PMC6465683_01
Brain MRI Demonstrating ETMR Response to Dasatinib Treatment. (A) Cystic component and tumor component measurements demonstrating increased ETMR tumor response to dasatinib treatment. Marked reductions in both cystic and tumor components was noted. (B) Treatment time course demonstrating overall clinical time course. Baseline MRI and Post Induction Treatment (Rx) MRI demonstrated interval increase in bulk of peripheral gyriform enhancing tumor mantle with re-accumulation of the large cystic cavity. Post dasatinib Rx MRI displayed an overall volume reduction of tumor, cystic cavity, and mantle involvement within the parieto-occipital region. Tumor volume reduced from 1.66 cm to 1.36 cm. (AP: Anterior-Posterior; SI: Superior-Inferior). * Tumor Component measured at widest margin.
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As shown (Fig. 1a, b), the anterior to posterior cystic component was markedly decreased by a 3.46 cm reduction which also coincided with a 0.3 cm reduction in size for the solid tumor component. The MRI images of the post operation and 2-year follow up were also found to be clear of visible tumor component (Fig. 1B). Dasatinib therapy significantly reduced the brain tumor size allowing for a total resection of the residual tumor (Fig. 1B).
Patient tumor molecular response and ultrastructural changes to dasatinib treatment. (A) Ki-67 immunopositivity decreased from (i) 50-60% to (ii) 5% post-dasatinib treatment. (B) Aberrant activation of (i) RTKs: PDGFRa/b, (ii) SFKs: SRC, FYN, and LYN, and (iii) downstream ERK1/2 and STAT1/3 effectors were significantly reduced in the post-dasatinib Rx tumor. Student's t-tests were employed using SigmaStat3.1 software. p values < 0.05 (*) and < 0.01 (**) were considered statistically significant. (C) Ultrastructural examination of ETMR tumor pre- (i, ii) and post-dasatinib Rx (iii, iv). Autophagocytic vacuoles (green arrows) and predominance of nuclear heterochromatin (red arrows) compared to euchromatin (blue arrows) are indicated.
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The analysis of pre- and post-dasatinib was observed to be molecularly effective in the treatment of this progressive refractory ETMR based on Ki67 proliferation index staining, which displayed decreased proliferation activity (Fig. 2A). Analysis of tumor cell signaling molecules revealed that dasatinib treatment decreased activation of receptor tyrosine kinases PDGFRa and PDGFRb (Fig. 2Bi). Analysis of the activated forms of Src family kinases including SRC, FYN, and LYN were all observed to be significantly reduced (Fig. 2Bii). In addition, activated forms of downstream molecules including STAT1, STAT3, and ERK1/2 were also markedly reduced in response to dasatinib treatment (Fig. 2Biii). Transmission electron microscopy (TEM) of pre- (Fig. 2Ci, Cii) and post dasatinib therapy (Fig. 2Ciii, Civ) illustrated the impact by allowing visualization of increased changes with tumor ultrastructure suggestive of induced cellular autophagy of the ETMR.