Bcl-xL inhibition - a novel strategy for glioma therapy

gliomas represent highly aggressive brain tumors and include glioblastoma as the most common primary brain tumor in adults. This disease is related to a life expectancy of less than 2 years after diagnosis despite best standard of care involving surgery, chemo-and radiotherapy. With a relatively modest, but significant effect on patient survival, the alkylating agent temozolomide is commonly administered to patients with glioblastoma, however, even when combined with radiotherapy the prognosis of patients suffering from a glioblastoma does not improve in a satisfactory manner [1]. Thus, there is an urgent quest for unraveling more efficient therapeutic approaches. Amongst the several routes scientists and clinicians have taken is the strategy to interfere with amino acid metabolism. In our recently published manuscript, we have taken advantage of this approach by utilizing L-asparaginase, which is an approved drug for acute lymphoblastic leukemia, for the treatment of glio-blastoma. While this idea has been pursued for brain tumors before, we have further refined this strategy by combining L-asparaginase with an orally available inhibitor targeting Bcl-xL [2]. In that regard, we utilized one of the recently designed BH3-mimetics, ABT-263, which aside from Bcl-xL also interferes with Bcl-2 [3]. While other compounds that interfere with Bcl-xL and or Bcl-2 have been described before, the ABT-compounds are unique by their high-affinity target binding within the low nanomolar range. Recently, in a study led by researchers from the University of Ulm, a structural relative of ABT-263 (ABT-199, Venetoclax) demonstrated remarkable efficacy in chronic lympho-cytic leukemia patients that harbor a loss of chromosome 17p [4]. These results led to the designation of " fast-track approval " for ABT-199 (Venetoclax) by the US Food and Drug Administration [5]. In our study, we demonstrated that the combination treatment of ABT-263 and L-asparaginase resulted in a potent synergistic reduction in proliferation of a range of genetically diverse glioblastoma cells [2]. This was also true in glioblastoma cells that were resistant to L-asparaginase alone. Mechanistically, the combination treatment induced apoptosis with activation of effector caspases and loss of mitochondrial membrane potential. It remains to be determined as to whether other forms of Editorial cell death are involved. For instance, it is known that L-asparaginase induces autophagy in model systems of myeloid leukemia. While a significant proportion of glioblastomas harbor mutations in TP53, it appeared that the combination treatment does not require an active p53 pathway since mutated p53 cells responded to ABT-263 and L-asparaginase. …