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New insights emerge in an effort to repurpose Novartis’ cancer drug Tasigna in Parkinson’s disease

Last Update:2019-03-14   |   Comments:0 A+ A-

Brief:A research team at Georgetown University Medical Center previously repurposed Novartis’ blood cancer drug Tasigna for Parkinson’s disease, and turned up promising results in a preclinical mouse study and in a small group of patients. Now, they have return

 3D反对紫色背景的脑子
A Georgetown University Medical Center research team showed Novartis' cancer drug Tasigna could target a misfolded protein implicated in Parkinson's. (alex-mit/iStock/Getty Images Plus)

A research team at Georgetown University Medical Center previously repurposed Novartis’ blood cancer drug Tasigna for Parkinson’s disease, and turned up promising results in a preclinical mouse study and in a small group of patients. Now, they have returned with further insight into how the drug works in people with Parkinson’s.

 

A pharmacology analysis of 75 Parkinson’s patients who are currently participating in a phase 2 study showed that Tasigna can reduce levels of toxic alpha-synuclein protein clumps that are the hallmark of the disease. That increases the levels of dopamine in the patients’ brains. The Georgetown team reported their findings in the journal Pharmacology Research & Perspectives.

 

Tasigna (nilotinib) is approved by the FDA as a treatment for chronic myeloid leukemia. It is meant to be given twice daily at a recommended dose of as much as 400 mg for adults. In the Parkinson's study, the Georgetown researchers found that the drug could improve Parkinson’s biomarkers at a lower dose.

 

The team, led by Charbel Moussa, first  demonstrated Tasigna’s anti-neurodegeneration potential in 2013, testing the drug in mice that over-express alpha-synuclein. When the protein folds in the wrong way, it can block the brain from releasing neurotransmitters such as dopamine from small storage vesicles. That loss of dopamine can lead to motor symptoms like the impaired coordination that's commonly seen in Parkinson’s.

 

After the mouse trial showed that Tasigna could help clear the harmful accumulation of alpha-synuclein and improve movement, Moussa and colleagues moved to a small trial of 12 people with either advanced Parkinson’s or dementia with Lewy bodies. The observed improvements in motor functioning and cognitive outcomes, according to a 2016 report in the Journal of Parkinson’s Disease.  But in an editorial that ran alongside it, critics cautioned that the small sample size and lack of a control group made it impossible to rule out a placebo effect.

RELATED: Novartis cancer drug to be tested for Parkinson’s disease

 

In collaboration with the Michael J. Fox Foundation and others, the Georgetown researchers started the larger phase 2 trial. While the primary goal was to determine the safety of Tasigna, the researchers also searched patients’ cerebral spinal fluid (CSF) for traces of Parkinson’s biomarkers. They measured levels of 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the CSF. Because these molecules are produced when dopamine is metabolized, they could indicate how much dopamine was being used in the brain.

 

The patients were divided into five groups that received Tasigna at 150 mg, 200 mg, 300 mg or 400 mg or a placebo. After a single dose of Tasigna, the researchers found higher levels of DOPAC and HVA than were seen in the control group.

 

“When the drug is used, levels of these breakdown molecules quickly rise,” Moussa said in a statement. “This is exciting because this kind of potential treatment for Parkinson’s could increase use of a patient's own dopamine instead of using or periodically increasing drugs that mimic dopamine.”

 

Furthermore, Tasigna at 200 mg—which the team found to be the optimal dose for elevating DOPAC and HVA—also significantly increased the level of TREM-2 in the central nervous system. Because of TREM2’s anti-inflammatory role in the brain, some have suggested it could target misfolded alpha-synuclein and other harmful plaques in neurodegenerative disorders.

 

Other scientists are also investigating potential new uses of approved drugs in neurodegeneration. A team at University College London, for example, previously showed that GLP-1 receptor agonist exenatide, which is the active ingredient in AstraZeneca’s Byetta and Bydureon for Type 2 diabetes, also improved motor functions in some Parkinson’s patients.

 

Fernando Pagan, principal investigator of the Tasigna phase 2 trial and first author of the paper said the findings suggest the Novartis drug can reduce protect dopamine-secreting neurons. But how that can be translated into clinical outcomes remains to be seen. The trial is expected to be completed in mid-2020, according to a listing on ClinicalTrials.gov.

 




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