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Targeting circ-0034880-enriched tumor extracellular vesicles to impede SPP1highCD206+ pro-tumor macrophages mediated pre-metastatic niche formation in colorectal cancer liver metastasis 靶向circ-0034880富集的肿瘤细胞外囊泡,阻止SPP1高CD206+促肿瘤巨噬细胞介导的结直肠癌肝转移前转移龛形成
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-20 DOI: 10.1186/s12943-024-02086-9
Jing Zhou, Qing Song, Haoze Li, Yicun Han, Yunzhou Pu, Ling Li, Wenqing Rong, Xiaodie Liu, Ziyuan Wang, Jian Sun, Yuqing Song, Xueyan Hu, Guanghao Zhu, Huirong Zhu, Liu Yang, Guangbo Ge, Hongshan Li, Qing Ji
Information transmission between primary tumor cells and immunocytes or stromal cells in distal organs is a critical factor in the formation of pre-metastatic niche (PMN). Understanding this mechanism is essential for developing effective therapeutic strategy against tumor metastasis. Our study aims to prove the hypothesis that circ-0034880-enriched tumor-derived extracellular vesicles (TEVs) mediate the formation of PMN and colorectal cancer liver metastasis (CRLM), and targeting circ-0034880-enriched TEVs might be an effective therapeutic strategy against PMN formation and CRLM. We utilized qPCR and FISH to measure circRNAs expression levels in human CRC plasma, primary CRC tissues, and liver metastatic tissues. Additionally, we employed immunofluorescence, RNA sequencing, and in vivo experiments to assess the effect mechanism of circ-0034880-enriched TEVs on PMN formation and CRC metastasis. DARTS, CETSA and computational docking modeling were applied to explore the pharmacological effects of Ginsenoside Rb1 in impeding PMN formation. We found that circ-0034880 was highly enriched in plasma extracellular vesicles (EVs) derived from CRC patients and closely associated with CRLM. Functionally, circ-0034880-enriched TEVs entered the liver tissues and were absorbed by macrophages in the liver through bloodstream. Mechanically, TEVs-released circ-0034880 enhanced the activation of SPP1highCD206+ pro-tumor macrophages, reshaping the metastasis-supportive host stromal microenvironment and promoting overt metastasis. Importantly, our mechanistic findings led us to discover that the natural product Ginsenoside Rb1 impeded the activation of SPP1highCD206+ pro-tumor macrophages by reducing circ-0034880 biogenesis, thereby suppressing PMN formation and inhibiting CRLM. Circ-0034880-enriched TEVs facilitate strong interaction between primary tumor cells and SPP1highCD206+ pro-tumor macrophages, promoting PMN formation and CRLM. These findings suggest the potential of using Ginsenoside Rb1 as an alternative therapeutic agent to reshape PMN formation and prevent CRLM.
原发肿瘤细胞与远端器官的免疫细胞或基质细胞之间的信息传递是形成转移前生态位(PMN)的关键因素。了解这一机制对于制定有效的肿瘤转移治疗策略至关重要。我们的研究旨在证明一个假设,即circ-0034880富集的肿瘤源性细胞外囊泡(TEVs)介导了PMN和结直肠癌肝转移(CRLM)的形成,而靶向circ-0034880富集的TEVs可能是针对PMN形成和CRLM的有效治疗策略。我们利用 qPCR 和 FISH 技术测定了人 CRC 血浆、原发 CRC 组织和肝转移组织中 circRNAs 的表达水平。此外,我们还利用免疫荧光、RNA测序和体内实验评估了circ-0034880富集的TEVs对PMN形成和CRC转移的影响机制。应用DARTS、CETSA和计算对接模型探讨了人参皂苷Rb1阻碍PMN形成的药理作用。我们发现circ-0034880高度富集于CRC患者的血浆细胞外囊泡(EVs)中,并与CRLM密切相关。在功能上,circ-0034880富集的TEV通过血液进入肝脏组织并被肝脏中的巨噬细胞吸收。从机理上讲,TEV释放的circ-0034880增强了SPP1高CD206+亲肿瘤巨噬细胞的活化,重塑了支持转移的宿主基质微环境,促进了肿瘤的明显转移。重要的是,我们的机理研究结果使我们发现,天然产物人参皂苷 Rb1 通过减少 circ-0034880 的生物生成,阻碍了 SPP1highCD206+ 亲肿瘤巨噬细胞的活化,从而抑制了 PMN 的形成并抑制了 CRLM。富含circ-0034880的TEV可促进原发性肿瘤细胞与SPP1highCD206+原癌巨噬细胞之间的强烈相互作用,促进PMN的形成和CRLM。这些发现表明,人参皂苷 Rb1 有可能作为一种替代治疗药物,重塑 PMN 的形成并预防 CRLM。
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引用次数: 0
Implications of PD-L1 expression on the immune microenvironment in HER2-positive gastric cancer PD-L1 表达对 HER2 阳性胃癌免疫微环境的影响
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-20 DOI: 10.1186/s12943-024-02085-w
Yang Chen, Keren Jia, Xiaoyi Chong, Yi Xie, Lei Jiang, Haoxin Peng, Dan Liu, Jiajia Yuan, Yanyan Li, Xujiao Feng, Yu Sun, Jian Li, Xiaotian Zhang, Lin Shen
In the KEYNOTE-811 study, anti-HER2 and immunotherapy treatments resulted in longer survival in HER2-positive gastric cancer patients with CPS ≥ 1, whereas CPS < 1 patients lacked notable benefits. We studied this in a real-world cohort of 106 HER2-positive, CPS < 1 patients and found no survival differences between those treated with anti-HER2 therapy alone or with added immunotherapy. Thus, we investigate the tumor microenvironment variations in 160 HER2-positive patients, CPS ≥ 1 cases exhibited elevated spatial effective scores of immune cells, including CD4, CD8 subtypes, and NK cells, compared to CPS < 1. Furthermore, through single-cell sequencing in eight HER2-positive individuals, gene expressions revealed regulation of T-cell co-stimulation in CPS ≥ 1 and IL-1 binding in CPS < 1 cases. Notably, we discovered a CPS < 1 subtype marked by CXCR4+M2 macrophages, associated with poor prognosis, whose proportion and expression were reduced when benefiting from anti-HER2 therapy. These findings suggest CPS ≥ 1 patients, due to their immune microenvironment composition, may respond better to anti-PD-1/PD-L1 therapy.
在 KEYNOTE-811 研究中,抗 HER2 和免疫疗法延长了 CPS≥1 的 HER2 阳性胃癌患者的生存期,而 CPS<1 的患者则没有明显的获益。我们在一个由 106 名 HER2 阳性、CPS < 1 的患者组成的真实世界队列中对此进行了研究,结果发现,单独接受抗 HER2 治疗或同时接受免疫治疗的患者的生存率没有差异。因此,我们对 160 例 HER2 阳性患者的肿瘤微环境变异进行了调查,与 CPS < 1 的患者相比,CPS ≥ 1 的病例表现出免疫细胞(包括 CD4、CD8 亚型和 NK 细胞)空间有效评分升高。此外,通过对8例HER2阳性患者的单细胞测序,基因表达显示了CPS≥1病例中T细胞协同刺激的调控和CPS<1病例中IL-1结合的调控。值得注意的是,我们发现了一种以 CXCR4+M2 巨噬细胞为标志的 CPS < 1 亚型,该亚型与预后不良有关,在接受抗 HER2 治疗后,其比例和表达均有所降低。这些发现表明,CPS≥1患者由于其免疫微环境组成,可能对抗PD-1/PD-L1疗法反应更好。
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引用次数: 0
The CD47/TSP-1 axis: a promising avenue for ovarian cancer treatment and biomarker research. CD47/TSP-1 轴:卵巢癌治疗和生物标志物研究的前景广阔的途径。
IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-14 DOI: 10.1186/s12943-024-02073-0
Aurélie Moniot, Christophe Schneider, Laure Chardin, Elisa Yaniz-Galende, Catherine Genestie, Marion Etiennot, Aubéri Henry, Coralie Drelon, Audrey Le Formal, Benoit Langlois, Laurence Venat, Christophe Louvet, Laure Favier, Alain Lortholary, Dominique Berton-Rigaud, Nadine Dohollou, Christophe Desauw, Michel Fabbro, Emmanuelle Malaurie, Coraline Dubot, Jean Emmanuel Kurtz, Nathalie Bonichon Lamichhane, Éric Pujade-Lauraine, Albin Jeanne, Alexandra Leary, Stéphane Dedieu

Background: Ovarian cancer (OC) remains one of the most challenging and deadly malignancies facing women today. While PARP inhibitors (PARPis) have transformed the treatment landscape for women with advanced OC, many patients will relapse and the PARPi-resistant setting is an area of unmet medical need. Traditional immunotherapies targeting PD-1/PD-L1 have failed to show any benefit in OC. The CD47/TSP-1 axis may be relevant in OC. We aimed to describe changes in CD47 expression with platinum therapy and their relationship with immune features and prognosis.

Methods: Tumor and blood samples collected from OC patients in the CHIVA trial were assessed for CD47 and TSP-1 before and after neoadjuvant chemotherapy (NACT) and multiplex analysis was used to investigate immune markers. Considering the therapeutic relevance of targeting the CD47/TSP-1 axis, we used the CD47-derived TAX2 peptide to selectively antagonize it in a preclinical model of aggressive ovarian carcinoma.

Results: Significant reductions in CD47 expression were observed post NACT. Tumor patients having the highest CD47 expression profile at baseline showed the greatest CD4+ and CD8+ T-cell influx post NACT and displayed a better prognosis. In addition, TSP-1 plasma levels decreased significantly under NACT, and high TSP-1 was associated with a worse prognosis. We demonstrated that TAX2 exhibited a selective and favorable biodistribution profile in mice, localizing at the tumor sites. Using a relevant peritoneal carcinomatosis model displaying PARPi resistance, we demonstrated that post-olaparib (post-PARPi) administration of TAX2 significantly reduced tumor burden and prolonged survival. Remarkably, TAX2 used sequentially was also able to increase animal survival even under treatment conditions allowing olaparib efficacy.

Conclusions: Our study thus (1) proposes a CD47-based stratification of patients who may be most likely to benefit from postoperative immunotherapy, and (2) suggests that TAX2 is a potential alternative therapy for patients relapsing on PARP inhibitors.

背景:卵巢癌(OC)仍然是当今女性面临的最具挑战性和致命性的恶性肿瘤之一。尽管PARP抑制剂(PARPis)改变了晚期卵巢癌女性患者的治疗格局,但许多患者仍会复发,PARP耐药患者的医疗需求仍未得到满足。以 PD-1/PD-L1 为靶点的传统免疫疗法未能在 OC 中显示出任何疗效。CD47/TSP-1 轴可能与 OC 相关。我们旨在描述CD47表达在铂治疗中的变化及其与免疫特征和预后的关系:方法:在新辅助化疗(NACT)前后,对CHIVA试验中收集的OC患者的肿瘤和血液样本进行CD47和TSP-1评估,并使用多重分析法研究免疫标记物。考虑到靶向 CD47/TSP-1 轴的治疗意义,我们在侵袭性卵巢癌的临床前模型中使用了 CD47 衍生的 TAX2 肽来选择性地拮抗它:结果:NACT后观察到CD47表达明显减少。基线CD47表达最高的肿瘤患者在NACT后CD4+和CD8+T细胞流入量最大,预后较好。此外,TSP-1 的血浆水平在 NACT 后显著下降,TSP-1 高与预后较差有关。我们证明,TAX2 在小鼠体内具有选择性和良好的生物分布特征,可在肿瘤部位定位。我们利用显示 PARPi 耐药性的相关腹膜癌模型,证明了在奥拉帕利(PARPi)后给药 TAX2 能显著减轻肿瘤负担并延长生存期。值得注意的是,即使在奥拉帕利疗效允许的治疗条件下,连续使用 TAX2 也能提高动物的存活率:因此,我们的研究(1)提出了基于 CD47 的患者分层,这些患者最有可能从术后免疫疗法中获益;(2)表明 TAX2 是 PARP 抑制剂复发患者的潜在替代疗法。
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引用次数: 0
Novel humanized monoclonal antibodies against ROR1 for cancer therapy 用于癌症治疗的新型人源化 ROR1 单克隆抗体
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-13 DOI: 10.1186/s12943-024-02075-y
Rong Wei, Xun Liao, Jiao Li, Xiaoyu Mu, Yue Ming, Yong Peng
Overexpression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) contributes to cancer cell proliferation, survival and migration, playing crucial roles in tumor development. ROR1 has been proposed as a potential therapeutic target for cancer treatment. This study aimed to develop novel humanized ROR1 monoclonal antibodies and investigate their anti-tumor effects. ROR1 expression in tumor tissues and cell lines was analyzed by immunohistochemistry and flow cytometry. Antibodies from mouse hybridomas were humanized by the complementarity-determining region (CDR) grafting technique. Surface plasmon resonance spectroscopy, ELISA assay and flow cytometry were employed to characterize humanized antibodies. In vitro cellular assay and in vivo mouse experiment were conducted to comprehensively evaluate anti-tumor activity of these antibodies. ROR1 exhibited dramatically higher expression in lung adenocarcinoma, liver cancer and breast cancer, and targeting ROR1 by short-hairpin RNAs significantly inhibited proliferation and migration of cancer cells. Two humanized ROR1 monoclonal antibodies were successfully developed, named h1B8 and h6D4, with high specificity and affinity to ROR1 protein. Moreover, these two antibodies effectively suppressed tumor growth in the lung cancer xenograft mouse model, c-Myc/Alb-cre liver cancer transgenic mouse model and MMTV-PyMT breast cancer mouse model. Two humanized monoclonal antibodies targeting ROR1, h1B8 and h6D4, were successfully developed and exhibited remarkable anti-tumor activity in vivo.
受体酪氨酸激酶样孤儿受体 1(ROR1)的过度表达有助于癌细胞的增殖、存活和迁移,在肿瘤发生发展过程中起着至关重要的作用。ROR1 已被认为是癌症治疗的潜在靶点。本研究旨在开发新型人源化 ROR1 单克隆抗体并研究其抗肿瘤作用。通过免疫组化和流式细胞术分析了肿瘤组织和细胞系中 ROR1 的表达。通过互补决定区(CDR)嫁接技术对小鼠杂交瘤中的抗体进行了人源化处理。采用表面等离子体共振光谱法、ELISA 检测法和流式细胞仪来表征人源化抗体。通过体外细胞实验和体内小鼠实验,全面评估了这些抗体的抗肿瘤活性。ROR1在肺腺癌、肝癌和乳腺癌中的表达量显著升高,短发夹RNA靶向ROR1能明显抑制癌细胞的增殖和迁移。研究人员成功开发了两种人源化的 ROR1 单克隆抗体,分别命名为 h1B8 和 h6D4,它们对 ROR1 蛋白具有高度的特异性和亲和性。此外,这两种抗体还能有效抑制肺癌异种移植小鼠模型、c-Myc/Alb-cre肝癌转基因小鼠模型和MMTV-PyMT乳腺癌小鼠模型的肿瘤生长。两种靶向 ROR1 的人源化单克隆抗体(h1B8 和 h6D4)研制成功,并在体内表现出显著的抗肿瘤活性。
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引用次数: 0
Targeting PI3K family with small-molecule inhibitors in cancer therapy: current clinical status and future directions 在癌症治疗中使用小分子抑制剂靶向 PI3K 家族:临床现状与未来方向
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-10 DOI: 10.1186/s12943-024-02072-1
Hongyao Li, Xiang Wen, Yueting Ren, Zhichao Fan, Jin Zhang, Gu He, Leilei Fu
The Phosphatidylinositol-3-kinase (PI3K) family is well-known to comprise three classes of intracellular enzymes. Class I PI3Ks primarily function in signaling by responding to cell surface receptor stimulation, while class II and III are more involved in membrane transport. Under normal physiological conditions, the PI3K signaling network orchestrates cell growth, division, migration and survival. Aberrant activation of the PI3K signaling pathway disrupts cellular activity and metabolism, often marking the onset of cancer. Currently, the Food and Drug Administration (FDA) has approved the clinical use of five class I PI3K inhibitors. These small-molecule inhibitors, which exhibit varying selectivity for different class I PI3K family members, are primarily used in the treatment of breast cancer and hematologic malignancies. Therefore, the development of novel class I PI3K inhibitors has been a prominent research focus in the field of oncology, aiming to enhance potential therapeutic selectivity and effectiveness. In this review, we summarize the specific structures of PI3Ks and their functional roles in cancer progression. Additionally, we critically evaluate small molecule inhibitors that target class I PI3K, with a particular focus on their clinical applications in cancer treatment. Moreover, we aim to analyze therapeutic approaches for different types of cancers marked by aberrant PI3K activation and to identify potential molecular targets amenable to intervention with small-molecule inhibitors. Ultimately, we propose future directions for the development of therapeutic strategies that optimize cancer treatment outcomes by modulating the PI3K family.
众所周知,磷脂酰肌醇-3-激酶(PI3K)家族由三类细胞内酶组成。I 类 PI3K 主要通过响应细胞表面受体的刺激来发挥信号功能,而 II 类和 III 类则更多地参与膜转运。在正常生理条件下,PI3K 信号网络协调细胞的生长、分裂、迁移和存活。PI3K 信号通路的异常激活会扰乱细胞活动和新陈代谢,通常标志着癌症的发生。目前,美国食品和药物管理局(FDA)已批准临床使用五种 I 类 PI3K 抑制剂。这些小分子抑制剂对不同的 I 类 PI3K 家族成员具有不同的选择性,主要用于治疗乳腺癌和血液系统恶性肿瘤。因此,开发新型 I 类 PI3K 抑制剂一直是肿瘤学领域的研究重点,目的是提高潜在的治疗选择性和有效性。在这篇综述中,我们总结了 PI3K 的具体结构及其在癌症进展中的功能作用。此外,我们还对针对 I 类 PI3K 的小分子抑制剂进行了严格评估,尤其关注它们在癌症治疗中的临床应用。此外,我们还旨在分析针对以 PI3K 异常激活为特征的不同类型癌症的治疗方法,并确定可通过小分子抑制剂进行干预的潜在分子靶点。最终,我们提出了通过调节 PI3K 家族优化癌症治疗效果的治疗策略的未来发展方向。
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引用次数: 0
A case of response to combination treatment with TSA-DC-CTL immunotherapy and osimertinib in EGFR mutated advanced lung adenocarcinoma 一例表皮生长因子受体突变晚期肺腺癌患者对TSA-DC-CTL免疫疗法和奥希替尼联合治疗的应答病例
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-09 DOI: 10.1186/s12943-024-02070-3
Zhiyi Han, Tao Li, Heng Zhang, Kai Liang, Mingcong You, Mengdi Xu, Fan Bai, Tongmei Zhang
This study details a case of a patient with advanced lung adenocarcinoma harboring an exon 19 deletion in the EGFR gene. A 46-year-old female patient was diagnosed with stage IVb left lung adenocarcinoma, with multiple bone and lymph node metastases. Following the identification of tumor-specific antigen peptides, the patient received a combination treatment of immunotherapy (TSA-DC-CTL) and oral osimertinib. Peripheral blood circulating immune cells and circulating tumor cells (CTCs) were monitored before and after treatment. PET-CT and CT scans were used to assess the tumor response to treatment. A significant increase in total lymphocyte percentage and decrease in the number of CTCs in the patient was observed. Imaging studies showed a notable reduction in tumor metastases. This report demonstrates the safety and efficacy of TSA-DC-CTL cell immunotherapy combined with osimertinib in the treatment of a patient with advanced lung adenocarcinoma with an EGFR exon 19 deletions. This study describes a promising new treatment option for patients with advanced lung cancer with EGFR mutations.
本研究详细介绍了一例表皮生长因子受体基因第19外显子缺失的晚期肺腺癌患者。一名 46 岁的女性患者被诊断为左肺腺癌 IVb 期,并伴有多处骨和淋巴结转移。在鉴定出肿瘤特异性抗原肽后,患者接受了免疫疗法(TSA-DC-CTL)和口服奥希替尼的联合治疗。治疗前后对外周血循环免疫细胞和循环肿瘤细胞(CTC)进行了监测。PET-CT 和 CT 扫描用于评估肿瘤对治疗的反应。结果显示,患者的总淋巴细胞比例明显增加,CTC数量明显减少。影像学研究显示肿瘤转移明显减少。本报告展示了 TSA-DC-CTL 细胞免疫疗法联合奥希替尼治疗表皮生长因子受体外显子 19 缺失的晚期肺腺癌患者的安全性和有效性。这项研究为表皮生长因子受体(EGFR)突变的晚期肺癌患者提供了一种前景广阔的新治疗方案。
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引用次数: 0
Efficacy and safety of chiauranib in a combination therapy in platinum-resistant or refractory ovarian cancer: a multicenter, open-label, phase Ib and II study 巧拉尼联合疗法治疗铂类耐药或难治性卵巢癌的疗效和安全性:一项多中心、开放标签、Ib 期和 II 期研究
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-09 DOI: 10.1186/s12943-024-02076-x
Jin Li, Jihong Liu, Rutie Yin, Dongling Zou, Hong Zheng, Junning Cao, Zhendong Chen, Wei Sun, Yunong Gao, Songling Zhang, Linjuan Zeng, Ruifang An, Xianping Lu, Shuang Ye, Xiaohua Wu
Platinum-resistant or refractory ovarian cancer is a highly lethal gynecologic disease with limited treatment options. Chiauranib is a novel small-molecule selective inhibitor, which could effectively target multiple pathways including Aurora B and CSF-1R to inhibit cell cycle process and improve anti-tumor immune function, as long as VEGF pathway for tumor extinction. A phase II study was sequentially conducted after a phase Ib monotherapy study to evaluate the efficacy of chiauranib combined with chemotherapy. Chinese patients with recurrent ovarian cancer were enrolled. Eligible patients received chiauranib combined with a maximum of six cycles of chemotherapy: etoposide (CE group) or weekly-paclitaxel (CP group). Patients, who exhibited a complete or partial response, or stable disease following combo treatment, progressed to maintenance phase to receive chiauranib monotherapy. Primary endpoint was progression-free survival (PFS) according to RECIST v1.1. From November 2017 to March 2019, 25 patients were enrolled in a phase 1b study and a median PFS of 3.7 months (95% CI 1.8–NE) was achieved by chiauranib monotherapy. From July 2019 to December 2020, a total of 47 patients were enrolled in the phase II study. One CP patient did not receive the study drugs, and three patients withdrew before the first tumor assessment. Thus, 43 patients (CE group: 22 patients; CP group: 21 patients) were included in the evaluation. The median PFS was 5·4 months (95% CI 2·8–5·6) and 5·6 months (95% CI 3·4–7·0), respectively. This was the first study to evaluate chiauranib, a novel multi-targeted kinase inhibitor in patients with ovarian cancer. The administration of chiauranib along with etoposide or weekly-paclitaxel significantly enhanced the efficacy with manageable adverse events. This warrants further clinical studies on this novel treatment. A phase III study is promising and ongoing. ClinicaTrials.gov identifier: NCT03901118 (phase II) and NCT03166891 (phase Ib).
铂耐药或难治性卵巢癌是一种致死率极高的妇科疾病,但治疗方案却十分有限。Chiauranib是一种新型小分子选择性抑制剂,可有效靶向包括Aurora B和CSF-1R在内的多条通路,抑制细胞周期过程,提高抗肿瘤免疫功能,同时也可靶向VEGF通路消灭肿瘤。在Ib期单药治疗研究之后,我们又进行了一项II期研究,以评估chiauranib联合化疗的疗效。研究招募了中国复发性卵巢癌患者。符合条件的患者接受巧拉尼联合化疗,最多6个周期:依托泊苷(CE组)或每周紫杉醇(CP组)。如果患者在联合治疗后出现完全或部分应答,或病情稳定,则进入维持治疗阶段,接受chiauranib单药治疗。根据RECIST v1.1标准,主要终点为无进展生存期(PFS)。2017年11月至2019年3月,25名患者入组1b期研究,接受chiauranib单药治疗的中位PFS为3.7个月(95% CI 1.8-NE)。2019年7月至2020年12月,共有47名患者入组II期研究。一名 CP 患者未接受研究药物,三名患者在首次肿瘤评估前退出。因此,43 名患者(CE 组:22 名患者;CP 组:21 名患者)被纳入评估。中位生存期分别为 5-4 个月(95% CI 2-8-5-6 )和 5-6 个月(95% CI 3-4-7-0)。这是第一项评估卵巢癌患者使用新型多靶点激酶抑制剂chiauranib的研究。chiauranib与依托泊苷或每周紫杉醇合用可显著提高疗效,且不良反应可控。因此,有必要对这种新型疗法进行进一步的临床研究。目前正在进行的III期研究前景广阔。ClinicaTrials.gov 标识符:NCT03901118(II 期)和 NCT03166891(Ib 期)。
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引用次数: 0
Refining the diagnostic utility of OLFM4 in gastric cancer precursors: a call for rigorous methodologies 完善 OLFM4 在胃癌前体中的诊断作用:呼吁采用严格的方法学
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-08 DOI: 10.1186/s12943-024-02077-w
Tai Zhang, Xudong Tang
This commentary offers a thoughtful discussion of the study by Wei et al. published in the journal on the role of Olfactomedin 4 (OLFM4) in incomplete intestinal metaplasia, a gastric precancerous condition. The original paper introduces OLFM4 as a novel biomarker with potential enhanced diagnostic efficacy compared to established markers. However, several methodological and interpretive considerations are noted. The histopathological findings could be refined by using higher magnification to better elucidate the cellular localization of OLFM4. Including high-resolution images for key stainings would enhance the study’s robustness in expression profiling. The statistical approach could be strengthened by employing more rigorous, quantitative methodologies. Additionally, integrating immunofluorescence double-staining may improve the reliability of the results. Discrepancies in immunohistochemical signals across datasets suggest a need for further investigation into tissue section representativeness. Clarifying the term “precancerous lesions of gastric carcinoma cells” to align with widely accepted definitions would enhance clarity. The choice of the GES-1 cell model treated with MNNG could be reconsidered in favor of more established models such as organoids, air-liquid interface models, and gastric cancer-specific cell lines. The in vivo MNNG-alcohol combination model might require additional empirical support, given the limited and conflicting literature on this approach, to ensure an accurate portrayal of IM pathogenesis. The commentary concludes with a call for stringent and standardized methodologies in biomarker research to ensure the clinical applicability and reliability of biomarker studies, particularly in the context of gastric cancer detection and intervention.
这篇评论对 Wei 等人发表在该杂志上的研究进行了深思熟虑的讨论,该研究涉及 Olfactomedin 4 (OLFM4) 在胃癌前病变--不完全性肠化生中的作用。原论文将 OLFM4 介绍为一种新型生物标记物,与已有的标记物相比,其诊断效果可能更强。不过,本文也指出了一些方法学和解释学方面的注意事项。组织病理学研究结果可以通过使用更高的放大倍率来完善,以更好地阐明 OLFM4 的细胞定位。将关键染色的高分辨率图像纳入研究将提高表达谱分析的稳健性。统计方法可以通过采用更严格的定量方法来加强。此外,整合免疫荧光双重染色可提高结果的可靠性。不同数据集之间免疫组化信号的差异表明,有必要进一步调查组织切片的代表性。明确 "胃癌细胞癌前病变 "这一术语,使其与广泛接受的定义相一致,将使结果更加清晰。可以重新考虑选择用 MNNG 处理的 GES-1 细胞模型,转而使用器官组织、气液界面模型和胃癌特异性细胞系等更成熟的模型。鉴于有关这种方法的文献有限且相互矛盾,体内 MNNG-酒精组合模型可能需要更多的经验支持,以确保准确描述 IM 的发病机制。评论最后呼吁在生物标志物研究中采用严格的标准化方法,以确保生物标志物研究的临床适用性和可靠性,尤其是在胃癌检测和干预方面。
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引用次数: 0
Essential gene screening identifies the bromodomain-containing protein BRPF1 as a new actionable target for endocrine therapy-resistant breast cancers 基本基因筛选确定含溴结构域蛋白 BRPF1 为内分泌治疗耐药乳腺癌的新靶点
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-07 DOI: 10.1186/s12943-024-02071-2
Annamaria Salvati, Giorgio Giurato, Jessica Lamberti, Ilaria Terenzi, Laura Crescenzo, Viola Melone, Luigi Palo, Alessandro Giordano, Francesco Sabbatino, Giuseppina Roscigno, Cristina Quintavalle, Gerolama Condorelli, Francesca Rizzo, Roberta Tarallo, Giovanni Nassa, Alessandro Weisz
Identifying master epigenetic factors controlling proliferation and survival of cancer cells allows to discover new molecular targets exploitable to overcome resistance to current pharmacological regimens. In breast cancer (BC), resistance to endocrine therapy (ET) arises from aberrant Estrogen Receptor alpha (ERα) signaling caused by genetic and epigenetic events still mainly unknown. Targeting key upstream components of the ERα pathway provides a way to interfere with estrogen signaling in cancer cells independently from any other downstream event. By combining computational analysis of genome-wide ‘drop-out’ screenings with siRNA-mediated gene knock-down (kd), we identified a set of essential genes in luminal-like, ERα + BC that includes BRPF1, encoding a bromodomain-containing protein belonging to a family of epigenetic readers that act as chromatin remodelers to control gene transcription. To gather mechanistic insights into the role of BRPF1 in BC and ERα signaling, we applied chromatin and transcriptome profiling, gene ablation and targeted pharmacological inhibition coupled to cellular and functional assays. Results indicate that BRPF1 associates with ERα onto BC cell chromatin and its blockade inhibits cell cycle progression, reduces cell proliferation and mediates transcriptome changes through the modulation of chromatin accessibility. This effect is elicited by a widespread inhibition of estrogen signaling, consequent to ERα gene silencing, in antiestrogen (AE) -sensitive and -resistant BC cells and pre-clinical patient-derived models (PDOs). Characterization of the functional interplay of BRPF1 with ERα reveals a new regulator of estrogen-responsive BC cell survival and suggests that this epigenetic factor is a potential new target for treatment of these tumors.
确定控制癌细胞增殖和存活的主表观遗传因素,有助于发现新的分子靶点,从而克服对现有药物疗法的耐药性。在乳腺癌(BC)中,对内分泌疗法(ET)的耐药性源于雌激素受体α(ERα)信号传导异常,其原因主要是遗传和表观遗传事件,目前仍不清楚。靶向雌激素受体α通路的关键上游成分为干扰癌细胞中的雌激素信号提供了一种独立于任何其他下游事件的方法。通过将全基因组 "退出 "筛选的计算分析与 siRNA 介导的基因敲除 (kd) 相结合,我们确定了一组管腔样、ERα + BC 中的重要基因,其中包括 BRPF1,它编码一种含溴结构域的蛋白,属于表观遗传阅读器家族,可作为染色质重塑器控制基因转录。为了从机理上深入了解BRPF1在BC和ERα信号转导中的作用,我们应用了染色质和转录组图谱分析、基因消减和靶向药理抑制以及细胞和功能测试。结果表明,BRPF1与ERα在BC细胞染色质上结合,阻断BRPF1可抑制细胞周期的进展,减少细胞增殖,并通过调节染色质的可及性介导转录组的变化。在抗雌激素(AE)敏感和耐受的 BC 细胞以及临床前患者衍生模型(PDOs)中,ERα 基因沉默导致的雌激素信号传导受到广泛抑制,从而产生了这种效应。BRPF1与ERα功能相互作用的特征揭示了雌激素反应性BC细胞存活的新调节因子,并表明这种表观遗传因子是治疗这些肿瘤的潜在新靶点。
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引用次数: 0
Circular RNA ACVR2A promotes the progression of hepatocellular carcinoma through mir-511-5p targeting PI3K-Akt signaling pathway 环状 RNA ACVR2A 通过 mir-511-5p 靶向 PI3K-Akt 信号通路促进肝细胞癌的进展
IF 37.3 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-06 DOI: 10.1186/s12943-024-02074-z
Du Fei, Fang Wang, Yaohui Wang, Ji Chen, Shendong Chen, Lianpeng Fan, Luhan Yang, Qingyi Ren, Suwit Duangmano, Fukuan Du, Hao Liu, Jie Zhou, Jing Sheng, Yueshui Zhao, Xu Wu, Mingxing Li, Zhangang Xiao, Zhuo Zhang, Xian Jiang
Circular RNA (circRNA) is thought to mediate the occurrence and development of human cancer and usually acts as a tiny RNA (miRNA) sponge to regulate downstream gene expression. However, it is not clear whether and how circACVR2A (hsa_circ_0001073) is involved in the progression of HCC. The purpose of this study is to clarify the potential role and molecular mechanism of circACVR2A in regulating the progression of hepatocellular carcinoma cells (HCC). The abundance of related proteins in circACVR2A, microRNA (miR511-5p) and PI3K-Akt signaling pathway was determined by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) or Western blotting. Cell viability, invasion and apoptosis were analyzed by CCK-8, Transwell analysis and Tunel staining, respectively. The interaction between circACVR2A and microRNA was evaluated by double luciferase reporter gene assay. The results showed that circACVR2A was highly expressed in hepatocellular carcinoma cell lines. Our in vivo and in vitro data showed that circACVR2A promoted the proliferation, migration and invasion of HCC. In terms of mechanism, we found that circACVR2A can directly interact with miR511-5p and act as a miRNA sponge to regulate the expression of related proteins in PI3K-Akt signaling pathway. In HCC, circACVR2A can mediate miR-511-5p/mRNA network to activate PI3K signal pathway. This shows that the molecular regulatory network with circACVR2A as the core is a new potential target for diagnosis and treatment of hepatocellular carcinoma.
环状 RNA(circRNA)被认为介导人类癌症的发生和发展,通常作为微小 RNA(miRNA)海绵调控下游基因的表达。然而,尚不清楚 circACVR2A (hsa_circ_0001073) 是否以及如何参与 HCC 的进展。本研究旨在阐明 circACVR2A 在调控肝癌细胞(HCC)进展中的潜在作用和分子机制。研究采用定量逆转录酶聚合酶链反应(RT-PCR)或 Western 印迹法测定了 circACVR2A、microRNA(miR511-5p)和 PI3K-Akt 信号通路中相关蛋白的丰度。细胞活力、侵袭和凋亡分别通过 CCK-8、Transwell 分析和 Tunel 染色进行分析。通过双荧光素酶报告基因实验评估了 circACVR2A 与 microRNA 之间的相互作用。结果显示,circACVR2A 在肝癌细胞系中高表达。我们的体内和体外数据显示,circACVR2A 促进了 HCC 的增殖、迁移和侵袭。在机制方面,我们发现 circACVR2A 可直接与 miR511-5p 相互作用,并作为 miRNA 海绵调控 PI3K-Akt 信号通路中相关蛋白的表达。在 HCC 中,circACVR2A 可介导 miR-511-5p/mRNA 网络激活 PI3K 信号通路。这表明,以 circACVR2A 为核心的分子调控网络是诊断和治疗肝细胞癌的潜在新靶点。
{"title":"Circular RNA ACVR2A promotes the progression of hepatocellular carcinoma through mir-511-5p targeting PI3K-Akt signaling pathway","authors":"Du Fei, Fang Wang, Yaohui Wang, Ji Chen, Shendong Chen, Lianpeng Fan, Luhan Yang, Qingyi Ren, Suwit Duangmano, Fukuan Du, Hao Liu, Jie Zhou, Jing Sheng, Yueshui Zhao, Xu Wu, Mingxing Li, Zhangang Xiao, Zhuo Zhang, Xian Jiang","doi":"10.1186/s12943-024-02074-z","DOIUrl":"https://doi.org/10.1186/s12943-024-02074-z","url":null,"abstract":"Circular RNA (circRNA) is thought to mediate the occurrence and development of human cancer and usually acts as a tiny RNA (miRNA) sponge to regulate downstream gene expression. However, it is not clear whether and how circACVR2A (hsa_circ_0001073) is involved in the progression of HCC. The purpose of this study is to clarify the potential role and molecular mechanism of circACVR2A in regulating the progression of hepatocellular carcinoma cells (HCC). The abundance of related proteins in circACVR2A, microRNA (miR511-5p) and PI3K-Akt signaling pathway was determined by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) or Western blotting. Cell viability, invasion and apoptosis were analyzed by CCK-8, Transwell analysis and Tunel staining, respectively. The interaction between circACVR2A and microRNA was evaluated by double luciferase reporter gene assay. The results showed that circACVR2A was highly expressed in hepatocellular carcinoma cell lines. Our in vivo and in vitro data showed that circACVR2A promoted the proliferation, migration and invasion of HCC. In terms of mechanism, we found that circACVR2A can directly interact with miR511-5p and act as a miRNA sponge to regulate the expression of related proteins in PI3K-Akt signaling pathway. In HCC, circACVR2A can mediate miR-511-5p/mRNA network to activate PI3K signal pathway. This shows that the molecular regulatory network with circACVR2A as the core is a new potential target for diagnosis and treatment of hepatocellular carcinoma.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":null,"pages":null},"PeriodicalIF":37.3,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Molecular Cancer
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