Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy

Abstract

Medulloblastoma (MB) is the most common solid tumour in children and, despite current treatment with a rather aggressive combination therapy, accounts for 10% of all deaths associated with paediatric cancer. Breaking the tumour cells’ intrinsic resistance to therapy-induced cell death should lead to less aggressive and more effective treatment options. In other tumour entities, this has been achieved by modulating the balance between the various pro- and anti-apoptotic members of the Bcl-2 family with small molecule inhibitors. To evaluate the therapeutic benefits of ABT-199 (Venetoclax), a Bcl-2 inhibitor, and ABT-263 (Navitoclax), a dual Bcl-XL/Bcl-2 inhibitor, increasingly more relevant model systems were investigated. Starting from established MB cell lines, progressing to primary patient-derived material and finally an experimental tumour system imbedded in an organic environment were chosen. Assessment of the metabolic activity (a surrogate readout for population viability), the induction of DNA fragmentation (apoptosis) and changes in cell number (the combined effect of alterations in proliferation and cell death induction) revealed that ABT-263, but not ABT-199, is a promising candidate for combination therapy, synergizing with cell death-inducing stimuli. Interestingly, in the experimental tumour setting, the sensitizing effect of ABT-263 seems to be predominantly mediated via an anti-proliferative and not a pro-apoptotic effect, opening a future line of investigation. Our data show that modulation of specific members of the Bcl-2 family might be a promising therapeutic addition for the treatment of MB.

Noxa and Mcl-1 expression influence the sensitivity to BH3-mimetics that target Bcl-xL in patient-derived glioma stem cells

“…We characterized the sensitivity of two representative GSC-ECLs (G03 and G09) towards treatments with ABT-263 and WEHI-539 by dose-dependent experiments, both with and without TMZ (Supplementary Fig. S3 ) Based on this and on bibliography 28 , 30 – 33 , we selected a concentration of 1 μM for both inhibitors. In response to single treatments with these BH3-mimetics, G01, G03, G08, and G09 cell lines underwent a significant increase in cell death (Fig.…”

Combination drug screen identifies synergistic drug interaction of BCL-XL and class I histone deacetylase inhibitors in MYC-amplified medulloblastoma cells

“…However, it is important to note that knockdown of BCL-XL alone did not induce a significant reduction of viable cells in our data. Previously published data describes an apoptosis sensitizing effect of BCL-XL inhibition in MYC -amplified MB cell lines when additionally treated with apoptosis inducing chemotherapeutic agents such as doxorubicin [ 49 ]. This suggests that part of the observed synergistic cytotoxicity of class I HDACi and BCL-XLi may be caused by the additional apoptosis inducing effect of class I HDACi.…”

The identification of BCL-XL and MCL-1 as key anti-apoptotic proteins in medulloblastoma that mediate distinct roles in chemotherapy resistance

“…Anti-apoptotic BCL-2 proteins are commonly highly expressed in cancer and are readily targetable by a suite of BH3 mimetics [ 49 ]. In this regard, a small number of studies previously suggested BCL-XL as a potential target in medulloblastoma [ 50 – 52 ]. Using BH3 profiling and dynamic BH3 profiling following cisplatin treatment, we identified BCL-XL as the dominant anti-apoptotic dependency, while cisplatin with WEHI-539 had a synergistic effect on cell viability.…”