Maria Laura De Angelis, Federica Francescangeli, Eleonora Aricò, Paola Verachi, Massimo Zucchetti, Cristina Matteo, Elena Petricci, Emanuela Pilozzi, Isabella Orienti, Alessandra Boe, Adriana Eramo, Rachele Rossi, Tiberio Corati, Daniele Macchia, Anna Maria Pacca, Ann Zeuner, Marta Baiocchi
{"title":"芬瑞替尼纳米胶囊口服制剂可促进 HER2/neu 转基因小鼠局部和转移性乳腺癌的休眠。","authors":"Maria Laura De Angelis, Federica Francescangeli, Eleonora Aricò, Paola Verachi, Massimo Zucchetti, Cristina Matteo, Elena Petricci, Emanuela Pilozzi, Isabella Orienti, Alessandra Boe, Adriana Eramo, Rachele Rossi, Tiberio Corati, Daniele Macchia, Anna Maria Pacca, Ann Zeuner, Marta Baiocchi","doi":"10.1186/s13046-024-03213-6","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Prevention and treatment of metastatic breast cancer (BC) is an unmet clinical need. The retinoic acid derivative fenretinide (FeR) was previously evaluated in Phase I-III clinical trials but, despite its excellent tolerability and antitumor activity in preclinical models, showed limited therapeutic efficacy due to poor bioavailability. We recently generated a new micellar formulation of FeR, Bionanofenretinide (Bio-nFeR) showing enhanced bioavailability, low toxicity, and strong antitumor efficacy on human lung cancer, colorectal cancer, and melanoma xenografts. In the present study, we tested the effect of Bio-nFeR on a preclinical model of metastatic BC.</p><p><strong>Methods: </strong>We used BC cell lines for in vitro analyses of cell viability, cell cycle and migratory capacity. For in vivo studies, we used HER2/neu transgenic mice (neuT) as a model of spontaneously metastatic BC. Mice were treated orally with Bio-nFeR and at sacrifice primary and metastatic breast tumors were analyzed by histology and immunohistochemistry. Molecular pathways activated in primary tumors were analyzed by immunoblotting. Stem cell content was assessed by flow cytometry, immunoblotting and functional assays such as colony formation ex vivo and second transplantation assay in immunocompromised mice.</p><p><strong>Results: </strong>Bio-nFeR inhibited the proliferation and migration of neuT BC cells in vitro and showed significant efficacy against BC onset in neuT mice. Importantly, Bio-nFeR showed the highest effectiveness against metastatic progression, counteracting both metastasis initiation and expansion. The main mechanism of Bio-nFeR action consists of promoting tumor dormancy through a combined induction of antiproliferative signals and inhibition of the mTOR pathway.</p><p><strong>Conclusion: </strong>The high effectiveness of Bio-nFeR in the neuT model of mammary carcinogenesis, coupled with its low toxicity, indicates this formulation as a potential candidate for the treatment of metastatic BC and for the adjuvant therapy of BC patients at high risk of developing metastasis.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.4000,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536529/pdf/","citationCount":"0","resultStr":"{\"title\":\"A nanoencapsulated oral formulation of fenretinide promotes local and metastatic breast cancer dormancy in HER2/neu transgenic mice.\",\"authors\":\"Maria Laura De Angelis, Federica Francescangeli, Eleonora Aricò, Paola Verachi, Massimo Zucchetti, Cristina Matteo, Elena Petricci, Emanuela Pilozzi, Isabella Orienti, Alessandra Boe, Adriana Eramo, Rachele Rossi, Tiberio Corati, Daniele Macchia, Anna Maria Pacca, Ann Zeuner, Marta Baiocchi\",\"doi\":\"10.1186/s13046-024-03213-6\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Prevention and treatment of metastatic breast cancer (BC) is an unmet clinical need. The retinoic acid derivative fenretinide (FeR) was previously evaluated in Phase I-III clinical trials but, despite its excellent tolerability and antitumor activity in preclinical models, showed limited therapeutic efficacy due to poor bioavailability. We recently generated a new micellar formulation of FeR, Bionanofenretinide (Bio-nFeR) showing enhanced bioavailability, low toxicity, and strong antitumor efficacy on human lung cancer, colorectal cancer, and melanoma xenografts. In the present study, we tested the effect of Bio-nFeR on a preclinical model of metastatic BC.</p><p><strong>Methods: </strong>We used BC cell lines for in vitro analyses of cell viability, cell cycle and migratory capacity. For in vivo studies, we used HER2/neu transgenic mice (neuT) as a model of spontaneously metastatic BC. Mice were treated orally with Bio-nFeR and at sacrifice primary and metastatic breast tumors were analyzed by histology and immunohistochemistry. Molecular pathways activated in primary tumors were analyzed by immunoblotting. Stem cell content was assessed by flow cytometry, immunoblotting and functional assays such as colony formation ex vivo and second transplantation assay in immunocompromised mice.</p><p><strong>Results: </strong>Bio-nFeR inhibited the proliferation and migration of neuT BC cells in vitro and showed significant efficacy against BC onset in neuT mice. Importantly, Bio-nFeR showed the highest effectiveness against metastatic progression, counteracting both metastasis initiation and expansion. The main mechanism of Bio-nFeR action consists of promoting tumor dormancy through a combined induction of antiproliferative signals and inhibition of the mTOR pathway.</p><p><strong>Conclusion: </strong>The high effectiveness of Bio-nFeR in the neuT model of mammary carcinogenesis, coupled with its low toxicity, indicates this formulation as a potential candidate for the treatment of metastatic BC and for the adjuvant therapy of BC patients at high risk of developing metastasis.</p>\",\"PeriodicalId\":50199,\"journal\":{\"name\":\"Journal of Experimental & Clinical Cancer Research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":11.4000,\"publicationDate\":\"2024-11-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536529/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Experimental & Clinical Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13046-024-03213-6\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Experimental & Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13046-024-03213-6","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景:预防和治疗转移性乳腺癌(BC预防和治疗转移性乳腺癌(BC)是一项尚未满足的临床需求。视黄酸衍生物非格列汀(FeR)曾在 I-III 期临床试验中接受过评估,尽管它在临床前模型中具有极佳的耐受性和抗肿瘤活性,但由于生物利用度较低,因此疗效有限。我们最近生成了一种新的铁线肽胶束制剂--Bionanofenretinide(Bio-nFeR),其生物利用度提高,毒性降低,对人类肺癌、结直肠癌和黑色素瘤异种移植物具有很强的抗肿瘤疗效。在本研究中,我们测试了 Bio-nFeR 对转移性 BC 临床前模型的作用:我们使用 BC 细胞系进行细胞活力、细胞周期和迁移能力的体外分析。在体内研究中,我们使用 HER2/neu 转基因小鼠(neuT)作为自发性转移性 BC 的模型。小鼠口服 Bio-nFeR,牺牲时通过组织学和免疫组化对原发性和转移性乳腺肿瘤进行分析。用免疫印迹法分析原发肿瘤中激活的分子通路。干细胞含量通过流式细胞术、免疫印迹法和功能检测(如体内外集落形成和免疫缺陷小鼠第二次移植检测)进行评估:结果:Bio-nFeR 在体外抑制了 neuT BC 细胞的增殖和迁移,对 neuT 小鼠 BC 的发病有显著疗效。重要的是,Bio-nFeR 对转移进展表现出最高的效力,既能抑制转移的发生,也能抑制转移的扩大。Bio-nFeR 的主要作用机制是通过联合诱导抗增殖信号和抑制 mTOR 通路来促进肿瘤休眠:结论:Bio-nFeR 在乳腺癌 neuT 模型中的高效性及其低毒性表明,该制剂是治疗转移性 BC 和辅助治疗高转移风险 BC 患者的潜在候选药物。
A nanoencapsulated oral formulation of fenretinide promotes local and metastatic breast cancer dormancy in HER2/neu transgenic mice.
Background: Prevention and treatment of metastatic breast cancer (BC) is an unmet clinical need. The retinoic acid derivative fenretinide (FeR) was previously evaluated in Phase I-III clinical trials but, despite its excellent tolerability and antitumor activity in preclinical models, showed limited therapeutic efficacy due to poor bioavailability. We recently generated a new micellar formulation of FeR, Bionanofenretinide (Bio-nFeR) showing enhanced bioavailability, low toxicity, and strong antitumor efficacy on human lung cancer, colorectal cancer, and melanoma xenografts. In the present study, we tested the effect of Bio-nFeR on a preclinical model of metastatic BC.
Methods: We used BC cell lines for in vitro analyses of cell viability, cell cycle and migratory capacity. For in vivo studies, we used HER2/neu transgenic mice (neuT) as a model of spontaneously metastatic BC. Mice were treated orally with Bio-nFeR and at sacrifice primary and metastatic breast tumors were analyzed by histology and immunohistochemistry. Molecular pathways activated in primary tumors were analyzed by immunoblotting. Stem cell content was assessed by flow cytometry, immunoblotting and functional assays such as colony formation ex vivo and second transplantation assay in immunocompromised mice.
Results: Bio-nFeR inhibited the proliferation and migration of neuT BC cells in vitro and showed significant efficacy against BC onset in neuT mice. Importantly, Bio-nFeR showed the highest effectiveness against metastatic progression, counteracting both metastasis initiation and expansion. The main mechanism of Bio-nFeR action consists of promoting tumor dormancy through a combined induction of antiproliferative signals and inhibition of the mTOR pathway.
Conclusion: The high effectiveness of Bio-nFeR in the neuT model of mammary carcinogenesis, coupled with its low toxicity, indicates this formulation as a potential candidate for the treatment of metastatic BC and for the adjuvant therapy of BC patients at high risk of developing metastasis.
期刊介绍:
The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications.
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