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  • Combined Bcl-2 & BH3 Profiling as a Method to Define Therapeutic Response and Resistance in Grade IV Astrocytomas

    Final Number:
    1544

    Authors:
    Monica Rodriguez Silva BS; Angel Chinea BS; Zachary Aberman BS; Sergio M. Gonzalez-Arias MD, PhD, FACS; Jeremy W. Chambers PhD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2016 Annual Meeting

    Introduction: Grade IV astrocytomas, formerly known as glioblastoma multiforme (GBM), are the most common primary brain tumors and have the highest mortality. The therapeutic standard for managing this malignancy remains a combination of surgery, chemotherapy, and radiotherapy; however, there is no cure, nor has there been any significant advancement in the clinical approach to GBM since this protocol was established in 2005. This study aims to better understand the molecular and metabolic characteristics of GBM-derived cell lines to better define treatment groups and potentially identify new avenues for therapy.This study utilized ten continuous GBM cell lines and examined the concentrations of Bcl-2 family proteins on mitochondria and metabolic activity for each of the cell lines.

    Methods: Cellular viability in the presence of increasing doses of TMZ was determined for ten continuous GBM cell lines. Concentrations of Bcl-2 family of proteins were obtained via Western blot for each cell line. The metabolic activity for each of these cell lines was also assessed using the Seahorse XF analyzer. Measures of Bcl-2 family proteins was then correlated to IC50 values for temozolamide (TMZ).

    Results: Western blot analysis of pro-survival and pro-apoptotic Bcl-2 proteins revealed that Bcl-2 levels corresponded to chemo-sensitivity, while increased levels of Bim promoted chemo-sensitivity in GBM cell lines. The ratio of Bcl-2 and Bim expression was found to be significantly correlated (p<0.0001) to TMZ responsiveness (r = 0.9755). Induction of TMZ resistance in U87 cell by exposure to a hypoxic environment increased the Bcl-2/Bim ratio.

    Conclusions: We found that Bcl-2 and BH3-only protein profiling was a useful means to determine therapeutic response and resistance in established GBM cell lines.

    Patient Care: This project aims to identify molecular processes occurring within glioblastoma cell lines, as potential targets for the development of novel therapeutic modalities.

    Learning Objectives: By the conclusion of this session, participants should be able to: 1) Discuss Bcl-2 family of proteins in the context of molecular profiling for GBM, 2)Describe chemosensitivity of different cell lines as determined by their metabolic and molecular profiles, 3)Discuss clinical significance of observed therapeutic response

    References:

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