Targeting clonal mutations with synthetic microbes

Recently concluded, large-scale cancer genomics studies involving multiregion sequencing of primary tumors and paired metastases appear to indicate that many or most cancer patients have one or more “clonal" mutations in their tumors. Clonal mutations are those that are present in all of a patient’s cancer cells. Clonally mutated proteins can potentially be targeted by inhibitors or E3 ligase small molecule glues, but developing new small molecule drugs for each patient is not feasible currently. Certain companies are using immunotherapies to target clonal mutations. I have devised another approach for exploiting clonal mutations, which I call “Oncolytic Vector Efficient Replication Contingent on Omnipresent Mutation Engagement” (OVERCOME). The ideal version of OVERCOME would likely employ a bioengineered facultative intracellular bacterium. The bacterium would initially be attenuated, but (transiently) reverse its attenuation upon clonal mutation detection. [Display omitted] •Clonal mutations are those that are present in all of a given patient’s cancer cells.•TRACERx results suggest that many or most cancer patients have at least one clonal mutation.•Small molecules and immunotherapies may not be the best ways to exploit clonal mutations.•“OVERCOME” would exploit clonal mutations with an intracellular microbe.•OVERCOME could also target a small set of subclonal mutations that together are present in all the patient’s cancer cells.