Using mice to model cancer cures


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Gerard Evan
UCSF Helen Diller Family Comprehensive Cancer Centre, San Francisco, USA

Abstract

<p>Cancers are lethal disease in desperate need of new therapeutic approaches: despite dramatic advances in the use of conventional chemo and radiotherapy and the growth of more “targeted” drugs, many cancers are still incurable. The principal problem is that we have no systematic or informed way of predicting which, out of the legion of aberrant processes in pancreatic cancer cells, is the best to target with drugs or where, within that process the most effective molecular targets lie.</p><p>To address this problem, we employ a novel class of genetically engineered mouse (GEM) in which individual oncogenes and/or tumour suppressor genes may be systemically toggled off and on, reversibly and at will, <i>in vivo</i>. In this way we can identify the most effective therapeutic targets irrespective of contemporary (and ephemeral) prejudices as to their “druggability”. This approach will be illustrated by two such GEMs: one mouse that models pharmacological inhibition of Myc, a core component of the replicative machinery of all tumour and normal cells and a downstream conduit for many (perhaps all) oncogenic growth signals, and a second mouse that models pharmacological restoration of the p53 tumour suppressor that is functionally inactivated in most human cancers. Since it is the endogenous oncogene or tumour suppressor that is toggled in such GEMs, they can be easily applied to any existing or new preclinical mouse cancer model. Using these two GEMs, we have directly ascertained the therapeutic impact, efficacy and side effects of Myc inhibition and p53 restoration - establishing both mechanism of action and therapeutic index.</p><br>