Sokolova Viktorija, Gruber Rebecca, Pammer Lorenz M, Kocher Florian, Klieser Eckhard, Amann Arno, Pichler Renate, Günther Michael, Ormanns Steffen, Neureiter Daniel, Seeber Andreas
Department of Nuclear Medicine, Provincial Hospital of Bolzano (SABES-ASDAA), Teaching Hospital of the Paracelsus Medical Private University, Bolzano-Bozen, Italy.
Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.
Mol Biol Rep. 2024 Dec 27;52(1):87. doi: 10.1007/s11033-024-10169-5.
In the last decades the survival of metastatic gastrointestinal (GI) cancer patients could have been significantly extended due to the introduction of targeted- and immunotherapy. However, only the minority of patients will experience long-lasting survival. Hence, novel therapeutics are clearly necessary for GI cancer patients. Molecular high-throughput profiling techniques have revealed potential novel targetable molecular alterations, emphasizing the necessity for tailored therapeutic approaches. Nuclear export proteins, particularly Exportin-1 (XPO1), have emerged as promising targets in cancer therapy due to their crucial role in cellular homeostasis and regulation of key cellular functions. Dysregulation of XPO1-mediated nuclear export leads to the functional loss of tumor suppressors and pro-apoptotic factors, facilitating cancer progression. Selinexor, a XPO1 inhibitor, has shown promising activity in preclinical and clinical studies, particularly in hematological malignancies. However, its efficacy in GI cancers remains underexplored. This review aims to elucidate the functional and pathophysiological role of XPO1 in GI cancers. Despite the potential of XPO1 inhibitors in suppressing cell proliferation and inducing apoptosis, comprehensive molecular landscape data and validation of selective inhibitors in GI cancers are lacking. Targeting XPO1 presents a significant therapeutic potential for the treatment of GI cancer patients. Further research is necessary to fully elucidate the molecular landscape according to XPO1 expression in GI tumors and to validate the efficacy of selective XPO1 inhibitors. These efforts are expected to contribute to the development of more effective and personalized therapeutic strategies for GI cancer patients.
在过去几十年中，由于靶向治疗和免疫治疗的引入，转移性胃肠道（GI）癌患者的生存期得到了显著延长。然而，只有少数患者能实现长期生存。因此，显然需要为胃肠道癌患者开发新的治疗方法。分子高通量分析技术揭示了潜在的可靶向的新分子改变，强调了量身定制治疗方法的必要性。核输出蛋白，特别是染色体区域维护蛋白1（XPO1），因其在细胞稳态和关键细胞功能调节中的关键作用，已成为癌症治疗中有前景的靶点。XPO1介导的核输出失调会导致肿瘤抑制因子和促凋亡因子功能丧失，促进癌症进展。塞利尼索，一种XPO1抑制剂，在临床前和临床研究中显示出有前景的活性，尤其是在血液系统恶性肿瘤中。然而，其在胃肠道癌中的疗效仍未得到充分探索。本综述旨在阐明XPO1在胃肠道癌中的功能和病理生理作用。尽管XPO1抑制剂有抑制细胞增殖和诱导凋亡的潜力，但缺乏关于胃肠道癌的全面分子图谱数据和选择性抑制剂的验证。靶向XPO1为胃肠道癌患者的治疗提供了显著的治疗潜力。有必要进一步研究，以根据胃肠道肿瘤中XPO1的表达全面阐明分子图谱，并验证选择性XPO1抑制剂的疗效。这些努力有望为胃肠道癌患者开发更有效和个性化的治疗策略做出贡献。
