Chloroquine as a Chemopreventation of Burkitts Lymphoma in Holoendemic Areas
This project is to plan a chemoprevention trial for Burkitt's lymphoma in East Africa (Uganda, Kenya and Tanzania). Endemic Burkitt's lymphoma (eBL) is the most common pediatric cancer in areas of equatorial Africa where malaria is endemic. It has long been known that there is a relationship between malaria and Epstein Barr virus (EBV) infection in the genesis of eBL. The increased viral load and the concomitant polyclonal B cell activation with enhanced B cell survival may augment the risk of eBL development in children living in malaria-endemic areas. Oncogenes such as Myc cooperate with loss of function mutations in the Atm-p53 pathway to accelerate tumorigenesis. Therefore, agents targeting this pathway might influence the outcome of Myc-induced tumor formation. There have been previous attempts to prevent eBL by using malarial prophylaxis. Geser et al. conducted a clinical trial with chloroquine in North Mara District, Tanzania. Immediately after initiation of this suppression trial, the incidence of malaria fell but soon it rose again to pretrial levels in spite of continued chloroquine administration. However, they found that during the years of chloroquine distribution, the incidence rate of eBL there fell by about 75% and stayed low until two years after the end of the study. Recent data from the Kastan lab has demonstrated that inhibition of autophagy by chloroquine blocks recycling of energy and MYC-mediated lymphomagenesis. Intermittent chloroquine use effectively prevents cancer in mouse models of two human cancer syndromes, Burkitt's lymphoma and ataxia telangiectasia, suggesting that agents targeting lysosome-mediated degradation may be effective in cancer prevention. Given these new data, one possible interpretation of the Geser trial results is a direct effect of chloroquine on the tumor cells as the primary mechanism of reducing the incidence of eBL. We are conducting a clinical trial to test the hypothesis that administration of chloroquine will reduce the incidence of eBL via inhibition of autophagy salvage pathways in tumor cell lysosomes. We are collecting current and historical data on eBL incidence and then define treatment and control populations. During the treatment and follow up phases we will collect data on incidence of eBL and malaria and collect specimens to look for biomarkers of drug activity, and measure viral and malarial loads by PCR.
Cancer Center Development in Mwanza