Existing Drug May Limit Recurrence and Metastasis of Glioblastoma Multiforme

Existing Drug May Limit Recurrence and Metastasis of Glioblastoma Multiforme
Existing Drug May Limit Recurrence and Metastasis of Glioblastoma Multiforme

In a significant breakthrough, researchers have identified propentofylline (PPF) as a drug that could help treat patients with deadly brain cancer. As described in the Journal of NeuroOncology (doi:10.1007/s11060-015-1981-0), PPF works to limit the spread of glioblastoma multiforme (GBM) by targeting a protein called TROY.

In addition, laboratory results suggest that PPF increases the effectiveness of temozolomide (TMZ), a standard-of-care chemotherapy drug, and radiation to treat glioblastoma.

"We showed that PPF decreased glioblastoma cell expression of TROY, inhibited glioma cell invasion, and made brain cancer cells more vulnerable to TMZ and radiation," said Nhan Tran, PhD, associate professor and head of TGen's Central Nervous System Tumor Research Laboratory at the Translational Genomics Research Institute (TGen) in Phoenix, Arizona.

An advantage of small-molecule PPF, which has been previously used in clinical trials in an attempt to treat Alzheimer's disease and dementia, is that it can penetrate the blood-brain barrier and reach the tumor. In addition, the FDA has already approved it.

"Our data suggests that PPF, working in combination with TMZ and radiation, could limit glioblastoma invasion and improve the clinical outcome for brain tumor patients," said senior author Tran.

One of the primary treatments for glioblastoma is surgical removal of the tumor. However, because of the aggressive way glioblastomas invade surrounding brain tissue, removing all parts of the tumors is impossible, and the cancer eventually returns and spreads. This insidious cancer invasion also limits the effectiveness of chemotherapy drugs and radiation therapy.

The TGen research found that PPF works to limit the spread of glioblastomas by targeting and knocking down the expression of the TROY protein. The researchers have linked TROY to the cellular mechanisms that enable glioblastomas to invade normal brain cells, and resist anticancer drugs.

"New therapeutic strategies that target the molecular drivers of invasion are required for improved clinical outcome," said lead author Harshil Dhruv, PhD, a TGen research assistant professor. "Propentofylline may provide a pharmacologic approach to targeting TROY, inhibiting cell invasion, and reducing therapeutic resistance in glioblastomas."

One of the fundamental challenges in treating brain cancer with drugs is the blood-brain barrier, which separates circulating blood from the brain extracellular fluid in the central nervous system. This barrier works to protect the brain from toxins. However, this security system is so effective at protecting the brain that it prevents many life-saving drugs, including all but some small-molecule drugs, from being able to treat cancer and other diseases of the brain.

As a result, little progress had been made in recent decades in finding new effective treatments for GBM. Median survival for patients with newly diagnosed GBM is only 14.6 months. Only 5% of patients survive more than 5 years.

"Clinical trials revealed that PPF can cross the blood-brain barrier, and has minimal side effects," Tran said. "PPF could be easily translated to the clinic as an adjuvant therapy in combination with standard of care treatment for GBM patients."

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