Brain Tumor Can Be Effectively Treated With Onalespib

Onalespib can cross the blood-brain barrier and when combined with temozolomide improves treatment outcome in glioblastoma.

The effectiveness of the targeted therapy onalespib in preclinical studies of glioblastoma has been discovered by researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove ResearchInstitute (OSUCCC - James).

Onalespib is designed to inhibit a molecule called HSP90. The molecule helps newly made protein molecules fold into their final functional form. A large number of receptor and DNA-damage-response proteins require HSP90 to achieve their functional conformation. In cancer cells, HSP90 can be expressed up to 10 times higher than in normal cells.

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Brain tumors are the abnormal growth of brain cells that may be benign or metastatic. Brain tumors account for about 2.4% of all the tumor diagnosesandare most challenging due to their critically delicate location.

‘Onalespib can efficiently breach the blood-brain barrier and reach tumor cells better than other HSP90 inhibitors.’

This study showed that onalespib blocked HSP90 activity and thereby reduced the expression of cell-survival proteins such as AKT and endothelial growth factor receptor in several glioma cell lines and in glioma stem cells obtained from patient tumors. This, in turn, reduced the survival, proliferation, invasion, and migration of the cells.

In animal models of glioblastoma (GBM), the agent crossed the blood-brain barrier and showed effectiveness as a single agent, and the greater effectiveness in combination with temozolomide, improving survival in both cases.

"Our studies show that onalespib can efficiently breach the blood-brain barrier and reach tumor cells better than other HSP90 inhibitors," says principal investigator Vinay Puduvalli, professor and director of the Division of Neuro-Oncology at Ohio State and a clinician-researcher at the OSUCCC - James.

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An abnormal growth of cells in the brain is called brain tumor. Most tumors arise within the brain (primary). They can be benign or cancerous.

"By inhibiting HSP90, onalespib disrupts several key signaling pathways that drive the proliferation, metastasis, and survival of glioblastoma cells. These findings suggest that this agent, in combination with chemotherapeutic temozolomide, could be an exciting new therapy for GBM. Based on the results of this study, we have generated a clinical trial that will determine whether onalespib in combination with standard therapy is safe and effective in patients with newly diagnosed glioblastoma," he says.

Glioblastoma is the most common and deadly form of brain cancer. More than 12,000 new cases are expected to be diagnosed in 2017, with overall survival averaging 16-18 months.

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Glioblastomas are tumors that arise from astrocytes that make up the supportive tissue of the brain. Glioblastomas are usually highly malignant.

The disease remains incurable, largely because GBM is difficult to remove surgically, because the blood-brain barrier prevents most chemotherapy from reaching these tumors and because these tumors tend to be radiation resistant.

The study's key findings include:

Onalespib levels were higher in brain tissue compared with plasma after intravenous administration in a mouse model, showing that the agent can cross the blood-brain barrier.
Tumor cells derived from patients and implanted into a mouse model showed that onalespib plus temozolomide significantly improved survival compared with mice treated with a neutral agent or either agent alone.

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Source-Eurekalert