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.

Figure 1. The complexity of inter- and intratumoral heterogeneity in glioblastoma.

(A) Heterogeneity between individual patient tumors stems from both the cell of origin and the subsequent major epigenetic and genetic alterations. These variations produce different types of tumor-initiating cells (TICs). (B) TICs expand and establish genetically divergent clonal cell populations. During this clonal evolution process, cellular offspring acquire diverse genetic alterations and engender a variety of clones. Cells with similar types of genetic alterations exist in close spatial proximity, but their invasive properties will lead to clonal mixing and normal brain invasion. (C) Further heterogeneity at the cellular level is added by environmental factors. Proximity to blood vessels (vascular and hypoxic niches), paracrine signals between tumor cells, and immune responses (inflammatory niche), will influence individual tumor cell biology, including regulating stemness versus differentiation state of glioma stem cells (GSCs).

Figure 2. Treatment and tumor recurrence in glioblastoma.

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.

Figure 3. 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.