Scientists target Glioblastoma growth

Researchers at Hopkins Medical School have found that targeting multiple developmental neural pathways with several drugs simultaneously is more effective at controlling the growth of malignant brain tumors than targeting each pathway individually. The research, conducted by Charles Eberhart and his colleagues, was published in the journal Clinical Cancer Research.

Glioblastoma is known as the most common and aggressive type of primary malignant brain tumor in humans. Glial cells of the central nervous system are targeted, resulting in an average survival period of less than two years.

Studies have shown that there are various subtypes affecting different oncogenes — genes likely to cause cancer when mutated or expressed in overabundance — and signaling pathways. As a result, it is unlikely for a single type of treatment to work against all forms of glioblastoma. However, glioblastomas are known to build up resistance to chemo- and radiotherapy targeted against specific signaling pathways.

Notch, Wnt and Hedgehog pathways are crucial signaling pathways involved in the development and growth of neurons. Most treatments for glioblastoma target only one pathway. However, initial response to medication followed by increased resistance led researchers to consider the possibility of tumor cells turning on a different pathway to compensate for the inhibited pathway.

Eberhart and his colleagues used gamma-secretase inhibitors to block only the Notch pathway, while observing the Hedgehog and Wnt pathways. Researchers found that treatment with gamma-secretase inhibitors resulted in increased activity in both the Hedgehog and Wnt.

Moreover, experiments show that some proteins involved in the Notch signaling pathway are also directly affecting proteins in the Hedgehog pathway.

When both the Notch and Hedgehog pathways were blocked, using a gamma-secretase inhibitor and cyclopamine respectively, cell growth decreased by nearly 90 percent. In addition, combinatorial therapy increased apoptosis, or natural cell death, and decreased the tendency of colony formation of cells.

Certain unexpected interactions in the signaling pathways were observed only in a subset of cell lines in specific cancer types, suggesting that other factors that affect glioblastoma growth have yet to be discovered.

The experiments were conducted using glioblastoma neurosphere lines, medulloblastoma lines and primary human glioblastoma cultures.

Replication of the study using cell cultures of other cancers, including prostate, lung, ovarian, skin and hematopoetic, showed that similar results were found in a melanoma-derived line.

In vivo studies are required to determine the effectiveness of usage of the combinatorial therapy to treat cancer patients. Future studies also aim to explore other pathways involving tumor growth, and molecular relationships between the Notch, Hedgehog and Wnt pathways.