Medulloblastomas (MBs) are malignant brain tumors that arise by transformation of neural progenitor cells in the cerebellum in children. Aggressive treatment approaches combining surgery, craniospinal radiation, and chemotherapy result in 5-year survival rates exceeding 70%. Treatment- related neurotoxicity has created a critical need to identify signaling molecules that can be targeted therapeutically to maximize tumor growth suppression and minimize collateral brain damage. The overall objective of this research is to use a mouse model of MB, which we developed using the RCAS/tv-a gene transfer system, as a preclinical testing platform for molecular targeted MB therapy. This experimental system uses a retroviral vector (RCAS) derived from avian leukosis virus and a transgenic mouse line that expresses the retrovirus receptor under control of the Nestin gene promoter, which is active in neural progenitor cells during normal cerebellar development. Using this system, we showed that ectopic expression of Sonic Hedgehog (Shh) in the postnatal cerebellum induces MBs in mice. Furthermore, we identified proteins belonging to different functional classes that cooperate with Shh to enhance MB formation. These enhancing factors are (a) Myc oncoproteins, which stimulate proliferation of neural progenitors during normal development, (b) Bcl-2, which potently inhibits apoptosis, (c) insulin-like growth factor-II, which concomitantly stimulates proliferation and blocks apoptosis by activating the phosphatidylinositol 3-kinase (PI3K) signal transduction pathway, and (d) hepatocyte growth factor (HGF), a growth factor with pleiotropic effects on tumor growth. The fact that all of these proteins are highly expressed in human MBs indicates that their tumor-promoting activity in mice accurately reflects the pathogenesis of the human disease. Moreover, these proteins and their downstream signaling molecules can be considered therapeutic targets.
Specific aim 1 is to determine whether inhibiting Shh signaling cooperates with blockade of HGF signaling to enhance treatment response in mice bearing Shh?induced MBs.
Specific aim 2 is to determine whether MB growth suppression by HGF monoclonal antibody therapy can be enhanced by pharmacologic inhibition of the HGF receptor c- Met or downstream PI3K signaling.
Specific aim 3 is to use the RCAS/tv-a system to identify genes that cause Shh-induced MBs to metastasize to the spine. Spinal metastasis is a highly unfavorable prognostic factor for patients with MBs. Achievement of these aims will make it possible to translate the mechanistic discoveries to molecular targeted therapies for children with MB.
Although aggressive treatment regimens in children with medulloblastoma result in favorable survival rates, treatment-related neurotoxicity has created a critical need to identify signaling molecules that can be targeted therapeutically to maximize tumor growth suppression and minimize collateral brain damage. The overall objective of this research is to use a mouse model of medulloblastoma as a preclinical testing platform for molecular targeted therapy. The results can be translated to promoting long-term survival and improving neurological outcome for patients with medulloblastomas.
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