Neuroblastoma, the most common extracranial solid tumor of childhood, has a predictable outcome based on the differential expression of TrkA and TrkB receptors. Favorable-prognosis NB tumors tend to ...express relatively high levels of TrkA, while poor-prognosis tumors are associated with increased BDNF and TrkB expression. Our goal is to determine the role of Trk receptor expression and activation in the biophysiology of NB tumors, and to determine if there is an association between these observations and prognostic outcome. We hypothesize that activation of TrkA and TrkB signaling pathways modulate the sensitivity of NB cells to chemotherapy. Additionally, we posit that NB tumor cells use a BDNF/TrkB signal transduction pathway to protect themselves from chemotherapy-induced cytotoxicity. In our studies, we evaluated the ability of BDNF to decrease the chemosensitivity of NB cells to a number of common chemotherapeutic agents. Using NB cell lines, which expressed TrkB under the control of a tetracycline-repressible promoter, we studied the apoptotic effects of various treatments (including cisplatin, doxorubicin, etoposide and vinblastine). High dose (100ng/ml) BDNF treatment of TrkB-expressing cells, including AS-TB8, TB8, and TB3 cells, could block the effects of chemotherapy in these experiments. Furthermore a Trk tyrosine kinase inhibitor, K252a, and a PI-3 kinase inhibitor, LY294002, were able to block the effect of BDNF/TrkB activation on chemotherapy. These results suggest that TrkB and BDNF can contribute to the chemoresistance of poor prognosis tumors, and that suppression of PI3K activity might improve the ability of these agents to induce death in NB tumors. In our in vivo studies, we developed an animal model for the study of xenografted cell lines. These studies suggest that implantation of cultured NB cell lines in an orthotopic site results in a more biologically relevant tumor growth than heterotopic models. This model has been used in ongoing research to study the effect of Trk expression on NB growth, and we believe that it will be a very valuable resource to improve our understanding of the biology and treatment of NB.
Purpose: Glioblastoma multiforme (GBM) is an aggressive primary brain tumor that is radio-resistant and recurs despite aggressive surgery, chemo and radiotherapy. Autotaxin (ATX) is over expressed in ...various cancers including GBM and is implicated in tumor progression, invasion, and angiogenesis. Using the ATX specific inhibitor, PF-8380, we studied ATX as a potential target to enhance radiosensitivity in GBM.Methods and Materials: Mouse GL-261 and Human U87MG cells were used as GBM cell models. Clonogenic survival assays and tumor transwell invasion assays were performed using PF-8380 to evaluate role of ATX in survival and invasion. Radiation dependent activation of Akt was analyzed by immunoblotting. Tumor induced angiogenesis was studied using the dorsal skin-fold model in Gl-261. Heterotopic mouse GL-261 tumors were used to evaluate the efficacy of PF-8380 as a radiosensitizer.Results: Pretreatment of GL-261 and U87-MG cells with 1µM PF-8380 followed by 4Gy irradiation resulted in decreased clonogenic survival, decreased migration (33% in GL-261;P = 0.002 and 17.9% in U87; P = 0.012) decreased invasion (35.6% in GL-261; P = 0.0037 and 31.8% in U87; P = 0.002), and attenuated radiation induced Akt phosphorylation. In the tumor window model inhibition of ATX abrogated radiation-induced tumor neovascularization (65%; P=0.011). In a heterotopic mouse GL-261 tumors untreated mice took 11.2 days to reach a tumor volume of 7000 mm3 , however combination of PF-8380 (10mg/kg) with irradiation (5 fractions of 2Gy) took more than 32 days to reach a tumor volume of 7000 mm3 .Conclusion: Inhibition of ATX by PF8380 led to decreased invasion and enhanced radiosensitization of glioma cells. Radiation induced activation of Akt was abrogated by inhibition of ATX. Furthermore, inhibition of ATX led to diminished tumor vascularity and delayed tumor growth. These results suggest that inhibition of ATX may ameliorate glioblastoma response to radiotherapy.
BACKGROUNDGross total resection of arteriovenous malformations (AVMs) of the central nervous system confirmed by formal angiography is accepted as a cure for patients. In some cases, this may not be ...possible. Even though in these cases other treatment modalities such as endovascular embolization and radiotherapy can be used, long-term follow-up is lacking in the literature. CASE DESCRIPTIONHere we report a case of a 57-year-old woman with history of a right-sided parieto-occipital/periatrial AVM, initially treated with a combination of endovascular embolization and radiotherapy. CONCLUSIONSThe patient subsequently presented (12 years later) with a symptomatic, enlarging, contrast-enhancing mass at the same location that was angiographically occult but ultimately proven to be an AVM on a background of reactive changes on pathology.
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