Overcoming therapeutic resistance in glioblastoma: the way forward
Satoru Osuka, Erwin G. Van Meir
Satoru Osuka, Erwin G. Van Meir
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Overcoming therapeutic resistance in glioblastoma: the way forward

Abstract

Glioblastoma is the most common and lethal primary malignant brain tumor in adults. Patients die from recurrent tumors that have become resistant to therapy. New strategies are needed to design future therapies that target resistant cells. Recent genomic studies have unveiled the complexity of tumor heterogeneity in glioblastoma and provide new insights into the genomic landscape of tumor cells that survive and initiate tumor recurrence. Resistant cells also co-opt developmental pathways and display stem-like properties; hence we propose to name them recurrence-initiating stem-like cancer (RISC) cells. Genetic alterations and genomic reprogramming underlie the innate and adaptive resistance of RISC cells, and both need to be targeted to prevent glioblastoma recurrence.

Authors

Satoru Osuka, Erwin G. Van Meir

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Figure 3

Opportunities for future molecularly targeted therapy for glioblastoma.

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Opportunities for future molecularly targeted therapy for glioblastoma. ...
(A) The primary tumor is heterogeneous, and composed of several abundant cell subpopulations: cells with variable proliferation properties (pink and green), glioma stem cells (GSCs) (tan), and recurrence-initiating stem-like cancer (RISC) cells (red). Initial treatments successfully reduce the bulk tumor volume and its heterogeneity. However, subpopulations of RISC cells survive therapeutic intervention though intrinsic and adaptive resistance mechanisms (indicated by a blue ring). RISC cells initiate tumor recurrence through a second round of clonal evolution that repopulates the tumor. The current clinical strategies for GBM could be strengthened by adding molecular therapies to target: (i) initially resistant clones, (ii) adaptive resistance mechanisms, and (iii) the tumor when its population diversity and cell numbers are at their lowest. (B) Schematic showing the 4 proposed different cancer cell populations in the tumor (GSCs [tan], RISC cells [red], non-GSCs [light blue], and proliferating non-GSCs [dark blue]) and putative ways to target them (see also Table 2). RISC cells likely represent a subset of the GSC population with both innate and acquired resistance. The precise proportion of each cell population remains to be established. (C) Proposed optimal timing for each therapeutic option during the initial (primary treatment) and intermediate (stabilization/remission period before recurrence) phases of therapy.