Malignant gliomas, the most common human brain tumors, are considered to be among the deadliest of cancers: despite maximum treatment efforts, median survival of the most aggressive gliomas ranges from nine to twelve months. Recently, drugs that specifically target tyrosine kinases have proven effective in blocking tumor growth in a subset of lung cancers, breast cancers, and leukemias. However, currently available receptor tyrosine kinase (RTK) inhibitors have had minimal impact on glioma, possibly because the RTKs that promote glioma growth and survival are unknown. Therefore, the goal of this fellowship is to identify novel activated RTKs in malignant gliomas and characterize their potential contribution to the growth and survival of the tumor cells. This will be achieved through the following specific aims: (1) Because the PI 3-kinase pathway is a critical downstream modulator of tyrosine kinase signaling and plays a prominent role in the pathogenesis of most tumors, glioma cell lines will be screened for RTKs that are activating PI 3-kinase. PI 3-kinase activating proteins will be identified by immunoprecipitating PI 3- kinase from multiple glioma cell lines, followed by immunoblotting with antibodies to candidate binding proteins or identifcation of silver stained proteins by LC/MS/MS. (2) To determine the relevance of the identified RTKs to in vivo tumorigenesis, the activation of these RTKs will be verified in human patient samples. An array CGH database will be examined for candidate RTK amplification and immunohistochemistry will be performed on archived primary human gliomas. (3) The impact of the RTKs on in vitro cell transformation will be analyzed by measuring cell proliferation, survival, motility, anchorage-independent growth, and PI 3-kinase activation in gain-of-function and loss-of-function systems. The long-term objective of these studies is to generate xenograft and transgenic mouse models that will enable the study of in vivo RTK signaling and the origins and progression of glioblastoma, as well as provide a platform for pre-clinical testing of agents targeting the glioma RTKs. Public Health Relevance: These studies will add to our knowledge of the molecular lesions driving the tumorigenesis of malignant glioma. Ideally, these studies will lead to the creation of mouse models that more faithfully recapitulate the biology of the human disease, and supply us with new molecular targets for effective chemotherapeutic agents. ? ? ?
| Stommel, Jayne M; Kimmelman, Alec C; Ying, Haoqiang et al. (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287-90 |
