Targeting TORC2 in Multiple Myeloma

描述（由申请人提供）： mTOR激酶在两种多蛋白复合物TORC 1和TORC 2中起作用，是一种肿瘤促进蛋白。我们将使用酵母双杂交筛选来鉴定可以中断mTOR与TORC 2复合物中其伴侣结合的化合物，因为这种结合是mTORC 2功能所需的，并且对于多发性骨髓瘤肿瘤细胞的生长和存活至关重要。这些化合物将被进一步测试和开发为可能的抗骨髓瘤药物。这需要在明确定义的骨髓瘤细胞系和从患者骨髓中获得的原代肿瘤细胞制剂中评估其分子效应和体外细胞效应。我们还将在骨髓瘤生长的异种移植鼠模型中鉴定化合物的抗骨髓瘤功效。此外，我们还将鉴定TORC 2的关键底物，当被我们的药物抑制时，其导致细胞凋亡并抑制骨髓瘤细胞粘附和迁移。

DESCRIPTION (provided by applicant): The mTOR kinase functions in two multiprotein complexes, TORC1 and TORC2, and is a tumor promoting protein. We will use a yeast-2-hybrid screen to identify compounds that can interrupt binding of mTOR to its partners within the TORC2 complex as this binding is required for mTORC2 function and appears critical for growth and survival of multiple myeloma tumor cells. These compounds will be further tested and developed as possible anti-myeloma agents. This entails assessment of their molecular effects and in vitro cellular effects in well defined myeloma cell lines and primary tumor cell preparations obtained from bone marrows of patients. We will also identify the compounds' anti-myeloma efficacy in xenograft murine models of myeloma growth. In addition, we will also identify the critical substrates of TORC2 which, when inhibited by our agents, results in apoptosis and inhibited myeloma cell adhesion and migration.