Imatinib mesylate, a tyrosine kinase inhibitor of platelet derived growth factor receptor-alpha and -beta, c-fms, c-kit, abl and arg kinase (imatinib targets), has been shown to prevent tumor progression in early studies of recurrent gliomas, but has shown weak activity in randomized controlled trials.
Responses to imatinib observed in patients where imatinib inhibitable tyrosine kinases were documented on the original biopsy are marginally better than that previously reported in imatinib treatment of unselected recurrent glioblastoma patients. Hassler et al. present a suggestion for defining a patient sub-population who might potentially benefit from imatinib 1).
It is used in chronic myeloid leukemia (CML) treatment. Imatinib has contributed to complete and prolong cytogenetic responses so that it is now the standard treatment of CML.
Recently, Imatinib mesylate has shown a significantly prolonged progression-free survival and overall survival in metastatic and locally advanced c-Kit positive gastro-intestinal stromal tumors (GISTs) and more recently a prolonged disease-free survival in operated high risk GIST.
In case of locally advanced or metastatic chordomas, medical treatment is frequently discussed. While chemotherapy is ineffective, it would appear that some molecular targeted therapies, in particular imatinib, could slow down the tumor growth in case-reports, retrospective series, and phase I or II trials. Nineteen publications, between January 1990 and September 2014, have been found describing the activity of these targeted therapies. A systematic analysis of these publications shows that the best objective response with targeted therapies was stabilization in 52 to 69% of chordomas. Given the indolent course of advanced chordoma and because of the absence of randomized trial, the level of evidence to treat chordomas with molecular therapy is low (level III), whatever the drug. Furthermore, we could not draw firm conclusion on the activity of imatinib. Other putative targets have also been described. Therefore, further clinical trials are expected, especially with these targets. Nevertheless, it seems essential, in those future studies, to consider the naturally slow course of the disease 2).
Neurodegeneration can be prevented by imatinib mesylate (Gleevec or STI571) that regulates c-Abl tyrosine kinases, which elicit protective effects in neurodegenerative disease models. However, the protective effect of STI571 against prion disease remains unknown. In the present study, the effect of STI571 on prion peptide-induced neuronal death was investigated. Results showed that STI571 rescued neurons from PrP106-126-induced neurotoxicity by preventing mitochondrial dysfunction. STI571-inhibited c-Abl tyrosine kinases prevented PrP106-126-induced reduction in mitochondrial potential, Bax translocation to the mitochondria and cytochrome c release. The protective effect of STI571 against mitochondrial dysfunction was related to the activation of BIM expression. This study is the first to demonstrate the protective effect of STI571 against prion-mediated neurotoxicity. Our results suggested that imatinib mesylate treatment may be a novel therapeutic strategy to treat prion-mediated neurotoxicity 3).
Responses to imatinib observed in patients where imatinib inhibitable tyrosine kinases were documented on the original biopsy are marginally better than that previously reported in imatinib treatment of unselected recurrent glioblastoma patients. Hassler et al. present a suggestion for defining a patient sub-population who might potentially benefit from imatinib 1).
It is used in chronic myeloid leukemia (CML) treatment. Imatinib has contributed to complete and prolong cytogenetic responses so that it is now the standard treatment of CML.
Recently, Imatinib mesylate has shown a significantly prolonged progression-free survival and overall survival in metastatic and locally advanced c-Kit positive gastro-intestinal stromal tumors (GISTs) and more recently a prolonged disease-free survival in operated high risk GIST.
In case of locally advanced or metastatic chordomas, medical treatment is frequently discussed. While chemotherapy is ineffective, it would appear that some molecular targeted therapies, in particular imatinib, could slow down the tumor growth in case-reports, retrospective series, and phase I or II trials. Nineteen publications, between January 1990 and September 2014, have been found describing the activity of these targeted therapies. A systematic analysis of these publications shows that the best objective response with targeted therapies was stabilization in 52 to 69% of chordomas. Given the indolent course of advanced chordoma and because of the absence of randomized trial, the level of evidence to treat chordomas with molecular therapy is low (level III), whatever the drug. Furthermore, we could not draw firm conclusion on the activity of imatinib. Other putative targets have also been described. Therefore, further clinical trials are expected, especially with these targets. Nevertheless, it seems essential, in those future studies, to consider the naturally slow course of the disease 2).
Neurodegeneration can be prevented by imatinib mesylate (Gleevec or STI571) that regulates c-Abl tyrosine kinases, which elicit protective effects in neurodegenerative disease models. However, the protective effect of STI571 against prion disease remains unknown. In the present study, the effect of STI571 on prion peptide-induced neuronal death was investigated. Results showed that STI571 rescued neurons from PrP106-126-induced neurotoxicity by preventing mitochondrial dysfunction. STI571-inhibited c-Abl tyrosine kinases prevented PrP106-126-induced reduction in mitochondrial potential, Bax translocation to the mitochondria and cytochrome c release. The protective effect of STI571 against mitochondrial dysfunction was related to the activation of BIM expression. This study is the first to demonstrate the protective effect of STI571 against prion-mediated neurotoxicity. Our results suggested that imatinib mesylate treatment may be a novel therapeutic strategy to treat prion-mediated neurotoxicity 3).
Complications
Imatinib is a well tolerated treatment with few side effects mainly gastro-intestinal symptoms (nausea, vomiting and diarrhea), headaches, rash and periorbital edema. Hemorrhage incidents are rare in patients treated with Imatinib. They are more frequently seen in CML patients. Hemorrhage incidents in CML include in many cases upper gastro-intestinal (GI) tract bleeding and central nervous system bleeding in rare ones. In GIST patients treated with Imatinib, hemorrhage incidents are exclusively made of upper GI tract bleeding consecutive to tumor perforation or necrosis. In our observation, we present the case of a subdural hematoma occurring in a patient treated with adjuvant Imatinib for a high risk localized gastric GIST. No other case of subdural hematoma in GIST treated with Imatinib has been reported in literature 4).
1) Hassler MR, Vedadinejad M, Flechl B, Haberler C, Preusser M, Hainfellner JA, Wöhrer A, Dieckmann KU, Rössler K, Kast R, Marosi C. Response to imatinib as a function of target kinase expression in recurrent glioblastoma. Springerplus. 2014 Feb 25;3:111. doi: 10.1186/2193-1801-3-111. eCollection 2014. PubMed PMID: 25674429; PubMed Central PMCID: PMC4320134.
2) Lebellec L, Aubert S, Zaïri F, Ryckewaert T, Chauffert B, Penel N. Molecular targeted therapies in advanced or metastatic chordoma patients: Facts and hypotheses. Crit Rev Oncol Hematol. 2015 Jan 30. pii: S1040-8428(15)00013-X. doi: 10.1016/j.critrevonc.2015.01.010. [Epub ahead of print] Review. PubMed PMID: 25682222.
3) Pan Y, Sun L, Wang J, Fu W, Fu Y, Wang J, Tong Y, Pan B. STI571 protects neuronal cells from neurotoxic prion protein fragment-induced apoptosis. Neuropharmacology. 2015 Feb 11. pii: S0028-3908(15)00045-3. doi: 10.1016/j.neuropharm.2015.01.029. [Epub ahead of print] PubMed PMID: 25681617.
4) Feki J, Marrekchi G, Boudawara T, Rekik N, Maatouq S, Boudawara Z, Frikha M. Subdural hematoma during therapy of gastro-intestinal stromal tumor (GIST) with Imatinib mesylate. Gulf J Oncolog. 2015 Jan;1(17):92-95. PubMed PMID: 25682460.