Despite relatively rapid advances in our knowledge of gliomagenic lesions and decades of technological advances in neurosurgery, radiation therapy and clinical trials of conventional and novel therapies, little improvement in median survival has been achieved for patients with Grade IV glioblastoma multiforme (GBM). One of the genetic indicator lesions in these tumors is amplification or mutation of the epidermal growth factor receptor (EGFR). This would suggest a rationale for therapeutic targeting of the EGFR and several clinical studies have shown some encouraging responses using EGFR-specific inhibitors. However, many patients whose tumors express amplified WT or mutant EGFR and so would be expected to respond, do not. Moreover, even those patients who do show clear clinical or radiological responses to EGFR inhibitors show progression after some time. These observations indicate that EGFR inhibitor therapies have promise but that a deeper mechanistic understanding of resistance to them is needed. We also hypothesize that EGFR/EGFR* signaling interacts epistatically with other pathways, particularly the PI3-K pathway, that is also a frequent target of genetic alteration in GBM, and that this decreases the effectiveness of EGFR-directed therapeutics. In order to test this and to determine the mechanisms for resistance to these therapies, we propose 2 complementary Aims. Specifically we will: 1) exploit a model of EGFR*-dependent glioma formation, developed during the first funding period of this Program, and current receptor-specific small molecule and antibody-based inhibitory approaches, to define mechanisms by which the requirement for the mutant receptor can be bypassed for tumor survival or which contribute towards eliciting therapeutic resistance;and, 2) define alternative mechanisms that mimic PTEN mutation and hence result in activation of PI3-K pathway signaling.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA095616-09
Application #
8234811
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
2011-12-31
Budget Start
2011-03-01
Budget End
2012-02-29
Support Year
9
Fiscal Year
2011
Total Cost
$584,993
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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
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
Leonard, Paul G; Satani, Nikunj; Maxwell, David et al. (2016) SF2312 is a natural phosphonate inhibitor of enolase. Nat Chem Biol 12:1053-1058
Gilhooly, Neville S; Carrasco, Carolina; Gollnick, Benjamin et al. (2016) Chi hotspots trigger a conformational change in the helicase-like domain of AddAB to activate homologous recombination. Nucleic Acids Res 44:2727-41

Showing the most recent 10 out of 142 publications