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 2

Treatment and tumor recurrence in glioblastoma.

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Treatment and tumor recurrence in glioblastoma. Top: MRI scans of a pati...
Top: MRI scans of a patient with a primary glioblastoma before treatment, after initial gross total resection followed by chemo- and radiotherapy, and after tumor recurrence. Middle: A cartoon rendering of the associated changes in clonal populations in the tumor at each stage. Surgery successfully removes the tumor and eliminates many subclones. Postoperative chemo- and radiotherapies can further reduce tumor burden around the surgical cavity. However, a small fraction of tumor cells survive and initiate the formation of the recurrent tumor. The length of each line is proportional to the number of mutations acquired between each clone and branching indicates acquisition of divergent mutations. We have proposed calling these surviving cells recurrence-initiating stem-like cancer (RISC) cells. Bottom: Phylogenetic tree showing the process of clonal evolution in the primary tumor, the survival of RISC cells that have acquired adaptive resistance to therapy after initial treatments, and their evolution into a recurrent tumor. The length of each line is proportional to the number of mutations acquired between each clone, and branching indicates acquisition of divergent mutations.