Application

Despite progress in cancer genomics and targeted therapy, most tumors with key mutations—like in MLH1 and TP53—still lack effective treatments. MLH1 mutations cause mismatch repair deficiency, common in colorectal and other cancers, while TP53 is the most frequently mutated tumor suppressor gene. These mutations drive cancer progression and resistance to therapy.

However, tumors with these mutations often depend on alternative survival pathways, creating a therapeutic vulnerability known as synthetic lethality (SL). SL remains underutilized, with only PARP inhibitors approved clinically. Broader application has been limited by technical constraints, particularly the challenges of screening in genetically complex cancer cell lines.

Our Innovation

Our platform introduces a genome-wide CRISPR screening approach in haploid human embryonic stem cells (hESCs) engineered to carry MLH1 or TP53 loss-of-function mutations. Using these clean genetic models, our study identified and validated novel synthetic lethal targets — EXO1, NR5A2, PLK2 for MLH1-deficient cells, and MYH10 for TP53-deficient cells. These targets were confirmed via genetic and pharmacological methods in cell lines and mouse xenografts, positioning them for development into targeted cancer therapies.

Advantages

  • High-Specificity Platform: Haploid hESCs offer a stable, mutation-free background, enabling high-confidence SL target discovery.
  • Clinically Relevant Targets: SL partners (e.g., PLK2, MYH10) validated across in vitro and in vivo cancer models including colorectal tumors.
  • Drug-Ready Hits: Validated small molecule inhibitors (e.g., BI2536, blebbistatin) already exist for lead targets, enabling rapid preclinical development.
  • Selective Killing of Cancer Cells: Demonstrated minimal effect on healthy cells, supporting a precision oncology approach.
  • Strong Translational Potential: Shown efficacy in both established cell lines and xenograft mouse models, bridging the gap to clinical testing.

Commercial Opportunity

This technology targets a substantial market: ~15% of colorectal cancers and many other tumors show MMR deficiency, and over 50% of all tumors harbor TP53 mutations. Potential commercial paths include:

  • Development of targeted therapeutics using identified inhibitors (e.g., BI2536 for MLH1-mutants, blebbistatin for TP53-mutants).
  • Licensing of validated SL gene panels for drug screening or companion diagnostics.
  • Strategic pharma partnerships for co-development or drug repurposing.
  • Expansion into other tumor suppressors, leveraging the same haploid hESC screening framework.

This approach not only identifies synthetic lethal interactions with unprecedented clarity but also offers a streamlined path toward personalized, mutation-targeted cancer therapies.