While studying its biological and biochemical properties, we identified the antiviral drug Ribavirin as a competitive inhibitor of the eukaryotic translation initiation factor 4E (eIF4E) (Kentsis et al, PNAS, 2004). We conducted three clinical trials (ClinicalTrials.gov NCT01056523, NCT00559091 and NCT02073838 -which is still ongoing). These trials focused on refractory / relapsed AML (Acute Myeloid Leukemia) patients and led to objective clinical responses including remissions (Assouline et al. Blood, 2009; Assouline et al., Haematologica, 2015). Ribavirin-induced relocalization of nuclear eIF4E to the cytoplasm and reduction of eIF4E levels in leukemic blasts from the patients were associated with clinical response. More information about this trial can be viewed at www.ribatrial.com.
We also identified a novel form of drug resistance to ribavirin and Ara-C in relapsed patients from our first two clinical trials (Zahreddine et al, Nature, 2014). Here, the sonic hedgehog transcription factor glioma-associated protein 1 (GLI1) and the UDP glucuronosyltransferase (UGT1A) family of enzymes were elevated in resistant cells. UGT1As add glucuronic acid to many drugs, modifying their activity in diverse tissues. We found that GLI1 alone is sufficient to drive drug resistance by upregulating UGT1A-dependent glucuronidation of ribavirin and Ara-C. To overcome resistance we are using pharmacological inhibition of GLI1 as a part of our third clinical trial (NCT02073838-ongoing). Combination of Ribavirin with Ara-C led to prolonged duration of responses in patients that acheived remission.
This study is done in collaboration with Jewish General Hospital and Hôpital Maisonneuve Rosemont (Montreal, Quebec) and Hamilton Health Sciences center (Hamilton, Ontario).
More information about this trial can be viewed at www.ribatrial.com