Multi-tyrosine kinase inhibitors in preclinical studies for pediatric CNS AT/RT: Evidence for synergy with Topoisomerase-I inhibition

Abstract

BackgroundCurrently, Atypical Teratoid Rhabdoid Tumor (AT/RT) constitutes one of the most difficult to treat malignancies in pediatrics. Hence, new knowledge of potential targets for therapeutics and the development of novel treatment approaches are urgently needed. We have evaluated the presence of cytokine pathways and the effects of two clinically available multi-tyrosine kinase inhibitors for cytotoxicity, target modulation and drug combinability against AT/RT cell lines.ResultsAT/RT cell lines expressed measurable quantities of VEGF, FGF, PDGF and SDF-1, although the absolute amounts varied between the cell lines. The targeted receptor tyrosine kinase inhibitor sorafenib inhibited the key signaling molecule Erk, which was activated following the addition of own conditioned media, suggesting the existence of autocrine/paracrine growth stimulatory pathways. The multi-tyrosine kinase inhibitors sorafenib and sunitinib also showed significant growth inhibition of AT/RT cells and their activity was enhanced by combination with the topoisomerase inhibitor, irinotecan. The loss of cytoplasmic NF-kappa-B in response to irinotecan was diminished by sorafenib, providing evidence for a possible benefit for this drug combination.ConclusionsIn addition to previously described involvement of insulin like growth factor (IGF) family of cytokines, a multitude of other growth factors may contribute to the growth and survival of AT/RT cells. However, consistent with the heterogeneous nature of this tumor, quantitative and qualitative differences may exist among different tumor samples. Multi-tyrosine kinase inhibitors appear to have effective antitumor activity against all cell lines studied. In addition, the target modulation studies and drug combinability data provide the groundwork for additional studies and support the evaluation of these agents in future treatment protocols.

Sorafenib Overcomes Irinotecan Resistance in Colorectal Cancer by Inhibiting the ABCG2 Drug-Efflux Pump

“…The sorafenib-irinotecan combination is not toxic in xenografted mice, and some clinical trials have reported that they can be associated for the treatment of KRAS-mutated tumors (29,36). Moreover, a not yet published phase II trial (42), carried out in patients with irinotecan-resistant and KRAS-mutated CRCs, shows hopeful results.…”

“…On the other hand, irinotecan failure can also be related to activation of NF-kB and inhibition of the apoptotic cascade. Jayanthan and colleagues (36) have shown that, in cell lines derived from atypical teratoid rhabdoid tumors of the central nervous system, sorafenib could interfere with irinotecan-mediated NF-kB activation by retaining NF-kB in the cytoplasm and, therefore, preventing induction of antiapoptotic genes. Another hypothesis is that sorafenib could modify metabolism of irinotecan.…”

Identification of Potential Off-Targets of Chemotherapeutic Agent Sorafenib: A Molecular Docking Approach

“…Sorafenib has been reported to demonstrate significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including VEGFR-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT [23]. The off-targets of Sorafenib that were retrieved using MEDIT SA MED-SuMo and were validated through literature are given in Table 2.…”

Atypical teratoid-rhabdoid tumors: molecular genetics feutures, perspectives of treatment. Review of literature

“…В исследовании, проведенном B. Koos et al, сообщалось, что иматиниб, мульти-TKI первого поколения, ингибирует рост клеток через c-Abl в рабдоидных линиях G401 и A204 [2,57]. Аналогичным образом, исследования in vitro клеточных линий АТРО идентифицировали двойной сосудистый эндотелиальный фактор роста/ингибиторы митоген-активируемой протеинкиназы 1 (VEGF/ MEK) с двойной специфичностью сорафениб и сунитиниб в качестве перспективных агентов при тестировании отдельно или в комбинации с иринотеканом, ингибитором топоизомеразы I [2,58,59]. В исследовании, проведенном J. Torchia et al, показано, что мульти-TKI второго поколения, нилотиниб и дазатиниб, снижали клеточную пролиферацию при наномолярных концентрациях, особенно в группе 2 АТРО, путем ингибирования бета-рецептора тромбоцитарного фактора роста (PDGFRβ), который дифференциально эпигенетически регулируется в разных подгруппах [2,6].…”