Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
J Exp Clin Cancer Res. 2024 Nov 5;43(1):296. doi: 10.1186/s13046-024-03213-6.
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.
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.
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.
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.
预防和治疗转移性乳腺癌（BC）是一个未满足的临床需求。维甲酸衍生物芬维 A 酯（FeR）曾在 I-III 期临床试验中进行评估，但尽管其在临床前模型中具有良好的耐受性和抗肿瘤活性，由于生物利用度差，其治疗效果有限。我们最近生成了 FeR 的一种新胶束制剂，Bionanofenretinide（Bio-nFeR），显示出增强的生物利用度、低毒性和对人肺癌、结直肠癌和黑色素瘤异种移植物的强大抗肿瘤功效。在本研究中，我们测试了 Bio-nFeR 对转移性 BC 的临床前模型的影响。
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。对于体内研究，我们使用 HER2/neu 转基因小鼠（neuT）作为自发性转移性 BC 的模型。小鼠经口给予 Bio-nFeR 治疗，处死时通过组织学和免疫组织化学分析原发性和转移性乳腺肿瘤。通过免疫印迹分析原发性肿瘤中激活的分子途径。通过流式细胞术、免疫印迹和体外集落形成和免疫缺陷小鼠二次移植试验等功能测定评估干细胞含量。
Bio-nFeR 抑制 neuT BC 细胞的增殖和迁移，并在 neuT 小鼠中显示出对 BC 发病的显著疗效。重要的是，Bio-nFeR 对转移性进展显示出最高的有效性，可同时抑制转移的起始和扩展。Bio-nFeR 作用的主要机制是通过联合诱导抗增殖信号和抑制 mTOR 途径来促进肿瘤休眠。
Bio-nFeR 在 neuT 乳腺肿瘤发生模型中的高有效性，加上其低毒性，表明该制剂是治疗转移性 BC 和治疗有发生转移高风险的 BC 患者的辅助治疗的潜在候选药物。
