/ASBTRACT The main objective of this project is to provide a rationale for future therapeutic targeting of the TORC2 multiprotein complex in patients with multiple myeloma.
The aims i nclude studying mTOR kinase inhibitors against myeloma cell lines and patient primary cell specimens in vitro and in murine models in vivo, identifying the key TORC2 substrates that are the critical targets for inhibition and testing the role of DEPTOR protein expression in regulating the sensitivity of myeloma cells to TORC2 inhibitors. The viability versus death of myeloma cells as well as their ability to adhere and migrate in vitro will be studied. The identification and development of novel compounds which prevent protein-protein interactions within the TORC2 complex will also be attempted.
PROJECT NARRATIVE The goal of the project is to provide further experimental support for development of TORC2 inhibitors against multiple myeloma. If successful, this new category of agents would present a significant addition to the current armamentarium of drugs used for this incurable malignancy.
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|Hoang, Bao; Benavides, Angelica; Shi, Yijiang et al. (2012) The PP242 mammalian target of rapamycin (mTOR) inhibitor activates extracellular signal-regulated kinase (ERK) in multiple myeloma cells via a target of rapamycin complex 1 (TORC1)/eukaryotic translation initiation factor 4E (eIF-4E)/RAF pathway and activ J Biol Chem 287:21796-805|
|Martin, Jheralyn; Masri, Janine; Cloninger, Cheri et al. (2011) Phosphomimetic substitution of heterogeneous nuclear ribonucleoprotein A1 at serine 199 abolishes AKT-dependent internal ribosome entry site-transacting factor (ITAF) function via effects on strand annealing and results in mammalian target of rapamycin co J Biol Chem 286:16402-13|
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