E. F. Garner1, G. K. Friedman3, V. R. Atigadda2, L. Nan3, B. P. Moore3, T. Etminan3, L. L. Stafman1, J. E. Stewart1, D. D. Muccio2, C. J. Grubbs4, E. A. Beierle1 1University Of Alabama at Birmingham,Division Of Pediatric Surgery,Birmingham, Alabama, USA 2University Of Alabama at Birmingham,Department Of Chemistry,Birmingham, Alabama, USA 3University Of Alabama at Birmingham,Division Of Pediatric Hematology And Oncology,Birmingham, Alabama, USA 4University Of Alabama at Birmingham,Department Of Surgery,Birmingham, Alabama, USA
Introduction: Medulloblastoma (MB) is the most common malignant brain tumor in children. There are four molecular subtypes of MB: WNT, SHH, Group 3 and Group 4, with Group 3 tumors having the most dismal prognosis. Our laboratory has previously shown that the novel retinoid, 9-cis-UAB30 (UAB30), inhibited MB proliferation in vitro and prolonged animal survival in a localized human patient-derived xenograft (PDX) MB mouse model. We hypothesized that UAB30 would also be effective in limiting the metastatic spread in a disseminated MB mouse model.
Methods: We used a mouse PDX model with bioluminescent imaging to follow the spread of disease. The group 3 MB PDX cell line D341 labeled with GLuc-GFP was used for the in vivo study. 5 x 105 cells were stereotactically injected into the right lateral ventricle of 5-week-old athymic nude mice. The mice were randomized into three groups to receive control chow (n=8), 13-cis-retinoic acid (RA)-treated chow (n=8), or UAB30-treated chow (n=8). Treatment was initiated on the day of injection. Bioluminescence imaging was performed on days 7, 11, 14, 18, and 20 post-tumor injection using the IVIS Lumina III (Perkin Elmer). The animals were euthanized on day 20 when they met IACUC parameters. Tumor burden was quantified using total flux (photons/sec) in both the brain and spine. Student’s t-test was used to compare the mean bioluminescence between groups with p ≤ 0.05 considered significant.
Results: Control mice had significantly greater tumor burden (9.87 x 107 photons/sec) in the brain at day 20 when compared to RA-treated (3.61 x 107 photons/sec; p = 0.02) and UAB30-treated (3.84 x 107 photons/sec; p = 0.03) mice (Fig. 1A and 1B). The UAB30-treated mice had significantly less spinal metastasis compared to the control mice at day 18 and day 20 (p = 0.02 and p= 0.04, respectively) (Fig. 1A and 1C). The RA-treated mice initially had less spinal metastasis than control mice at day 18 (p =0.05), but this difference was not significant at day 20 (Figure 1 C).
Conclusion: In this PDX model of disseminated MB, treatment with UAB30 significantly delayed progression of tumor burden in the brain and spine compared to untreated mice. These data suggest that this novel retinoid should be further explored as a potential therapeutic for MB.
