Luu Shelly, Fu Ning, Savage Paul, Pacholczyk Karina, Zaslavsky Taylor, Conner James, Swallow Carol J
Department of Surgery, University of Toronto, Toronto, Canada.
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.
J Gastrointest Oncol. 2024 Aug 31;15(4):1870-1879. doi: 10.21037/jgo-24-105. Epub 2024 Aug 2.
On a global scale, gastric adenocarcinoma (GCa) accounts for a large burden of death from cancer. Despite advances in systemic therapy and surgical technique, the fatality rate for GCa remains unacceptably high in Europe and North America, where diagnosis is typically made at an advanced stage. Biomarkers that can accurately predict response to new therapies and provide novel therapeutic strategies are urgently sought. FAM46C, a putative noncanonical nucleotidyltransferase, has garnered interest for its tumor suppressor function in multiple myeloma. A frequent and profound depletion of FAM46C has been described in GCa patients from China, Japan and now Canada. Furthermore, the degree of FAM46C depletion meaningfully portends cancer recurrence following resection, and death from GCa. In this review, we provide an updated summary of the literature regarding FAM46C as a biomarker in GCa and explore the potential mechanism(s) through which FAM46C depletion promotes GCa progression, including dis-inhibition of oncogenic Plk4 kinase activity. We highlight the potential for restoration of FAM46C levels as a therapeutic strategy. Norcantharidin, a synthetic analogue of the traditional Chinese medicine cantharidin derived from the blister beetle, is the only bio-available compound presently known to upregulate FAM46C expression and is under investigation in phase one trials in cancer patients.
在全球范围内，胃腺癌（GCa）是癌症死亡的一大负担。尽管全身治疗和手术技术取得了进展，但在欧洲和北美，GCa的死亡率仍然高得令人难以接受，在这些地区，诊断通常在晚期进行。迫切需要能够准确预测对新疗法的反应并提供新治疗策略的生物标志物。FAM46C是一种推定的非经典核苷酸转移酶，因其在多发性骨髓瘤中的肿瘤抑制功能而受到关注。在中国、日本以及现在的加拿大，GCa患者中均有频繁且显著的FAM46C缺失现象被报道。此外，FAM46C的缺失程度对切除术后癌症复发以及GCa导致的死亡具有重要的预示作用。在本综述中，我们提供了关于FAM46C作为GCa生物标志物的文献最新总结，并探讨了FAM46C缺失促进GCa进展的潜在机制，包括对致癌性Plk4激酶活性的去抑制作用。我们强调恢复FAM46C水平作为一种治疗策略的潜力。去甲斑蝥素是一种源自斑蝥的传统中药斑蝥素的合成类似物，是目前已知的唯一能上调FAM46C表达的生物可利用化合物，正在癌症患者的一期试验中进行研究。
