ALK inhibitor for Glioblastoma [Neurosurgery Wiki]

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====== ALK inhibitor for Glioblastoma ======

[[Glioblastoma]]'s lethality is derived from a number of factors including highly active pro-mitotic and pro-metastatic pathways. Two factors increasingly associated with the [[intracellular signaling]] and transcriptional machinery required for such changes are [[anaplastic lymphoma kinase]] (ALK) and the [[hepatocyte growth factor receptor]] (HGFR or, more commonly [[MET]]). Both receptors are members of the [[receptor tyrosine kinase]] (RTK) family, which has itself gained much attention for its role in modulating [[mitosis]], [[migration]], and survival in cancer cells. [[ALK]] was first described as a vital oncogene in lymphoma studies, but it has since been connected to many carcinomas, including non-Small-cell lung cancer and [[glioblastoma]]. As the receptor for HGF, MET has also been highly characterized and regulates numerous developmental and wound healing events which, when upregulated in cancer, can promote tumor progression. The wealth of information gathered over the last 30 years regarding these RTKs suggests three downstream cascades that depend upon activation of [[STAT3]], [[Ras]], and [[AKT]]
((Wallace GC 4th, Dixon-Mah YN, Vandergrift WA 3rd, Ray SK, Haar CP, Mittendorf AM, Patel SJ, Banik NL, Giglio P, Das A. Targeting oncogenic ALK and MET: a promising therapeutic strategy for glioblastoma. Metab Brain Dis. 2013 Sep;28(3):355-66. doi: 10.1007/s11011-013-9401-7. Epub 2013 Apr 2. PMID: 23543207; PMCID: PMC4314306.)).
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ALK targeting holds promise as a novel therapeutic approach in Glioblastoma, especially in combination schemes allowing multi-target therapy. Such schemes may incorporate detection-guided therapy and utilize next-generation inhibitory compounds with improved central nervous system penetration. Moreover, identification of ALK-mediated molecular pathway(s) related to Glioblastoma carcinogenesis/ pathology and putative therapy resistance is of high priority and warrants further exploitation
((Kalamatianos T, Denekou D, Stranjalis G, Papadimitriou E. Anaplastic Lymphoma Kinase in Glioblastoma: Detection/Diagnostic Methods and Therapeutic Options. Recent Pat Anticancer Drug Discov. 2018;13(2):209-223. doi: 10.2174/1574892813666180115151554. PMID: 29336268.)).

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The antitumor activity of various [[tyrosine kinase inhibitor]]s were tested against three humans [[glioblastoma cell line]]s ([[U87]]MG, [[LN229]], and [[GSC23]]) in [[Japan]], which expressed substantially low [[ALK]] levels; second-generation [[ALK inhibitor]]s, [[alectinib]] and [[ceritinib]], effectively induced [[Glioblastoma]] [[cell death]]. In addition, treatment with either [[alectinib]] or [[ceritinib]] modulated the activation of various molecules downstream of [[receptor tyrosine kinase]] (RTK) signaling and induced [[caspase]]-dependent/independent cell death mainly by inhibiting signal transducer and activator of transcription 3 activations in human Glioblastoma cells. In addition, [[alectinib]] and [[ceritinib]] also showed antitumor activity against a U87MG cell line with acquired temozolomide resistance. Finally, oral administration of alectinib and ceritinib prolonged the survival of mice harboring intracerebral Glioblastoma xenografts compared to controls. These results suggested that treatment with the second-generation ALK inhibitors, alectinib and ceritinib, might serve as potent therapeutic strategies against Glioblastoma
((Kawauchi D, Takahashi M, Satomi K, Yamamuro S, Kobayashi T, Uchida E, Honda-Kitahara M, Narita Y, Iwadate Y, Ichimura K, Tomiyama A. The [[ALK inhibitor]]s, [[alectinib]] and [[ceritinib]], induce ALK-independent and [[STAT3]]-dependent glioblastoma cell death. Cancer Sci. 2021 Mar 16. doi: 10.1111/cas.14885. Epub ahead of print. PMID: 33728771.)).

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