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Updated: Jun 6, 2025

Engineering Oncogenic Heterozygous Gain-of-Function Mutations in Human Hematopoietic Stem and Progenitor Cells
Published on: March 10, 2023
Targeting clonal mutations with synthetic microbes
1The University of Southern California Keck School of Medicine, The United States.
Abstract:
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.
Insights
A novel strategy, Oncolytic Vector Efficient Replication Contingent on Omnipresent Mutation Engagement (OVERCOME), targets clonal cancer mutations. This approach uses engineered bacteria that activate upon detecting mutations present in all cancer cells.
Area of Science:
- Oncology
- Genomics
- Bacteriology
Background:
- Large-scale cancer genomics studies reveal clonal mutations in most tumors.
- Clonal mutations, present in all cancer cells, are potential therapeutic targets.
- Current targeted therapies for clonal mutations face feasibility challenges.
Purpose of the Study:
- To propose a novel therapeutic strategy exploiting clonal cancer mutations.
- To introduce the "Oncolytic Vector Efficient Replication Contingent on Omnipresent Mutation Engagement" (OVERCOME) approach.
- To outline the potential use of bioengineered bacteria in cancer treatment.
Main Methods:
- Conceptualization of the OVERCOME strategy.
- Proposal of using a bioengineered facultative intracellular bacterium.
- Design of bacteria with conditional attenuation reversal based on mutation detection.
Main Results:
- The OVERCOME strategy offers a new way to target clonal mutations.
- Engineered bacteria could be attenuated and activated by specific mutations.
- This approach holds promise for personalized cancer therapy.
Conclusions:
- The OVERCOME strategy presents a viable new avenue for cancer treatment.
- Targeting clonal mutations with engineered bacteria could overcome current limitations.
- Further research into bioengineered bacterial vectors is warranted.
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