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 #
7P01CA095616-10
Application #
8378011
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
2014-02-28
Budget Start
2012-08-14
Budget End
2013-02-28
Support Year
10
Fiscal Year
2012
Total Cost
$315,111
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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
Frost, Bess; Bardai, Farah H; Feany, Mel B (2016) Lamin Dysfunction Mediates Neurodegeneration in Tauopathies. Curr Biol 26:129-36
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
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
Leonard, Paul G; Satani, Nikunj; Maxwell, David et al. (2016) SF2312 is a natural phosphonate inhibitor of enolase. Nat Chem Biol 12:1053-1058
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
Falchi, Lorenzo; Newberry, Kate J; Verstovsek, Srdan (2015) New Therapeutic Approaches in Polycythemia Vera. Clin Lymphoma Myeloma Leuk 15 Suppl:S27-33
Green, Adam L; Ramkissoon, Shakti H; McCauley, Dilara et al. (2015) Preclinical antitumor efficacy of selective exportin 1 inhibitors in glioblastoma. Neuro Oncol 17:697-707
Muller, Florian L; Aquilanti, Elisa A; DePinho, Ronald A (2015) Collateral Lethality: A new therapeutic strategy in oncology. Trends Cancer 1:161-173
Lee, Eudocia Q; Reardon, David A; Schiff, David et al. (2015) Phase II study of panobinostat in combination with bevacizumab for recurrent glioblastoma and anaplastic glioma. Neuro Oncol 17:862-7

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