Biomedical Department, Centre Scientifique de Monaco, Monaco, Principality of Monaco.
Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
J Cell Mol Med. 2019 Apr;23(4):2711-2718. doi: 10.1111/jcmm.14176. Epub 2019 Feb 19.
Most cases of medulloblastoma (MB) occur in young children. While the overall survival rate can be relatively high, current treatments combining surgery, chemo- and radiotherapy are very destructive for patient development and quality of life. Moreover, aggressive forms and recurrences of MB cannot be controlled by classical therapies. Therefore, new therapeutic approaches yielding good efficacy and low toxicity for healthy tissues are required to improve patient outcome. Cancer cells sustain their proliferation by optimizing their nutrient uptake capacities. The L-type amino acid transporter 1 (LAT1) is an essential amino acid carrier overexpressed in aggressive human cancers that was described as a potential therapeutic target. In this study, we investigated the therapeutic potential of JPH203, a LAT1-specific pharmacological inhibitor, on two independent MB cell lines belonging to subgroups 3 (HD-MB03) and Shh (DAOY). We show that while displaying low toxicity towards normal cerebral cells, JPH203 disrupts AA homeostasis, mTORC1 activity, proliferation and survival in MB cells. Moreover, we demonstrate that a long-term treatment with JPH203 does not lead to resistance in MB cells. Therefore, this study suggests that targeting LAT1 with JPH203 is a promising therapeutic approach for MB treatment.
大多数髓母细胞瘤（MB）发生在幼儿中。虽然总体存活率相对较高，但目前结合手术、化疗和放疗的治疗方法对患者的发育和生活质量具有很强的破坏性。此外，MB 的侵袭性形式和复发不能通过经典疗法控制。因此，需要新的治疗方法，既能提高疗效又能降低对健康组织的毒性，从而改善患者的预后。癌细胞通过优化其营养摄取能力来维持其增殖。L 型氨基酸转运蛋白 1（LAT1）是一种在侵袭性人类癌症中过度表达的必需氨基酸载体，被描述为一种潜在的治疗靶点。在这项研究中，我们研究了 JPH203（一种 LAT1 特异性药理抑制剂）对属于第 3 组（HD-MB03）和 Shh（DAOY）的两种独立的 MB 细胞系的治疗潜力。我们发现，虽然 JPH203 对正常脑细胞的毒性较低，但它会破坏 AA 动态平衡、mTORC1 活性、MB 细胞的增殖和存活。此外，我们证明 JPH203 的长期治疗不会导致 MB 细胞产生耐药性。因此，这项研究表明，用 JPH203 靶向 LAT1 是治疗 MB 的一种很有前途的治疗方法。
