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Abstract

Cancer and neurodegeneration include a group of diseases that are mechanistically distinct but may share common therapeutic targets. Autophagy is a common quality control mechanism shared by mitotic and post-mitotic cells and it can be exploited to accelerate clearance of unwanted oncogenes and reduce accumulation of toxic proteins in cancer and neurodegeneration respectively. Tyrosine kinase inhibition is a therapeutically relevant strategy that can induce autophagy. Our laboratory investigates TKIs that activate autophagy and are FDA-approved for cancer, thus significantly reducing research and development efforts and cost by re-purposing. In neurodegeneration, the non- receptor tyrosine kinase ABL is activated. Nilotinib and bosutinib are second generation BCR-ABL and SRC (short for Sacoma)-ABL inhibitors, respectively, that are therapeutically used for individuals with leukemia. A fraction of nilotinib and bosutinib crosses the blood-brain barrier (BBB), inhibits ABL and facilitates autophagic misfolded protein clearance, leading to neuroprotection and improved cognition and motor behavior. Mice treated with a much lower dose of these drugs (< 25% of the typical leukemia dose) show significant motor and cognitive improvement and degradation of misfolded proteins, leading to normal cell survival. We evaluated the effects of low doses of Nilotinib, on safety and pharmacokinetics in Parkinsonâ��s disease dementia or dementia with Lewy body. Twelve subjects were randomized into 150 mg (N=5) or 300 mg (N=7) groups and received oral daily doses of nilotinib for 24 weeks. The primary objectives were safety and tolerability; pharmacokinetics and target engagement were secondary, while clinical outcomes were exploratory. This study shows that 150 mg and 300 mg daily doses of nilotinib are safe and well tolerated in advanced Parkinsonâ��s disease. Nilotinib is detected in the CSF and seems to engage the target via Abl inhibition. Parkinson-related CSF biomarker, including homovanillic acid is significantly increased, DJ-1 is reduced and �±-synuclein is stable between baseline and 24-week nilotinib treatment. Exploratory cell death biomarkers including neuron specific enolase and tau are also reduced. Motor and cognitive performance suggests stabilization of clinical outcomes. These data support the potential of TKIs in the treatment of PD.

Biography

Email: cem46@georgetown.edu