Antiangiogenic Therapies in Glioblastoma Multiforme
Antiangiogenic Therapies in Glioblastoma Multiforme
Despite the progress in our understanding of the process of angiogenesis and the potential of targeting these processes for the treatment of GBM, many challenges remain. Considerations regarding the modes and underlying mechanisms of resistance to antiangiogenic therapy present both the directionality of future research and the outlines of a strategy for improving the treatment of human cancer with angiogenesis inhibitors.
Combination approaches focusing on the utilization of multiple therapies to target different pathways concurrently with the hope of preventing use of different pathways to evade the inhibition of a single molecule are necessary. This rationale is supported by the findings in a number of studies in which escape from antiangiogenesis occurred.
One report reveals that IL-8 is an important contributor to sunitinib resistance in clear cell renal cell carcinoma and a possible target to reverse acquired or intrinsic resistance to sunitinib in this malignancy. Another study shows that bevacizumab upregulates stromal cell-derived factor 1α, its receptor CXCR4, and CXCL6 and neuropilin 1 (co-receptor with neuropilin 2 for VEGF) in tumors from patients with rectal cancer and therefore could possibly be evaluated as potential targets for improving anti-VEGF therapy. Also, in U87-derived experimental glioma grown on the chick chorio-allantoic membrane or in the brain of xenografted mice, a combination of IL-6 and VEGF inhibitors is associated with synergistic anti-tumoral benefit and reduces global activity of major pathways of cell survival, proliferation and invasiveness in remaining tumor cells that may be induced by using VEGF or IL-6 inhibitors alone.
Uncontrolled proliferation and abnormal cell migration are two prominent characteristics of GBMs. The role of the receptor tyrosine kinase EPHB2 in controlling the proliferation/migration dichotomy of GBM has been investigated. EPHB2 has been demonstrated to have proinvasive and antiproliferative actions in GBM stem-like neurospheres, mediated in part by interactions between EPHB2 receptors and the non-receptor tyrosine kinase focal adhesion kinase. These findings suggest that tumor cell invasion could potentially be therapeutically targeted by inhibiting EPHB2 signaling, and that optimal anti-tumor responses to EPHB2 targeting may require concurrent use of antiproliferative agents.
The important role of both tumor cells and tumor microenvironment in determining the complex process of angiogenesis supports pharmacogenetic investigations of tumor and germline single nucleotide polymorphisms for antiangiogenic drugs. In a Phase III clinical trial of metastatic breast cancer, an association has been reported between different VEGF-A genotypes and median OS when using bevacizumab with paclitaxel chemotherapy. Similarly, the VEGFR-1 319 C/A single nucleotide polymorphism has been reported to be a potential predictive marker for bevacizumab plus chemotherapy in patients with metastatic colorectal carcinoma, as patients with the A allele appeared to have increased response rates. Whether these results are clinically meaningful and applicable to GBM research requires further validation.
Another unanswered question is whether cancer stem cells or glioma stem cells promote angiogenesis in malignant gliomas and whether these could be targeted specifically with novel therapy. Glioma-initiating or glioma-propagating cells are thought to represent a small subpopulation of cells giving rise to all types of tumor cells and seem particularly resistant to conventional therapeutic interventions; therefore, extension of our knowledge of brain tumor stem cell biology to form a basis for therapeutic agent development in this area is paramount.
Five-Year View
Despite the progress in our understanding of the process of angiogenesis and the potential of targeting these processes for the treatment of GBM, many challenges remain. Considerations regarding the modes and underlying mechanisms of resistance to antiangiogenic therapy present both the directionality of future research and the outlines of a strategy for improving the treatment of human cancer with angiogenesis inhibitors.
Combination approaches focusing on the utilization of multiple therapies to target different pathways concurrently with the hope of preventing use of different pathways to evade the inhibition of a single molecule are necessary. This rationale is supported by the findings in a number of studies in which escape from antiangiogenesis occurred.
One report reveals that IL-8 is an important contributor to sunitinib resistance in clear cell renal cell carcinoma and a possible target to reverse acquired or intrinsic resistance to sunitinib in this malignancy. Another study shows that bevacizumab upregulates stromal cell-derived factor 1α, its receptor CXCR4, and CXCL6 and neuropilin 1 (co-receptor with neuropilin 2 for VEGF) in tumors from patients with rectal cancer and therefore could possibly be evaluated as potential targets for improving anti-VEGF therapy. Also, in U87-derived experimental glioma grown on the chick chorio-allantoic membrane or in the brain of xenografted mice, a combination of IL-6 and VEGF inhibitors is associated with synergistic anti-tumoral benefit and reduces global activity of major pathways of cell survival, proliferation and invasiveness in remaining tumor cells that may be induced by using VEGF or IL-6 inhibitors alone.
Uncontrolled proliferation and abnormal cell migration are two prominent characteristics of GBMs. The role of the receptor tyrosine kinase EPHB2 in controlling the proliferation/migration dichotomy of GBM has been investigated. EPHB2 has been demonstrated to have proinvasive and antiproliferative actions in GBM stem-like neurospheres, mediated in part by interactions between EPHB2 receptors and the non-receptor tyrosine kinase focal adhesion kinase. These findings suggest that tumor cell invasion could potentially be therapeutically targeted by inhibiting EPHB2 signaling, and that optimal anti-tumor responses to EPHB2 targeting may require concurrent use of antiproliferative agents.
The important role of both tumor cells and tumor microenvironment in determining the complex process of angiogenesis supports pharmacogenetic investigations of tumor and germline single nucleotide polymorphisms for antiangiogenic drugs. In a Phase III clinical trial of metastatic breast cancer, an association has been reported between different VEGF-A genotypes and median OS when using bevacizumab with paclitaxel chemotherapy. Similarly, the VEGFR-1 319 C/A single nucleotide polymorphism has been reported to be a potential predictive marker for bevacizumab plus chemotherapy in patients with metastatic colorectal carcinoma, as patients with the A allele appeared to have increased response rates. Whether these results are clinically meaningful and applicable to GBM research requires further validation.
Another unanswered question is whether cancer stem cells or glioma stem cells promote angiogenesis in malignant gliomas and whether these could be targeted specifically with novel therapy. Glioma-initiating or glioma-propagating cells are thought to represent a small subpopulation of cells giving rise to all types of tumor cells and seem particularly resistant to conventional therapeutic interventions; therefore, extension of our knowledge of brain tumor stem cell biology to form a basis for therapeutic agent development in this area is paramount.