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.
Highlights
Medulloblastoma (MB) is the most common solid tumour in children and accounts for approximately 10% of all childhood cancer deaths [1]
To investigate the potential of this treatment approach in MB, the most common solid tumour in childhood, we first investigated the expression of key members of the Bcl-2 superfamily in four established MB cell lines (Figure 1a), using Acute Lymphoblastic Leukaemia (ALL)
Medulloblastoma (MB), the most common primary brain tumour in children, presents as a diverse spectrum of distinct disease entities, of which, a considerable percentage remains refractory to therapeutic interventions [24]
Summary
Medulloblastoma (MB) is the most common solid tumour in children and accounts for approximately 10% of all childhood cancer deaths [1]. WHO classification of central nervous system (CNS) tumours from 2016 has addressed four MB molecular subgroups, termed wingless (WNT), sonic hedgehog (SHH) with or without TP53 activation, Group 3 and Group 4, which are non-WNT/non-SHH activated [3]. WNT-activated, SHH-activated and the non-WNT/non-SHH MBs can be differentiated by several immunohistochemical markers, namely β-Catenin, Yap, p75NGFR, Otx and p53 [4,5]. Group 3, in contrast, has the worst prognosis and accounts for 25% of all MBs. The SHH and Group 4 tumours generally exhibit an intermediate prognosis, while the presence of mutated TP53 is a prognostic marker for poor survival in all subgroups [6]
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