Glioblastoma multiforme(GBM) is universally lethal and lacks durable responses to all targeted and conventional therapies tested to date including inhibitors of its signature lesion, EGFR. We believe that clinical progress will derive from a more comprehensive view of the underlying genetics of GBM and an intensive functional and clinical validation of targets in physiologically relevant preclinical model systems. Project 1 experiments are directed towards understanding tHe role of various signature mutations and several newly discovered cancer genes in the development of GBM and how these genetic factors influence GBM's tumor biological properties and their responses to therapy. We have developed a mouse model of high-grade glioma engineered with the same mutations encountered in human primary GBM: conditional activated EGFR knock-in as well as conditional Ink4a/Arf and Pten knockout alleles. As a result of our high resolution genomic and proteomic studies, we have also identified many new oncogenes (e.g., Bcl2L12) and tumor suppressor genes (e.g., p18INK4C) as well as a repertoire of novel functionally active receptor tyrosine kinases (RTKs) with notably distinct co-expression patterns. Remarkably, we have preliminary evidence showing that some of these co-expressed RTKs can functionally substitute for EGFR signaling upon treatment with EGFR inhibitors and that dual inhibition of EGFR and other RTKs yields dramatic biochemical and biological responses for the first time. These advances, together with our new mouse model and equivalent human systems, provide a strong foundation to validate several key genes in GBM pathogenesis with the goal of identifying the best targets and combination therapies for this disease. To accomplish these goals, we will work with Projects 2 and 3 and all of the Cores, to refine our high-grade glioma model (Gradell/lll) with additional key alleles. Specifically, OHT-responsive GFAP-CreER and tet-inducible transgenic strategies will be utilized to enable somatic alteration of PTEN, p18lnk4c, and/or Bcl2L12 in the adult brain, and hence provide an opportunity to assess whether these alleles alone or in combination can drive progression in the setting of EGFR activation and Ink4a/Arf deficiency. These models will be subjected to extensive characterization on the tumor biological, molecular and genomic levels and will be used to test the role of Bcl2L12 and certain RTKs including MET in the response to EGFR inhibition. With regard to RTKs, significant initial effort will be directed towards defining the role of MET in GBM pathogenesis and its ability to provide a bypass mechanism in the setting of EGFR inhibition. Along similar lines, genetic and pharmacologic strategies as well as mouse and human model systems will be used to determine whether several RTKs co-expressed and activated in GBM can drive the development of GBM and provide a basis for resistance to RTK therapy.
| Reardon, Colin; Murray, Kaitlin; Lomax, Alan E (2018) Neuroimmune Communication in Health and Disease. Physiol Rev 98:2287-2316 |
| Roncali, Emilie; Stockhoff, Mariele; Cherry, Simon R (2017) An integrated model of scintillator-reflector properties for advanced simulations of optical transport. Phys Med Biol 62:4811-4830 |
| Nanavaty, Vishal; Sandhu, Ranjodh; Jehi, Sanaa E et al. (2017) Trypanosoma brucei RAP1 maintains telomere and subtelomere integrity by suppressing TERRA and telomeric RNA:DNA hybrids. Nucleic Acids Res 45:5785-5796 |
| Liu, Rui; Yang, Guang; Zhou, Meng-Hua et al. (2016) Flotillin-1 downregulates K(+) current by directly coupling with Kv2.1 subunit. Protein Cell 7:455-60 |
| Schrager-Lavelle, Amanda; Herrera, Leslie A; Maloof, Julin N (2016) Tomato phyE Is Required for Shade Avoidance in the Absence of phyB1 and phyB2. Front Plant Sci 7:1275 |
| Hu, Baoli; Wang, Qianghu; Wang, Y Alan et al. (2016) Epigenetic Activation of WNT5A Drives Glioblastoma Stem Cell Differentiation and Invasive Growth. Cell 167:1281-1295.e18 |
| Poornima, Gopalakrishna; Shah, Shanaya; Vignesh, Venkadasubramanian et al. (2016) Arginine methylation promotes translation repression activity of eIF4G-binding protein, Scd6. Nucleic Acids Res 44:9358-9368 |
| Frost, Bess; Bardai, Farah H; Feany, Mel B (2016) Lamin Dysfunction Mediates Neurodegeneration in Tauopathies. Curr Biol 26:129-36 |
| Leonard, Paul G; Satani, Nikunj; Maxwell, David et al. (2016) SF2312 is a natural phosphonate inhibitor of enolase. Nat Chem Biol 12:1053-1058 |
| Hiu, Takeshi; Farzampour, Zoya; Paz, Jeanne T et al. (2016) Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target. Brain 139:468-80 |
Showing the most recent 10 out of 146 publications
