Chiu Chun-Lung, Zhang Dalin, Zhao Hongjuan, Wei Yi, Polasko Alexandra Lapat, Thomsen Mikkel Thy, Yang Vanessa, Yang Kasie Kexin, Hauck Spencer, Peterson Eric E, Wen Ru M, Qiu Zhengyuan, Corey Eva, Miao Yu Rebecca, Rankin Erinn B, Peehl Donna M, Huang Jiaoti, Giaccia Amato J, Brooks James D
Department of Urology, Stanford University School of Medicine, Stanford, California.
Department of Clinical Medicine, Aarhus University, Aarhus Centrum, Denmark.
Clin Cancer Res. 2025 Apr 1;31(7):1346-1358. doi: 10.1158/1078-0432.CCR-24-3028.
After failing primary and secondary hormonal therapy, castration-resistant and neuroendocrine prostate cancer metastatic to the bone is invariably lethal, although treatment with docetaxel and carboplatin can modestly improve survival. Therefore, agents targeting biologically relevant pathways in prostate cancer and potentially synergizing with docetaxel and carboplatin in inhibiting bone metastasis growth are urgently needed.
Phosphorylated (activated) AXL expression in human prostate cancer bone metastases was assessed by IHC staining. We evaluated the effects of a novel soluble AXL signaling inhibitor, sAXL (batiraxcept or AVB-S6-500), on tumor growth and lung metastases in prostate cancer patient-derived xenograft models that were implanted intratibially. After injection of LuCaP cells into the tibiae, tumors were treated with batiraxcept and docetaxel or carboplatin alone or in combination, and tumor growth was monitored by serum prostate-specific antigen or bioluminescence. Tumor burden was quantified by human-specific Ku70 staining, and metastasis to the lungs was determined using qPCR. Transcriptomic profiling, Western blotting, and immunohistochemistry were performed to identify treatment-regulated gene and protein profile changes.
High AXL phosphorylation in human prostate cancer bone metastases correlated with shortened survival. Batiraxcept alone or in combination with docetaxel or carboplatin significantly suppressed intratibial tumor growth and suppressed metastasis to the lungs through multiple mechanisms, including repression of cancer stemness genes (CD44, ALDH1A1, TACSTD2, and ATXN1) and the PI3K, JAK, MAPK, and E2F1/NUSAP1 signaling pathways.
Our study provides a robust preclinical rationale and mechanisms of action for using batiraxcept as a single agent or in combination with docetaxel or carboplatin to treat lethal metastatic prostate cancer.
在一线和二线激素治疗失败后，去势抵抗性和神经内分泌性前列腺癌发生骨转移通常是致命的，尽管多西他赛和卡铂治疗可适度提高生存率。因此，迫切需要能够靶向前列腺癌生物学相关通路并可能与多西他赛和卡铂协同抑制骨转移生长的药物。
通过免疫组化染色评估人前列腺癌骨转移灶中磷酸化（活化）AXL的表达。我们在经胫骨植入的前列腺癌患者来源异种移植模型中，评估了一种新型可溶性AXL信号抑制剂sAXL（batiraxcept或AVB-S6-500）对肿瘤生长和肺转移的影响。将LuCaP细胞注射到胫骨后，肿瘤分别接受batiraxcept、多西他赛或卡铂单独治疗或联合治疗，通过血清前列腺特异性抗原或生物发光监测肿瘤生长。通过人特异性Ku70染色对肿瘤负荷进行定量，并使用qPCR确定肺转移情况。进行转录组分析、蛋白质免疫印迹和免疫组化以确定治疗调节的基因和蛋白质谱变化。
人前列腺癌骨转移灶中高AXL磷酸化与生存期缩短相关。Batiraxcept单独使用或与多西他赛或卡铂联合使用可通过多种机制显著抑制胫骨内肿瘤生长并抑制肺转移，包括抑制癌症干细胞基因（CD44、ALDH1A1、TACSTD2和ATXN1）以及PI3K、JAK、MAPK和E2F1/NUSAP1信号通路。
我们的研究为使用batiraxcept作为单一药物或与多西他赛或卡铂联合治疗致命性转移性前列腺癌提供了有力的临床前理论依据和作用机制。
