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SUMMARY:Programmed evolution: Using asexual gene drives to sculpt tumor po
 pulations and combat genetic diversity - Justin Pritchard\, Penn State Col
 lege of Engineering
DTSTART:20240429T113000Z
DTEND:20240429T123000Z
UID:TALK213541@talks.cam.ac.uk
CONTACT:Kate Davenport
DESCRIPTION:Tumor heterogeneity is profound\, and it provides a remarkable
  substrate for evolution. Despite this tremendous heterogeneity\, single d
 rugs targeting single oncogenic driver mutations can create deep responses
  in patients. However\, these responses are ultimately lost due to the evo
 lution of drug resistance. What if a tumor’s astonishing capacity for ev
 olution could be hijacked to our benefit? Towards this idea\, we recently 
 developed a selection gene drive system that is stably introduced into can
 cer cells and is composed of two genes\, or switches\, that couple an indu
 cible fitness advantage to a shared fitness cost. Using stochastic models 
 of evolutionary dynamics\, we developed design criteria for effective sele
 ction gene drives. We then build prototypes that harness the selective pre
 ssure of multiple approved tyrosine kinase inhibitors by inducing drug res
 istance and then deploying a second “trojan horse” switch to collapse 
 a heterogeneous population using mechanisms as diverse as prodrug catalysi
 s and immune activity induction. Using saturation mutagenesis and genome-w
 ide sgRNA libraries\, we show that the dual-switch selection gene drives c
 onstitute a simple motif for evolutionary control that can eradicate diver
 se forms of genetic resistance in vitro. Finally\, using models to guide t
 reatment scheduling\, we demonstrate that carefully controlled switch enga
 gement starting in a small fraction of cells (10% or less) can eradicate t
 umors in vivo. 
LOCATION:CRUK CI Lecture Theatre
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