The broad objective of this proposal is to investigate the intrinsic mechanisms of tumor cell resistance to newly developed mTOR inhibitors such that their future use may be optimized in the clinic. We have identified an alternate mechanism of mRNA translation initiation that is activated upon mTOR inhibitor exposure allowing tumor cell survival in the face of global inhibition of protein synthesis. These experiments will delineate the signaling events promoting activation of this salvage pathway and will pre-clinically evaluate a novel small molecule inhibito targeting this pathway for synergistic antitumor effects in combination with mTOR inhibitors. Research Plan: We will investigate the molecular events leading to activation of this salvage pathway, as well as how this signaling cascade impinges on the cellular translational machinery to specifically synthesize proteins conferring tumor cell resistance. Additionally, we will evaluat a novel inhibitor of this pathway for synergistic antitumor effects in co-treatment studies with direct mTOR kinase inhibitors. Methodology: We will utilize a combination of genetic and biochemical approaches to address the molecular mechanisms by which the salvage protein synthesis pathway is activated in TOR inhibitor resistant brain cancers. We will utilize mouse models of these diseases to evaluate the efficacy of these inhibitors. Results: This is a new project and no results have been obtained. Clinical Significance: CNS malignancies are relatively frequently encountered in our Veterans and current treatment protocols have not advanced significantly. The development of additional treatment options may improve the current prognosis for patients, which remains at a dismal 10 months. Understanding the treatment of malignant glioblastomas may lead to the development of additional therapeutic options for the treatment of bowel, lung and prostate cancers, which are common in our Veteran population.
TOR kinase inhibitors are novel drugs with exciting and impressive antitumor activity in preclinical studies. It would thus, be critical to understand the molecular mechanisms by which tumor cells respond to these agents such that they can be used most effectively in the clinic. This proposal seeks to understand the mechanisms of tumor cell resistance to mTOR inhibitor and evaluate novel targeted therapies in combination with mTOR inhibition. These studies may potentially benefit both Veteran and non-Veteran populations and provide additional future treatment options.
|Holmes, B; Benavides-Serrato, A; Freeman, R S et al. (2018) mTORC2/AKT/HSF1/HuR constitute a feed-forward loop regulating Rictor expression and tumor growth in glioblastoma. Oncogene 37:732-743|
|Holmes, Brent; Lee, Jihye; Landon, Kenna A et al. (2016) Mechanistic Target of Rapamycin (mTOR) Inhibition Synergizes with Reduced Internal Ribosome Entry Site (IRES)-mediated Translation of Cyclin D1 and c-MYC mRNAs to Treat Glioblastoma. J Biol Chem 291:14146-59|
|Artinian, Nicholas; Cloninger, Cheri; Holmes, Brent et al. (2015) Phosphorylation of the Hippo Pathway Component AMOTL2 by the mTORC2 Kinase Promotes YAP Signaling, Resulting in Enhanced Glioblastoma Growth and Invasiveness. J Biol Chem 290:19387-401|
|Benavides-Serrato, Angelica; Anderson, Lauren; Holmes, Brent et al. (2014) mTORC2 modulates feedback regulation of p38 MAPK activity via DUSP10/MKP5 to confer differential responses to PP242 in glioblastoma. Genes Cancer 5:393-406|