Onalespib could be an effective treatment for glioblastoma, preclinical studies show

The targeted therapy onalespib has shown effectiveness in preclinical studies of glioblastoma by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

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.

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 then greater effectiveness in combination with temozolomide, improving survival in both cases.

The findings are published in the journal Clinical Cancer Research.

"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, MD, professor and director of the Division of Neuro-Oncology at Ohio State and a clinician-researcher at the OSUCCC – James.

"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. 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 survival compared with mice treated with a neutral agent or either agent alone.

 Ref : https://medicalxpress.com/journals/clinical-cancer-research/

Onalespib could be an effective treatment for glioblastoma, preclinical studies show

Flavopiridol drug could be effective strategy to impair brain cancer growth

Glioblastoma, the most common form of brain cancer is a deadly disease for which at present there is no cure. Now, researchers have
published research results that show how re   purposing the  old drug
flavopiridol could be an effective strategy to cut short sugar availability and impair cancer growth.

One of the most remarkable feature of glioblastoma cells is their ability to reprogram their metabolism switching towards a glycolytic energetic metabolism, which relies on high glucose uptake and consumption to sustain the cancer cell's malignant activities. However, because flavopiridol, a synthetic flavonoid already used in the past against cancer, inactivates the enzyme glycogen phosphorylase, this metabolic switching could be used as a therapeutic target. The authors set out to test whether flavopiridol could be used to restrain glioblastoma cell growth by decreasing the availability of glucose as substrate for the glycolytic process, cutting off the tumor's energy supply.

The results, published on the Journal of Cellular Physiology, comes from the Sbarro Health Research Organization (SHRO), at the Center for Biotechnology, Temple University and the University of L'Aquila and Siena in Italy.

The ability of Flavopiridol to reduce glycolisys in glioblastoma cells and inhibit their proliferation is a significant step toward deriving new treatments for what is currently an incurable form of cancer. According to Annamaria Cimini of the University of L'Aquila, lead author of the study, "This points toward a possible new use of this compound or flavopiridol-derived formulations in combination with
anti-proliferative agents in glioblastoma patients."

"The design of new flavopiridol-based formulations, aimed at starving cancer cells cutting short the sugar they're addicted to, may open up new therapeutic avenues for patients with glioblastoma," says Antonio Giordano, founder and director of the Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology at Temple University in Philadelphia, PA USA in collaboration with the Department of Medicine, Surgery & Neuroscience at the University of Siena, and University of L' Aquila Italy.

 Ref : https://shrodotorg.wordpress.com/2016/05/20/old-drug-could-fight-brain-cancer-by-starving-it-to-death/