azd-6244 and Astrocytoma

New therapeutic agents targeting the mitogen-activated protein (MAP) kinase pathway, including MEK inhibitors, are currently being evaluated in phase 1 and 2 clinical trials for pediatric brain tumors. Ophthalmologic side effects from MEK inhibitors have previously only been reported in adults and included retinal vein occlusion, central retinal artery occlusion, and separation of the neurosensory retina. We report 2 patients with optic pathway gliomas who developed outer retinal layer separation visualized by optical coherence tomography while taking the MEK inhibitor selumetinib. After discontinuation of selumetinib, the outer retinal layer separation resolved without visual sequelae. One patient has been retreated with selumetinib and experienced recurrence of these findings.

Topics: Acrylonitrile; Adolescent; Aniline Compounds; Astrocytoma; Benzimidazoles; Child; Female; Glioma; Humans; Male; Optic Nerve Neoplasms; Retinal Diseases; Tomography, Optical Coherence

Curative therapy for childhood glioma presents challenges when complete resection is not possible. Patients with recurrent low-grade tumors or anaplastic astrocytoma may receive radiation treatment; however, the long-term sequellae from radiation treatment can be severe. As many childhood gliomas are associated with activation of BRAF, we have explored the combination of ionizing radiation with MEK inhibition in a model of BRAF-mutant anaplastic astrocytoma.. The regulation of TORC1 signaling by BRAF was examined in BT-40 (BRAF mutant) and BT-35 (BRAF wild type) xenografts, in a cell line derived from the BT-40 xenograft and two adult BRAF mutant glioblastoma cell lines. The effect of MEK inhibition (selumetinib), XRT (total dose 10 Gy as 2 Gy daily fractions), or the combination of selumetinib and XRT was evaluated in subcutaneous BT-40 xenografts.. Inhibition of MEK signaling by selumetinib suppressed TORC1 signaling only in the context of the BRAF-mutant both in vitro and in vivo. Inhibition of MEK signaling in BT-40 cells or in xenografts lead to a complete suppression of FANCD2 and conferred hypersensitivity to XRT in BT-40 xenografts without increasing local skin toxicity.. Selumetinib suppressed TORC1 signaling in the context of BRAF mutation. Selumetinib caused a rapid downregulation of FANCD2 and markedly potentiated the effect of XRT. These data suggest the possibility of potentiating the effect of XRT selectively in tumor cells by MEK inhibition in the context of mutant BRAF or maintaining tumor control at lower doses of XRT that would decrease long-term sequelae.

Topics: Animals; Astrocytoma; Benzimidazoles; Blotting, Western; Cell Line, Tumor; Female; Humans; MAP Kinase Kinase Kinases; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, SCID; Multiprotein Complexes; Mutation; Neoplasms, Experimental; Proto-Oncogene Proteins B-raf; Radiotherapy; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

The BT-40 low-grade childhood astrocytoma xenograft model expresses mutated BRAF(V600E) and is highly sensitive to the MEK inhibitor selumetinib (AZD6244). In this study, we developed and characterized selumetinib resistance and explored approaches to circumventing the mechanisms of acquired resistance.. BT-40 xenografts were selected in vivo for selumetinib resistance. Resistant tumors were obtained and characterized, as were tumors that reverted to sensitivity. Characterization included expression profiling, assessment of MEK signature and compensatory pathways, MEK inhibition, BRAF expression, and cytokine levels. Combination treatment of BT-40/AZD-resistant tumors with the MEK inhibitor and a STAT3 inhibitor (LLL12) was assessed.. Resistance was unstable, tumors reverting to selumetinib sensitivity when passaged in untreated mice, and MEK was equally inhibited in sensitive and resistant tumors by selumetinib. Drug resistance was associated with an enhanced MEK signature and increased interleukin (IL)-6 and IL-8 expression. Selumetinib treatment induced phosphorylation of STAT3 (Y705) only in resistant xenografts, and similar results were observed in BRAF(V600E) astrocytic cell lines intrinsically resistant to selumetinib. Treatment of BT-40-resistant tumors with selumetinib or LLL12 had no significant effect, whereas combined treatment induced complete regressions of BT-40/AZD-resistant xenografts.. Resistance to selumetinib selected in vivo in BT-40 tumor xenografts was unstable. In resistant tumors, selumetinib activated STAT3, and combined treatment with selumetinib and LLL12 induced complete responses in resistant BT-40 tumors. These results suggest dual targeting BRAF (V600E) signaling and STAT3 signaling may be effective in selumetinib-resistant tumors or may retard or prevent onset of resistance.

Topics: Animals; Anthraquinones; Astrocytoma; Benzimidazoles; Cell Line, Tumor; Child; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Interleukin-6; Interleukin-8; MAP Kinase Kinase 1; Mice; Proto-Oncogene Proteins B-raf; STAT3 Transcription Factor; Sulfonamides