Cancer Drug Repurposing for Treating Amyotrophic Lateral Sclerosis (ALS)

The treatment of ALS is difficult because of multiple genetic causes and the interplay of genetics and environment as precipitating factors. However, drugs to counteract the effect of genetic mutations have not yet been found. The concept of repurposing existing drugs is attractive because much of the Phase I testing in humans has already been done by the manufacturer. One of the features of ALS shared with certain cancers is the activation of inflammatory processes. Certain anticancer drugs are effective in part due to their ability to reduce inflammation through targeting signaling pathways initiated by protein phosphorylation events. We selected four drugs that have these properties and screened them for their ability to decrease protein levels of one of the causative genes,Cu, Zn-superoxide dismutase (SOD1). Mutations in SOD1 are responsible for about 10-15% of the genetically linked disease. Our rationale was that compounds that reduce expression of the toxic protein would be beneficial to slow onset and/or disease progression. Imatinib (Gleevec) was the only kinase inhibitor in the group that decreases mutant SOD1 levels in vitro. Imatinib, used clinically, is a known inhibitor of the BCR-ABL fusion protein which arises from a chromosomal rearrangement (Philadelpha chromosome) in acute lymphoblastic leukemia. However, Imatinib inhibits other tyrosine protein kinases such as the PDGFA receptor so for treatment of ALS it might engage multiple targets. A pilot preclinical trial of Imatinib in the G93A-SOD1 mouse model of ALS was performed using a single low dose of drug (2.5 mg/kg, IP) starting approximately one month before ALS symptoms (tremor) appear. We found that Imatinib significantly delayed onset and disease progression, and modestly extended life by about 7 days. Moreover, the dose used in the mice translates to the range of dosage (200-800 mg/ day, PO ) used in humans for cancer treatment. Additional preclinical testing in a larger animal cohort at varying doses is warranted to determine whether Imatinib can significantly improve survival without toxic effects.