LAUSR

The anti-apoptotic Bcl-2 family of proteins, such as Bcl-2, Bcl-xL and Mcl-1, are pivotal in cell death regulation in cancer. More than three decades ago, the first of these cell death regulators was identified as part of a translocation, involving chromosome 14 and 18 [1]. This genetic alteration drives the overexpression of Bcl-2 and is part of the diagnostic panel for a particular Non-Hodgkin lymphoma, follicular lymphoma, which is histologically characterized by neoplastic follicles. While many oncogenes mainly drive cell cycle progression and hence cellular proliferation, the anti-apoptotic Bcl-2 family protein is different since it mainly antagonizes cell death downstream at the level of the outer membrane permeabilization of mitochondria (MOMP) by sequestering the pro-apoptotic Bcl-2 family members Bax and Bak, which together drive MOMP and subsequent release of cytochrome-c into the cytosol from the inner mitochondrial membrane space to engage in intrinsic apoptosis by activation of initiatorand effector caspases [2]. After the identification of Bcl-2, other antiapoptotic members were discovered, such as Bcl-xL and Mcl-1. While Bcl-xL shares many similarities to Bcl-2, particularly with regards to BAX/BAK sequestration, Mcl-1 is different in that it binds preferentially to BAK [2, 3]. Another molecule that interacts with Mcl-1 is Noxa, which has been shown to counteract the Mcl-1Bak interaction [4]. All these proteins are up regulated to various degrees in cancer and therefore offer a targetable therapeutic window. While Bcl-2 appears to be more important in hematological malignancies, Bcl-xL is more critical in solid tumors. Dual inhibition of Bcl2/Bcl-xL results in a compensatory inhibition of cell death mediated by Mcl-1. Therefore, to accomplish most efficient tumor cell killing, ideally all three members have to be inhibited. About a decade ago, BH3-mimetics were first described, such as ABT-737 and the oral derivative ABT-263. They inhibit Bcl-2 and Bcl-xL, but not Mcl1, which is the main mediator of therapeutic resistance to these compounds [5, 6]. These class of molecules are considered to be a significant advance in drug discovery since they are capable of binding to their target in the low nanomolar range. Cells being susceptible respond with rapid apoptosis upon treatment. Recently published work by our group has now unraveled a selective vulnerability of IDH1 mutant glioma/glioblastoma model systems [7]. The IDH1 mutation is particularly common in secondary glioblastomas and low-grade gliomas, such as oligodendrogliomas and the IDH1 R132H mutation can be readily detected by immunohistochemistry on patient samples. Moreover, tumors, harboring the IDH1 mutation, display an accumulation of an oncometabolite, 2-R-2hydroxyglutarate (2-HG), which can reach levels in the News