This application addresses PQ-22: "Why do many cancer cells die when suddenly deprived of a protein encoded by an oncogene?" Wnt canonical signaling has highly conserved functions in development, and its constitutively activation plays a role in the pathogenesis of an increasing number of tumor types. Human malignant gliomas are refractory to curative surgery, responsible for high morbidity and almost invariably lethal. We have recently demonstrated Wnt pathway activation by an autocrine mechanism at high frequency in human glioma lines and primary gliomas. Moreover, unlike other Wnt activated tumor types, which show only growth inhibition in response to Wnt downregulation, Wnt activated gliomas, are so addicted to Wnt signaling that they undergo massive apoptosis in response to pathway downregulation. We have discovered a novel Wnt transcriptional program, whose effectors are likely to be responsible for this addiction as well as expression alterations i less Wnt addicted tumor types that could help to explain their chemo-sensitization in response to Wnt downregulation. We plan to exploit these findings to 1) further elucidate the transcriptional program and signaling pathways responsible for Wnt addiction of human gliomas, 2) identify and characterize specific and potent Wnt targeted small molecule inhibitors utilizing Wnt addicted malignant glioma cells in a functional screen that has already provided promising hits, and 3) exploit those aspects of the Wnt addictive transcriptional program in Wnt positive gliomas that may be present in other Wnt activated tumor types to investigate how to better target such tumors. Thus, this project offers a unique opportunity to develop mechanistic insights that could improve therapies for Wnt positive human malignant gliomas and other tumor types as well.
Investigations within this project are directed toward elucidating mechanisms responsible for an extreme form of Wnt addiction discovered by us in human malignant gliomas and to identify the Wnt transcriptional program and pathways responsible. We will also utilize Wnt addicted glioma cells to further characterize promising Wnt small molecule inhibitors with specificity for these addicted tumor cells and will explore the basi of chemorsensitization induced by Wnt downregulation of other Wnt activated tumor types. Our efforts are aimed at mechanistic understanding that could lead to novel therapeutic interventions for Wnt activated tumors.
|Liscio, Paride; Carotti, Andrea; Asciutti, Stefania et al. (2014) Design, synthesis, crystallographic studies, and preliminary biological appraisal of new substituted triazolo[4,3-b]pyridazin-8-amine derivatives as tankyrase inhibitors. J Med Chem 57:2807-12|
|Grumolato, Luca; Liu, Guizhong; Haremaki, Tomomi et al. (2013) *-Catenin-independent activation of TCF1/LEF1 in human hematopoietic tumor cells through interaction with ATF2 transcription factors. PLoS Genet 9:e1003603|