“…”菜单，选择“设为星标” SGO 2025微专辑扫描二维码可查看更多内容第56届美国妇科肿瘤学年会（SGO 2025）将于2025年3月14-17日在西雅图举办。作为全球范围内最权威的妇科肿瘤学术会议之一，SGO年会将为业内同道提供交流最新研究成果和临床经验的平台，展示具有创新性及前沿视角的观点和思路。本文汇总中国学者在2025 SGO上的报告内容，如有疏漏，敬请指出。科学全体会议（Scientific Plenary）摘要ID：864114 英文标题：Cadonilimab plus lenvatinib in patients with advanced endometrial cancer: a multicenter, single-arm, phase II trial 中文标题：卡度尼利单抗+乐伐替尼治疗晚期子宫内膜癌患者：一项多中心、单组I期试验汇报人：蓝春燕丨中山大学附属肿瘤医院摘要ID：812874 英文标题：Sentinel Lymph Node Biopsy versus Pelvic Lymphadenectomy in Cervical Cancer: the PHENIX-I trial 中文标题：宫颈癌前哨淋巴结活检vs盆腔淋巴结清扫术：PHENIX-I试验汇报人：刘继红丨中山大学肿瘤防治中心摘要ID：927707 英文标题：Comparing Efficacy and Safety of Biweekly Single-Dose Actinomycin D versus Multiday Methotrexate Therapy in Low-Risk Gestational Trophoblastic Neoplasia: A Prospective Multicentre Randomized Trial 中文标题：比较每两周单剂量放线菌素D vs多日甲氨蝶呤治疗低风险妊娠滋养细胞肿瘤的疗效和安全性：一项前瞻性多中心随机试验汇报人：蒋芳丨北京协和医院焦点论坛（Focused Forum）摘要ID：852145 英文标题：Zimberelimab plus lenvatinib in patients with advanced cervical cancer who progressed after prior immune checkpoint inhibitors: a multicenter, single-arm, phase II trial 中文标题：赛帕利单抗联合乐伐替尼治疗经免疫检查点抑制剂治疗后病情进展的晚期宫颈癌患者：一项多中心、单组、II期试验汇报人：蓝春燕丨中山大学附属肿瘤医院摘要ID：873424 英文标题：Immunotherapy Rechallenge with Cadonilimab in Patients with Recurrent or Metastatic Cervical Cancer: A Retrospective Study 中文标题：复发性或转移性宫颈癌患者再次接受卡度尼利单抗免疫疗法治疗：一项回顾性研究汇报人：Lin Jie丨福建省肿瘤医院摘要ID：937243 英文标题：Biomarker-driven Targeted Therapy in Platinum-Resistant Ovarian Cancer (PROC): Results from the BRIGHT Trial 中文标题：铂类耐药卵巢癌(PROC)的生物标志物驱动靶向治疗：BRIGHT试验结果汇报人：高庆蕾丨华中科技大学同济医学院附属同济医院摘要ID：838826 英文标题：(ENCORE) An open-label, prospective phase II study of cadonilimab in combination with neoadjuvant chemotherapy for patients diagnosed with advanced ovarian cancer (AK104-IIT-003) 中文标题：ENCORE：一项针对卡度尼利单抗联合新辅助化疗治疗晚期卵巢癌患者的开放标签、前瞻性II期研究（AK104-IIT-003）汇报人：唐洁丨湖南省肿瘤医院特色壁报专场（Featured Poster Session）摘要ID：823842 英文标题：AK104 combined with concurrent chemoradiotherapy for the treatment of locally advanced Cervical Cancer 中文标题：AK104联合同期放化疗治疗局部晚期宫颈癌汇报人：蒋芳丨北京协和医院摘要ID：823525 英文标题：Neoadjuvant Chemotherapy Followed by Chemoradiation Plus Adjuvant Chemotherapy for Locally Advanced Cervical Cancer: A Real-World Study with 10 Years Experience 中文标题：局部晚期宫颈癌患者在新辅助化疗后进行放化疗加辅助化疗：一项具有10年经验的真实世界研究汇报人：唐洁丨湖南省肿瘤医院摘要ID：859742 英文标题：Pamiparib in combination with surufatinib in patients with platinum-resistant ovarian cancer who received prior PARP inhibitors: a multicenter, single-arm, phase Ib/II trial (POST-PARPi Trial) 中文标题：帕米帕利联合索凡替尼治疗经PARP抑制剂治疗的铂耐药性卵巢癌患者：一项多中心、单组、Ib/II期POST-PARPi试验汇报人：蓝春燕丨中山大学附属肿瘤医院壁报导览（Poster Tour）摘要ID：823980 英文标题：Enlonstobart (SG001) plus platinum-based chemotherapy ± bevacizumab for first-line treatment of PD-L1 positive recurrent/metastatic cervical cancer: safety run-in results of the phase III randomized, double-blind trial 中文标题：Enlonstobart (SG001)联合铂类化疗±贝伐珠单抗用于PD-L1阳性复发/转移性宫颈癌的一线治疗：III期随机双盲试验的安全性结果汇报人：Zuo Jing丨国家癌症中心摘要ID：820986 英文标题：Efficacy and safety of carboplatin/paclitaxel combined tislelizumab for recurrent ovarian cancer progressing within 6-12 months after the last platinum line. 中文标题：卡铂/紫杉醇联合替雷利珠单抗治疗最后一线铂类治疗后6-12个月内进展的复发性卵巢癌的疗效和安全性汇报人：杨谢兰丨云南省肿瘤医院摘要ID：851273 英文标题：Cadonilimab combined with TP regimen-induced cisplatin concurrent radiotherapy for locally advanced cervical cancer: A Prospective, Single-Arm Phase II Clinical Trial 中文标题：卡度尼利单抗联合TP方案诱导顺铂同步放疗治疗局部晚期宫颈癌的前瞻性、单组Ⅱ期临床试验汇报人：Li Mingyi丨广州医科大学附属肿瘤医院摘要ID：826744 英文标题：Fluzoparib plus apatinib maintenance in patients with platinum-sensitive recurrent ovarian cancer who had received first-line maintenance with a PARP inhibitor (FLASH): A single-arm exploratory trial 中文标题：氟唑帕利联合阿帕替尼维持治疗铂敏感复发性卵巢癌患者，且该患者已接受过PARP抑制剂(FLASH)的一线维持治疗：一项单组探索性试验汇报人：王金华丨江苏省肿瘤医院摘要ID：826959 英文标题：The safety and efficacy of cadonilimab in advanced, recurrent, or metastatic cervical cancer: A multicenter, prospective, real-world study 中文标题：卡度尼利单抗治疗晚期、复发或转移性宫颈癌的安全性和有效性：一项多中心、前瞻性、真实世界研究汇报人：Xu Yuanyuan丨河南省肿瘤医院手术影片：APP虚拟展示（Surgical Films: Virtual Display on the App）摘要ID：872539 英文标题：Minimally invasive total vaginectomy utilizing robotic-assisted minimally invasive surgery and laparoscopic techniques for the management of malignant melanoma in the female reproductive system 中文标题：机器人辅助微创全阴道切除术和腹腔镜技术治疗女性生殖系统恶性黑色素瘤汇报人：何海新丨福建省肿瘤医院摘要ID：814185 英文标题：Resection of Ilio-inguinal Mass and Reconstruction with Artificial Vascular Graft in Vulvar Cancer Recurrence after Lymphadenectomy and Radiotherapy 中文标题：髂腹股沟肿块切除、人工血管移植重建治疗外阴癌淋巴结清扫及放疗后的复发汇报人：Tu Hua丨中山大学肿瘤防治中心壁报专场（Poster Session）摘要ID：819672 英文标题：Efbemalenograstim Alfa for Primary Prophylaxis of Chemotherapy-Induced Neutropenia In Patients With Ovarian and Cervical Cancer: A Single-Arm, Multicenter Clinical Trial 中文标题：艾贝格司亭α注射液用于卵巢癌和宫颈癌患者化疗引起的中性粒细胞减少症的一级预防：一项单组、多中心临床试验汇报人：王丽梅丨山东大学齐鲁医院摘要ID：822135 英文标题：The immunohistochemical profile and clinicopathological features of Invasive stratified mucin-producing carcinoma. 中文标题：浸润性分层黏蛋白癌的免疫组化特征和临床病理特征汇报人：Wang Ru丨山东省肿瘤医院摘要ID：823810 英文标题：Long-term outcomes of local tumor destruction/excision not inferior to total hysterectomy for stage IA cervical cancer : A retrospective cohort study with propensity score matching analysis 中文标题：IA期宫颈癌进行局部肿瘤破坏/切除不劣全子宫切除术的长期疗效：一项倾向评分匹配分析的回顾性队列研究汇报人：Xu Qin丨福建省肿瘤医院摘要ID：837185 英文标题：Anlotinib + penpulimab plus chemo-less therapy in first-line treatment for persistent, recurrent, or metastatic cervical cancer: a single-arm, open-label phase a… study (ALTN-AK105-II-06) 中文标题：安罗替尼+派安普利单抗+无化疗疗法一线治疗持续性、复发性或转移性宫颈癌：一项单臂、开放标签Ⅱ期临床研究（ALTN-AK105-II-06）汇报人：Xu Qin丨福建省肿瘤医院摘要ID：819959 英文标题：A nomogram for predicting overall survival in patients with clear cell adenocarcinoma of the cervix: a population-based analysis 中文标题：一种预测宫颈透明细胞腺癌患者总生存期的列线图：基于人群的分析汇报人：Xu Qin丨福建省肿瘤医院摘要ID：828451 英文标题：Anlotinib Enhances Immunotherapy Efficacy in PIK3CA-Mutant Cervical Cancer by Inhibiting RPS26-Mediated Activation of the PI3K/AKT Pathway 中文标题：安罗替尼通过抑制RPS26介导的PI3K/AKT通路激活增强PIK3CA突变宫颈癌的免疫治疗效果汇报人：Xu Qin丨福建省肿瘤医院摘要ID：827266 英文标题：Exploring the Impact of Circulating Inflammatory Proteins on Cervical Cancer Lesion Progression: A Two-Sample Bidirectional Mendelian Randomization Study 中文标题：探索循环炎症蛋白对宫颈癌病变进展的影响：一项双样本双向孟德尔随机化研究汇报人：Xu Qin丨福建省肿瘤医院摘要ID：869961 英文标题：Development and Validation of a Radiomics Nomogram for Metastasis Prediction in Neuroendocrine Carcinoma of the Cervix 中文标题：宫颈神经内分泌癌的转移预测：放射组学列线图的开发与验证汇报人：Yu Haijuan丨福建省肿瘤医院摘要ID：841950 英文标题：Comparative Analysis of Laparoscopic versus Open Inguinal Lymphadenectomy in Vulvar Cancer Surgery from Single Cancer Center ten years data 中文标题：外阴癌手术采用腹腔镜vs开放腹股沟淋巴结清扫术：癌症单中心十年比较分析汇报人：张正茂丨河北医科大学第四医院&河北省肿瘤医院摘要ID：854711 英文标题：Proteomics signatures of biofluid-derived small extracellular vesicles for diagnostic biomarkers and potential therapeutic targets of epithelial ovarian cancer. 中文标题：生物流体衍生的小细胞外囊泡(sEVs)的蛋白质组学特征可作为上皮性卵巢癌的诊断生物标志物和潜在治疗靶点。汇报人：郑小翠丨上海交通大学医学院附属新华医院摘要ID：831183 英文标题：ALTER-GO-010: A multicenter, single-arm, phase 2 study of anlotinib combined with carboplatin plus paclitaxel and maintenance anlotinib as front-line treatment for newly diagnosed advanced ovarian cancer 中文标题：ALTER-GO-010：一项关于安罗替尼联合卡铂/紫杉醇和维持性安罗替尼作为新诊断晚期卵巢癌一线治疗的多中心、单组、II期临床研究汇报人：程文俊丨江苏省人民医院摘要ID：865356 英文标题：Laparoscopic Pelvic Lymph Node Dissection Plus Open Abdominal Radical hysterectomy 中文标题：腹腔镜盆腔淋巴结清扫术+开腹根治性子宫切除术的研究汇报人：Lin Jie丨福建省肿瘤医院摘要ID：827945 英文标题：A novel deep learning model for automatic segmentation in cervical cancer brachytherapy 中文标题：一种用于宫颈癌近距离放射治疗自动分割的新型深度学习模型汇报人：Xu Qin丨福建省肿瘤医院摘要ID：832908 英文标题：Comparison of long-term clinical outcomes between patients with and without neoadjuvant therapy before surgery in stage IB2-IIB cervical cancer: a propensity score-matched study 中文标题：IB2-IIB期宫颈癌患者术前接受和未接受新辅助治疗的长期临床结局比较：倾向评分匹配研究汇报人：Xu Qin丨福建省肿瘤医院摘要ID：823645 英文标题：The impact of the COVID-19 pandemic on the diagnosis, treatment, and prognosis of ovarian cancer in the United States:A retrospective cohort study based on the SEER database 中文标题：COVID-19疫情对美国卵巢癌诊断、治疗及预后的影响：基于SEER数据库的回顾性队列研究汇报人：Xu Qin丨福建省肿瘤医院摘要ID：827261 英文标题：Dynamic Role of Circulating Immune Cells in the Progression of Cervical Malignant Lesion: A Two-sample Mendelian Randomization Study 中文标题：循环免疫细胞在宫颈恶性病变进展中的动态作用：双样本孟德尔随机化研究汇报人：Xu Qin丨福建省肿瘤医院摘要ID：834366 英文标题：Nituzumab plus Serplulimab combined with SBRT in recurrent advanced cervical cancer: A prospective, multicenter, single-arm, phase II clinical trial 中文标题：尼妥珠单抗+斯鲁利单抗联合SBRT治疗复发性晚期宫颈癌：一项前瞻性、多中心、单组II期临床试验汇报人：Xu Qin丨福建省肿瘤医院摘要ID：827311 英文标题：Lipids, as fundamental components of cells, exert a substantial influence on diverse biological processes. Although significant, their precise impact on cervical cancer development remains largely uncertain. 中文标题：脂质作为细胞的基本成分对多种生物过程产生重大影响，但对发生宫颈癌的确切影响仍不太确定汇报人：Xu Qin丨福建省肿瘤医院（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2期临床结果免疫疗法

2025-02-18

·精准药物

【JMC】王红胜/罗海彬等报道一种新型选择性ALKBH5抑制剂，对三阴性乳腺癌有效

近日，中山大学王红胜/吴一诺、海南大学罗海彬课题组在国际顶级药物化学期刊《Journal of Medicinal Chemistry》上发表了一篇题为“发现一种新型选择性和细胞活性 N6-甲基腺苷 RNA 脱甲基酶 ALKBH5 抑制剂”的研究论文。该研究通过虚拟筛选和结构优化，成功发现了一种新型的、具有选择性和细胞活性的N6-甲基腺苷（m6A）RNA去甲基化酶ALKBH5共价抑制剂W23-1006，并系统性地验证了其在调控m6A修饰以及抑制三阴性乳腺癌（TNBC）发展中的潜在治疗价值。图片来源：ACS 01 Background 研究背景 ALKBH5在癌症中的作用 ALKBH5的致癌性：ALKBH5在多种癌症中表现出致癌性，包括乳腺癌、急性髓系白血病（AML）、胶质母细胞瘤和多发性骨髓瘤。在乳腺癌中，ALKBH5的高表达与不良预后相关，尤其是在三阴性乳腺癌（TNBC）中，其表达水平更高。 TNBC的特点及治疗挑战：TNBC是乳腺癌中最危险的亚型，缺乏雌激素受体（ER）、孕激素受体（PR）和HER2的表达，导致对内分泌治疗和HER2靶向治疗不敏感。目前，化疗是TNBC的主要治疗手段，但效果不佳，因此迫切需要开发新的治疗策略。 ALKBH5抑制剂的研究现状现有抑制剂的局限性：尽管已有研究报道了少数ALKBH5抑制剂，但大多数抑制剂存在选择性差、活性不足或缺乏体内验证等问题。例如，Malacrida等发现的MV1035虽然对胶质母细胞瘤细胞有效，但未测定其对ALKBH5的IC50值和选择性；Selberg等报道的两种化合物虽然对ALKBH5有抑制作用，但仅在高浓度下有效。鉴于ALKBH5在TNBC中的重要作用，开发高效、选择性强且具有细胞活性的ALKBH5抑制剂对于癌症治疗具有重要意义。因此，本研究旨在通过虚拟筛选和结构优化，发现并开发一种新型的ALKBH5抑制剂，以期为TNBC治疗提供新的策略。 02 Drug Design 药物设计与评价 ①AG-690/34437009是一种潜在的选择性 ALKBH5 抑制剂作者通过虚拟筛选和生化实验验证，发现化合物AG-690/34437009是一种潜在的选择性ALKBH5抑制剂。研究团队采用虚拟筛选策略，包括分子对接、分子动力学模拟和自由能计算，从超过20万种化合物中筛选出300个具有不同骨架的化合物，并进一步通过MD模拟和自由能计算筛选出35个候选化合物。为了验证这些化合物对ALKBH5的抑制作用，作者建立了限制性内切酶消化实验，使用含有m6A修饰的单链DNA作为底物，通过DpnII酶的消化反应来判断ALKBH5的活性。实验结果显示，AG-690/34437009在200 μM浓度下对ALKBH5表现出显著的抑制作用。进一步的MazF RNA内切酶实验表明，AG-690/34437009对ALKBH5的半数抑制浓度（IC50）为11.76 μM，且其对FTO的抑制作用较弱（IC50为135.7 μM），显示出对ALKBH5的选择性抑制作用。这一发现为后续的结构优化和药物开发提供了重要基础。图片来源：ACS ②苗头化合物 AG-690/34437009 的结构优化作者对初步筛选得到的化合物AG-690/34437009进行了结构优化，以提高其对ALKBH5的抑制活性和选择性。通过结合分子对接、结合模式分析以及实验验证，作者对AG-690/34437009的结构进行了系统改造，最终获得了活性更高的抑制剂W23-1006。研究团队首先分析了AG-690/34437009与ALKBH5的结合模式，发现该化合物通过与C200残基形成共价键以及与L129和R130形成氢键来抑制ALKBH5的活性。基于这一结合模式，作者对化合物的结构进行了优化，包括去除或替换某些基团以增强与ALKBH5的相互作用。例如，通过去除羟基、替换氯原子为甲氧基等策略，合成了多个衍生物（如W23-1001至W23-1008），并测试了它们对ALKBH5的抑制活性。在优化过程中，作者发现W23-1006（R1=4-OMe，R2=3-Br，R3=5-NO₂）表现出最佳的抑制活性，其对ALKBH5的IC₅₀值为3.848 μM，比AG-690/34437009降低了约3倍。此外，W23-1006对FTO的抑制活性较弱（IC₅₀为113.7 μM），显示出良好的选择性。通过分子对接和MM-GBSA计算，作者进一步确认了W23-1006的E异构体比Z异构体具有更稳定的结合能力，这可能是其高活性的原因之一。图片来源：ACS ③W23-1006 在 C200 处与 ALKBH5 共价结合首先，作者发现W23-1006对ALKBH5的抑制作用随着孵育时间的延长而增强，这提示W23-1006可能是一个共价抑制剂。为了验证这一点，作者进行了缓冲液置换实验，结果表明即使在去除W23-1006后，ALKBH5的去甲基化活性仍未恢复，这进一步支持了W23-1006是通过共价结合抑制ALKBH5的假设。接下来，作者利用液相色谱-质谱联用（LC-MS/MS）技术分析了W23-1006与ALKBH5的结合位点。实验结果显示，W23-1006处理后，ALKBH5蛋白中C200残基发生了质量变化，表明W23-1006与C200形成了共价键。此外，作者还通过突变实验进一步验证了这一点。他们构建了C200G突变体，并发现该突变体对W23-1006的抑制作用不敏感，而野生型ALKBH5则被W23-1006显著抑制。这些结果明确指出了W23-1006与ALKBH5的C200残基之间的共价结合。为了深入了解W23-1006与ALKBH5之间的反应机制，作者进行了动力学分析。通过测定抑制常数（KI）和最大失活速率常数（kinact），计算得到kinact/KI值为117.65 M⁻¹s⁻¹，表明W23-1006与ALKBH5的结合是一个两步过程：第一步是可逆结合，第二步是共价键的形成。此外，作者还通过微尺度热泳（MST）实验测定了W23-1006与ALKBH5之间的解离常数（Kd）为5.985 μM。最后，作者通过计算化学方法对W23-1006与C200之间的反应进行了理论分析。他们构建了两个模型，并通过内在反应坐标（IRC）计算和势能图分析，发现该反应是一个协同的亲核芳香取代反应（SNAr），且反应过程中没有中间体生成。模型计算表明，水分子可能参与了过渡态的形成和离去基团的释放，从而降低了反应的能垒。综上所述，本部分研究通过实验和理论计算，证实了W23-1006能够与ALKBH5的C200残基共价结合，并详细揭示了这种结合的机制和动力学特征。这一发现为理解W23-1006的抑制作用提供了重要依据，并为其作为潜在的抗癌药物开发奠定了基础。图片来源：ACS 03 In vitro In Vivo 体内外评价 ①W23-1006对TNBC细胞的细胞活性作者通过一系列细胞实验，系统地研究了W23-1006对三阴性乳腺癌（TNBC）细胞的活性。实验结果表明，W23-1006能够显著提高TNBC细胞系（MDA-MB-231和BT549）中mRNA的m6A水平，这一效果通过HPLC-MS/MS技术得到验证，且与ALKBH5基因敲低后的效果相似，进一步证实了W23-1006通过抑制ALKBH5来发挥作用。在细胞增殖方面，W23-1006显著抑制了MDA-MB-231和BT549细胞的增殖，其半数抑制浓度（IC50）分别为10.31 μM和6.338 μM，而对正常肝细胞系WRL68的毒性较低（IC50为50.29 μM），显示出对TNBC细胞的选择性毒性。此外，W23-1006还显著抑制了TNBC细胞的迁移能力，这一效果在划痕实验和Transwell实验中得到证实，且抑制作用并非由于细胞凋亡引起。在细胞周期方面，10 μM W23-1006处理后，细胞在G2/M期的比例显著下降，表明W23-1006可能通过调节细胞周期来抑制细胞增殖。此外，W23-1006还显著增强了TNBC细胞对阿霉素（Dox）的敏感性，使Dox的IC50值从2.970 μM降低到0.4178 μM，显示出潜在的化疗增敏作用。这些结果表明，W23-1006不仅能够通过抑制ALKBH5的活性来抑制TNBC细胞的增殖和迁移，还能够调节细胞周期并增强化疗药物的敏感性，为TNBC的治疗提供了新的策略。。图片来源：ACS ②W23-1006 通过 m6A 抑制 FN1 表达作者通过一系列实验揭示了W23-1006通过增加m6A修饰水平来抑制纤维连接蛋白1（FN1）的表达，进而抑制TNBC细胞的上皮-间质转化（EMT）过程和肿瘤进展。作者首先对MDA-MB-231细胞进行RNA测序（RNA-seq），发现W23-1006处理后，细胞中与细胞黏附相关的基因表达发生显著变化，且其基因表达谱与上皮-间质转化（EMT）相关基因集呈负相关，表明W23-1006可能通过调节EMT相关基因来抑制TNBC细胞的迁移和侵袭能力。通过分析EMT相关基因、m6A-seq数据以及差异表达基因的重叠，作者发现FN1是W23-1006处理后显著下调的基因之一。FN1在肿瘤的EMT过程中起关键作用，且在TNBC中高表达，与不良预后相关。实验结果显示，W23-1006处理显著降低了FN1的mRNA和蛋白表达水平，而ALKBH5的过表达则增强了FN1的表达，且这种增强作用可被W23-1006逆转。为了验证W23-1006是否通过m6A修饰来调控FN1表达，作者进行了m6A-RIP-RT-qPCR实验，结果显示W23-1006处理显著增加了FN1 mRNA上的m6A修饰水平。此外，W23-1006处理并未影响FN1的前体mRNA水平，表明其作用机制并非通过转录调控，而是通过增加m6A修饰来影响FN1 mRNA的稳定性。作者进一步通过Actinomycin D（ActD）实验评估了FN1 mRNA的稳定性，结果显示W23-1006处理显著缩短了FN1 mRNA的半衰期，从6.481小时降至1.544小时，表明m6A修饰加速了FN1 mRNA的降解。m6A修饰能够被YTHDF2等含有YT521-B同源（YTH）结构域的蛋白识别，进而促进其靶mRNA的降解。作者通过YTHDF2-RIP实验发现，W23-1006处理显著增加了YTHDF2在FN1 mRNA上的富集水平，且这种富集与FN1 mRNA的降解相关。此外，YTHDF2的过表达也加速了FN1 mRNA的降解，进一步证实了YTHDF2在W23-1006介导的FN1 mRNA降解中的关键作用。综上所述，W23-1006通过抑制ALKBH5的活性，增加了FN1 mRNA上的m6A修饰水平，进而加速了FN1 mRNA的降解，降低了FN1的表达。这一机制不仅解释了W23-1006抑制TNBC细胞迁移和侵袭的分子基础，还为m6A修饰在肿瘤治疗中的潜在应用提供了新的见解。图片来源：ACS ③W23-1006 的体内评估作者对W23-1006的体内抗肿瘤效果进行了全面评估，涵盖了药代动力学特性、急性毒性以及在三阴性乳腺癌（TNBC）模型中的抗肿瘤活性。研究显示，W23-1006在人微粒体中的半衰期为4.38分钟，而在小鼠体内，其血浆最大浓度在给药后15分钟达到峰值，半衰期为0.509−0.983小时，表明其在小鼠体内吸收和分布迅速，但代谢和清除也较快。在急性毒性实验中，小鼠接受100 mg/kg和250 mg/kg剂量的W23-1006后，在72小时内未出现明显的临床症状或死亡，显示出良好的耐受性。在体内抗肿瘤活性方面，作者构建了MDA-MB-231细胞的皮下移植瘤模型和MDA-MB-231LMF3细胞的肺转移模型。在皮下移植瘤模型中，W23-1006显著抑制了肿瘤的生长，降低了肿瘤体积和重量，且免疫组化染色显示FN1和Ki-67蛋白表达水平下降。在肺转移模型中，W23-1006显著减少了肺部转移灶的数量。此外，安全性评估显示，W23-1006处理的小鼠体重、饮食未受影响，多个器官的HE染色未见明显病理异常，血清中的ALT和AST水平也未出现显著差异，表明W23-1006对小鼠肝功能无明显影响。这些结果表明，W23-1006在体内具有显著的抗肿瘤活性，且安全性良好，为TNBC治疗提供了有力的体内证据。图片来源：ACS 总结尽管已有研究报道了多种ALKBH5抑制剂，但这些抑制剂大多存在选择性不足、活性较低或缺乏系统的体内抗肿瘤效果验证等问题。本研究通过虚拟筛选和结构优化，成功发现并开发了一种新型的、具有选择性和细胞活性的ALKBH5共价抑制剂W23-1006，其对ALKBH5的半数抑制浓度（IC₅₀）为3.848 μM，显示出比FTO和ALKBH3更强的抑制活性，且具有良好的特异性。实验结果表明，W23-1006能够显著抑制TNBC细胞的增殖、迁移和集落形成能力，同时增强细胞对阿霉素（Dox）的敏感性。研究进一步揭示了W23-1006的作用机制，通过RNA测序分析发现，W23-1006处理后，细胞中与上皮-间质转化（EMT）相关的基因表达发生显著变化，特别是纤维连接蛋白1（FN1）的表达水平显著降低。W23-1006通过增加FN1 mRNA上的m⁶A修饰水平，加速其降解，从而降低FN1的表达。这一机制不仅解释了W23-1006抑制TNBC细胞迁移和侵袭的分子基础，还为m⁶A修饰在肿瘤治疗中的潜在应用提供了新的见解。在体内实验中，W23-1006在MDA-MB-231细胞的皮下移植瘤模型和肺转移模型中均显示出显著的抗肿瘤活性，且未引起明显的毒性反应。这些结果进一步证实了W23-1006作为潜在TNBC治疗药物的前景。作者强调，TNBC是一种预后较差、易发生远处转移且复发率高的乳腺癌亚型，目前的治疗手段有限。本研究揭示了ALKBH5在TNBC中的致癌作用，并证实了W23-1006作为一种选择性ALKBH5抑制剂在TNBC治疗中的潜力。此外，ALKBH5在其他多种癌症中也表现出致癌性，因此W23-1006的发现不仅为TNBC治疗提供了新的策略，也为其他ALKBH5相关癌症的治疗提供了潜在的药物候选。综上所述，本研究通过系统的实验验证了W23-1006作为一种新型ALKBH5抑制剂在TNBC治疗中的潜在应用价值，其通过增加m⁶A修饰水平来抑制FN1表达的机制为肿瘤治疗提供了新的靶点和思路。未来的研究将进一步探索W23-1006的临床应用潜力，为癌症治疗提供新的选择。。参考来源： https://doi-org.libproxy1.nus.edu.sg/10.1021/acs.jmedchem.4c01542 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

100 项与放线菌素D 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00214	放线菌素D	L01DA01	DB00970

研发状态

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适应症	国家/地区	公司	日期
霍奇金淋巴瘤	中国	陕西得安制药有限责任公司	1995-01-01
神经母细胞瘤	中国	陕西得安制药有限责任公司	1995-01-01
绒毛膜癌	日本	Nobelpharma Co., Ltd.	1968-12-16
尤文肉瘤	美国	Recordati Rare Diseases, Inc.	1964-12-10
妊娠滋养细胞疾病	美国	Recordati Rare Diseases, Inc.	1964-12-10
局部肿瘤复发	美国	Recordati Rare Diseases, Inc.	1964-12-10
横纹肌肉瘤	美国	Recordati Rare Diseases, Inc.	1964-12-10
睾丸肿瘤	美国	Recordati Rare Diseases, Inc.	1964-12-10
肾母细胞瘤	美国	Recordati Rare Diseases, Inc.	1964-12-10

未上市

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适应症	最高研发状态	国家/地区	公司	日期
急性髓性白血病	临床2期	意大利	Actavia Life Sciences, Inc.	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


522 (ESGO2024)	N/A	妊娠滋养细胞疾病二线	324	5-day ACT-D regimen	簾觸憲夢餘餘網膚蓋襯(網構選壓網憲夢網簾餘) = 鬱鏇繭遞鹽淵壓壓製獵繭簾築壓艱鹹膚糧蓋選 (蓋鬱選繭鹽衊構構網膚 ) 更多	积极	2024-03-10
				Biweekly pulsed ACT-D regimen	簾觸憲夢餘餘網膚蓋襯(網構選壓網憲夢網簾餘) = 構顧夢製鏇觸鏇鬱簾鹹繭簾築壓艱鹹膚糧蓋選 (蓋鬱選繭鹽衊構構網膚 ) 更多
SOHO2023	N/A	-	-	Venetoclax + low-dose cytarabine + actinomycin D	齋顧壓餘選獵膚鹽膚醖(醖膚鑰鹹艱遞鑰鑰築選) = 11% 衊範餘觸餘築膚願願膚 (選鹽獵鹹積繭憲鏇窪構 ) 更多	-	2023-09-01
ASCO2020	N/A	尤文肉瘤一线	-	VAIA combination	衊襯顧鬱蓋製壓鬱鏇願(網窪憲鹹獵簾觸鏇艱廠) = 窪觸淵鹽鑰膚夢願憲壓觸壓顧獵餘壓鹹廠觸艱 (構網憲夢艱遞繭繭遞鑰 )	不佳	2020-05-25
NCT01014767 (CPT-SIOP-2009, CTgov)	临床3期	脉络丛肿瘤 \| 脑癌	27	Etoposide+Cyclophosphamide+Carboplatin+Vincristine (Standard Arm (1))	選餘網襯築鏇鹽齋鬱顧(淵範憲膚壓膚鏇鏇積壓) = 襯齋鏇鏇鏇壓淵齋鏇廠鑰憲簾齋餘顧鏇顧遞築 (鏇網鹹淵遞憲糧鹹膚鹽, 構襯簾夢選窪鑰憲遞觸 ~ 範製繭鑰選鏇鹹糧壓選) 更多	-	2019-08-20
				Etoposide+Cyclophosphamide+Carboplatin+doxorubicin+Dactinomycin+cisplatin+Vincristine (Doxorubicin/Cisplatin Arm (2))	選餘網襯築鏇鹽齋鬱顧(淵範憲膚壓膚鏇鏇積壓) = 鹽簾顧齋願簾觸構艱顧鑰憲簾齋餘顧鏇顧遞築 (鏇網鹹淵遞憲糧鹹膚鹽, 構遞構鑰構築窪醖獵獵 ~ 夢簾網構餘窪鹽齋築艱) 更多
NCT01535053 (NRG/GOG 275, CTgov)	临床3期	葡萄胎 \| 绒毛膜癌	57	Dactinomycin (Regimen I (Dactinomycin))	糧鬱壓壓積顧鹽膚鬱壓(壓遞餘淵鑰餘構鑰網獵) = 鹹積顧範艱構選蓋觸醖衊艱遞夢鹹鑰獵憲廠獵 (艱壓糧鏇簾壓糧範窪願, 積繭築糧顧餘鹹鹹壓獵 ~ 餘鬱衊膚淵鹽壓繭衊構) 更多	-	2019-08-13
				Methotrexate (Regimen II (Methotrexate))	糧鬱壓壓積顧鹽膚鬱壓(壓遞餘淵鑰餘構鑰網獵) = 製鏇範齋鏇糧顧製蓋遞衊艱遞夢鹹鑰獵憲廠獵 (艱壓糧鏇簾壓糧範窪願, 築窪積夢選繭醖餘餘齋 ~ 蓋簾齋範鹹窪積襯積膚) 更多
EHA2019	N/A	复发性急性髓细胞白血病	19	Venetoclax + Low dose cytarabine	憲齋鑰鬱網襯鏇膚艱淵(鬱醖簾衊獵獵淵醖糧糧) = sepsis (5/19, 26%), pneumonia (5/19, 26%), catheter related infections (3/19, 16%) and febrile neutropenia (3/19, 16%) 襯艱艱壓選齋廠壓顧鬱 (鬱齋糧顧齋願壓獵糧糧 ) 更多	-	2019-06-14
NCT00945009 (CTgov)	临床3期	肾母细胞瘤 \| Beckwith-Wiedemann综合征	249	Therapeutic Conventional Surgery+Doxorubicin Hydrochloride+Dactinomycin+Vincristine Sulfate (Arm 1 (Bilateral Wilms Tumors))	淵顧齋網鹽鹽製衊選網(鹹壓醖願鹽襯獵淵醖膚) = 鏇簾夢網願糧鑰淵獵觸範淵遞願網膚願簾製糧 (網廠網憲顧願選鹽膚膚, 範糧範襯顧壓醖夢選淵 ~ 觸願築鑰願壓壓廠築壓) 更多	-	2019-03-05
				Therapeutic Conventional Surgery+Doxorubicin Hydrochloride+Dactinomycin+Vincristine Sulfate (Arm 3 (DHPLN))	夢夢簾淵鬱襯選鬱範夢(窪願醖壓襯衊鏇觸餘膚) = 獵觸艱襯齋蓋窪醖廠淵觸遞選簾夢鏇糧顧築鬱 (齋遞願憲醖廠餘獵窪夢, 鹽壓顧壓簾鹹蓋蓋製艱 ~ 顧繭艱願齋範遞繭淵繭) 更多
NCT00354835 (Pubmed \| J Clin Oncol)	临床3期	横纹肌肉瘤	448	Vincristine, Dactinomycin, and Cyclophosphamide (VAC)	製淵鏇糧艱築蓋選窪遞(窪簾製製膚製醖鹹構壓) = 願繭膚築範築蓋製糧願網製憲糧繭鑰鹹願積餘 (廠繭壓蓋鏇窪艱齋網襯 ) 更多	-	2018-09-20
				Vincristine, Irinotecan, Dactinomycin, and Cyclophosphamide (VAC/VI)	製淵鏇糧艱築蓋選窪遞(窪簾製製膚製醖鹹構壓) = 簾築鏇簾廠壓簾鬱窪醖網製憲糧繭鑰鹹願積餘 (廠繭壓蓋鏇窪艱齋網襯 ) 更多
NCT01055314 (ARST08P1, CTgov)	临床2期	肉瘤 \| 小儿横纹肌肉瘤 \| 小泡型横纹肌肉瘤	175	Laboratory Biomarker Analysis+Etoposide+cyclophosphamide+Doxorubicin Hydrochloride+Ifosfamide+Dactinomycin+Cixutumumab+Irinotecan Hydrochloride+Vincristine Sulfate Liposome (Group 1 (Chemotherapy, Radiation Therapy, Cixutumumab))	繭憲餘醖蓋齋蓋壓糧淵(壓鹹襯醖簾糧憲廠簾齋) = 壓糧選齋築憲壓蓋獵窪鑰艱積觸簾鏇鑰觸繭壓 (鏇艱繭蓋壓觸蓋觸衊餘, 範齋遞鏇艱觸窪遞艱鏇 ~ 鹹製蓋網夢鹽壓憲餘齋) 更多	-	2017-07-28
				Laboratory Biomarker Analysis+Etoposide+cyclophosphamide+Temozolomide+Doxorubicin Hydrochloride+Ifosfamide+Dactinomycin+Irinotecan Hydrochloride+Vincristine Sulfate Liposome (Group 2 (Chemotherapy, Radiation Therapy, Temozolomide))	繭憲餘醖蓋齋蓋壓糧淵(壓鹹襯醖簾糧憲廠簾齋) = 鏇齋選築築積蓋膚製憲鑰艱積觸簾鏇鑰觸繭壓 (鏇艱繭蓋壓觸蓋觸衊餘, 簾衊襯鑰糧鹽餘夢製顧 ~ 獵觸蓋衊構襯製衊醖衊) 更多
NCT00002766 (CTgov)	临床3期	急性淋巴细胞白血病 \| 淋巴瘤	170	Mitoxantrone+ARA-C (All-2)	糧範構蓋顧齋顧糧艱觸(膚艱醖鏇鏇鏇淵蓋齋築) = 獵艱襯膚繭糧餘襯衊觸艱齋製顧鏇齋糧積鑰願 (鹹範願膚鑰鏇選鹹構積, 鹹獵繭構繭窪觸鬱簾鏇 ~ 鹹鹽膚糧鏇淵網襯觸糧) 更多	-	2016-02-22
				Prednisone+Vincristine (L-20)	糧範構蓋顧齋顧糧艱觸(膚艱醖鏇鏇鏇淵蓋齋築) = 襯淵積醖積廠壓醖齋範艱齋製顧鏇齋糧積鑰願 (鹹範願膚鑰鏇選鹹構積, 繭衊簾網齋餘築鹹憲蓋 ~ 衊醖餘蓋觸鏇膚製鑰鹹) 更多