Researchers identify novel molecular pathway that suppresses the spread of glioblastoma

UT Southwestern researchers have identified molecular pathways responsible for the spread of glioblastoma to the surrounding tissue in the brain, as well as drugs that restrain the growth of tumors in animal models. The findings, published in Nature Cell Biology, have caused clinical trials that can offer new hopes to patients with Glioblastoma, the most common form of brain cancer in adults who kill hundreds of thousands of people worldwide every year. “Invasive property Glioblastoma may be the most formidable barrier for treatment,” said Amyn Habib, M.D., Associate Professor of Neurology, members of The Brain Institute from Harold C. Simmons and Peter O’Donnell Jr. Brain in Utsw, and a doctor staff at the Dallas VA medical center.

Although some decades of research, the prognosis for most patients with glioblastoma remains gloomy, with an average survival after the diagnosis is only 15-18 months. Part of the challenge in treating this cancer is its invasive nature: Glioblastoma tumors attack around healthy brain tissue, sending extensions such as tentacles out of primary tumors that cannot be removed by surgery and are difficult to reach by chemotherapy.

The researchers have long considered the epidermal growth factor receptor (EGFR), a protein located on the surface of the cell, as a driver of this cancer, Dr. Habib explained. In almost half of the glioblastoma patients, genes that encode eGFR are amplified, causing glioblastoma cells to produce molecular signals that are much more driven by this protein and cause tumor cells to multiply. As a result, Dr. Habib added, several clinical trials had focused on inhibiting EGFR – but each failed to increase the prognosis for glioblastoma. EGFR in Glioblastoma cells can send these signals in two ways: either without encouragement, a condition known as constitutive signaling, or when stimulated with protein called ligands. The difference between the two paths has been considered unimportant, said Dr. Habib. Thus, glioblastoma patients with a messed up EGFR have been grouped together in clinical trials. In a new study, Dr. Habib and his colleagues in the Habib lab and elsewhere show that when cells with eGFRs that are messed up are stimulated with ligands, these receptors seem to act as tumor pressures, prevent invasion to healthy tissue both in laboratory and animal models. Further experiments show that cytoskeletal protein called BIN3 seems responsible for inhibiting this invasion. When researchers are thanks to animals with Glioblastoma EGFR tumors that are messed up with arthritis approved by the FDA called tofacitini which increases the number of eGFR and BIN3 ligands, the tumor remains smaller and smaller the possibility of attacking healthy brain tissue. In addition, these animals last significantly longer than animals that do not receive this drug.

Habib noted that Tofacitinib could offer a new way to extend life for patients with a relatively high eGFR and eGFR ligands, strategies that will be explored by his colleagues in the launch of clinical trials in September. For patients without high ligand numbers, he added, the strategy that was previously explored to inhibit EGFR has the potential to extend survival. “This approach can offer new tools in our weapons to fight Glioblastoma,” said Dr. Habib.