Department of Surgery, Indiana University School of Medicine, South Bend, Indiana, USA.
Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana, USA.
J Cell Mol Med. 2024 Sep;28(17):e18585. doi: 10.1111/jcmm.18585.
Cholangiocarcinoma (CCA), an aggressive biliary tract cancer, carries a grim prognosis with a 5-year survival rate of 5%-15%. Standard chemotherapy regimens for CCA, gemcitabine plus cisplatin (GemCis) or its recently approved combination with durvalumab demonstrate dismal clinical activity, yielding a median survival of 12-14 months. Increased serotonin accumulation and secretion have been implicated in the oncogenic activity of CCA. This study investigated the therapeutic efficacy of telotristat ethyl (TE), a tryptophan hydroxylase inhibitor blocking serotonin biosynthesis, in combination with standard chemotherapies in preclinical CCA models. Nab-paclitaxel (NPT) significantly enhanced animal survival (60%), surpassing the marginal effects of TE (11%) or GemCis (9%) in peritoneal dissemination xenografts. Combining TE with GemCis (26%) or NPT (68%) further increased survival rates. In intrahepatic (iCCA), distal (dCCA) and perihilar (pCCA) subcutaneous xenografts, TE exhibited substantial tumour growth inhibition (41%-53%) compared to NPT (56%-69%) or GemCis (37%-58%). The combination of TE with chemotherapy demonstrated enhanced tumour growth inhibition in all three cell-derived xenografts (67%-90%). PDX studies revealed TE's marked inhibition of tumour growth (40%-73%) compared to GemCis (80%-86%) or NPT (57%-76%). Again, combining TE with chemotherapy exhibited an additive effect. Tumour cell proliferation reduction aligned with tumour growth inhibition in all CDX and PDX tumours. Furthermore, TE treatment consistently decreased serotonin levels in all tumours under all therapeutic conditions. This investigation decisively demonstrated the antitumor efficacy of TE across a spectrum of CCA preclinical models, suggesting that combination therapies involving TE, particularly for patients exhibiting serotonin overexpression, hold the promise of improving clinical CCA therapy.
胆管癌（CCA）是一种侵袭性胆道癌，预后极差，5 年生存率为 5%-15%。CCA 的标准化疗方案为吉西他滨联合顺铂（GemCis）或最近批准的与 durvalumab 联合方案，临床疗效不佳，中位生存期为 12-14 个月。CCA 的致癌活性与血清素积累和分泌增加有关。本研究探讨了色氨酸羟化酶抑制剂托瑞司他乙酯（TE）阻断血清素生物合成与标准化疗联合在 CCA 临床前模型中的治疗效果。Nab-紫杉醇（NPT）显著提高了动物的存活率（60%），超过了 TE（11%）或 GemCis（9%）在腹膜扩散异种移植中的边缘效果。将 TE 与 GemCis（26%）或 NPT（68%）联合使用进一步提高了存活率。在肝内（iCCA）、远端（dCCA）和肝门（pCCA）皮下异种移植中，与 NPT（56%-69%）或 GemCis（37%-58%）相比，TE 表现出显著的肿瘤生长抑制（41%-53%）。TE 与化疗联合在所有三种细胞来源的异种移植中均显示出增强的肿瘤生长抑制作用（67%-90%）。PDX 研究显示，与 GemCis（80%-86%）或 NPT（57%-76%）相比，TE 显著抑制肿瘤生长（40%-73%）。同样，TE 与化疗联合具有相加作用。所有 CDX 和 PDX 肿瘤中，肿瘤细胞增殖减少与肿瘤生长抑制一致。此外，在所有治疗条件下，TE 治疗均能降低所有肿瘤中的血清素水平。本研究明确证明了 TE 在一系列 CCA 临床前模型中的抗肿瘤疗效，表明涉及 TE 的联合治疗方案，特别是对表现出血清素过表达的患者，有望改善 CCA 的临床治疗。
