Gagliardi Maria, Kean Rhonda, Dai Bingbing, Augustine Jithesh Jose, Roberts Michael, Fleming Jason, Hooper D Craig, Ashizawa Ana Tari
Bio-Path Holdings Inc., Bellaire, TX 77401, USA.
Department of Cancer Biology, Philadelphia, Thomas Jefferson University, PA 19107, USA.
Biomedicines. 2024 Aug 20;12(8):1901. doi: 10.3390/biomedicines12081901.
Overexpression and aberrant activation of signal transducer and activator of transcription 3 (STAT3) contribute to tumorigenesis, drug resistance, and tumor-immune evasion, making it a potential cancer therapeutic target. BP1003 is a neutral liposome incorporated with a nuclease-resistant P-ethoxy antisense oligodeoxynucleotide (ASO) targeting the STAT3 mRNA. Its unique design enhances BP1003 stability, cellular uptake, and target affinity. BP1003 efficiently reduces STAT3 expression and enhances the sensitivity of breast cancer cells (HER2, triple negative) and ovarian cancer cells (late stage, invasive ovarian cancer) to paclitaxel and 5-fluorouracil (5-FU) in both 2D and 3D cell cultures. Similarly, ex vivo and in vivo patient-derived models of pancreatic ductal adenocarcinoma (PDAC) show reduced tissue viability and tumor volume with BP1003 and gemcitabine combination treatments. In addition to directly affecting tumor cells, BP1003 can modulate the tumor microenvironment. Unlike M1 differentiation, monocyte differentiation into anti-inflammatory M2 macrophages is suppressed by BP1003, indicating its potential contribution to immunotherapy. The broad anti-tumor effect of BP1003 in numerous preclinical solid tumor models, such as breast, ovarian, and pancreatic cancer models shown in this work, makes it a promising cancer therapeutic.
信号转导和转录激活因子3（STAT3）的过表达和异常激活有助于肿瘤发生、耐药和肿瘤免疫逃逸，使其成为潜在的癌症治疗靶点。BP1003是一种中性脂质体，包含一种靶向STAT3 mRNA的耐核酸酶的P - 乙氧基反义寡脱氧核苷酸（ASO）。其独特设计增强了BP1003的稳定性、细胞摄取和靶标亲和力。在二维和三维细胞培养中，BP1003能有效降低STAT3表达，并增强乳腺癌细胞（HER2、三阴性）和卵巢癌细胞（晚期、侵袭性卵巢癌）对紫杉醇和5 - 氟尿嘧啶（5 - FU）的敏感性。同样，在胰腺导管腺癌（PDAC）的体外和体内患者来源模型中，BP1003与吉西他滨联合治疗显示组织活力和肿瘤体积减小。除了直接影响肿瘤细胞外，BP1003还可调节肿瘤微环境。与M1分化不同，BP1003抑制单核细胞分化为抗炎性M2巨噬细胞，表明其对免疫治疗的潜在贡献。BP1003在众多临床前实体瘤模型（如本文所示的乳腺癌、卵巢癌和胰腺癌模型）中具有广泛的抗肿瘤作用，使其成为一种有前景的癌症治疗药物。
