Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer

SUMMARY

The paucity of genetically informed, immune-competent tumor models impedes evaluation of conventional, targeted, and immune therapies. By engineering mouse fallopian tube (FT) organoids using lentiviral gene transduction and/or CRISPR/Cas9 mutagenesis, we generated multiple high grade serous ovarian carcinoma (HGSOC) models exhibiting mutational combinations seen in patients. Detailed analysis of homologous recombination (HR)-proficient (Tp53^-/-;Ccne1^OE;Akt2^OE; Kras^OE), HR-deficient (Tp53-/-;Brca1-/-;Myc^OE) and unclassified (Tp53^-/-;Pten^-/-;Nf1^-/-) organoids revealed differences in in vitro properties and tumorigenicity. Tumorigenic organoids had variable sensitivity to HGSOC chemotherapeutics and evoked distinct immune microenvironments. These findings enabled development of a chemotherapy/immunotherapy regimen that yielded durable, T-cell dependent responses in Tp53^-/-;Ccne1^OE;Akt2^OE;Kras HGSOC; by contrast, Tp53^-/-;Pten^-/-;Nf1^-/- tumors failed to respond. Genotype-informed, syngeneic organoid models could provide an improved platform for rapid evaluation of tumor biology and therapeutics.

HIGHLIGHTS

• Orthotopic injection of genetically defined fallopian tube organoids yield HGSOC.
• Ovarian tumors with different genotypes evoke distinct immune microenvironments
• Combining Gemcitabine, anti-PD-L1, and anti-CTLA-4 result in complete responses in Tp53^-/-;Ccne1^OE;Akt2^OE;Kras^OE organoid-derived HGSOC
• Therapeutic response is tumor genotype-specific

Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer
[preprint posted on bioRxiv 2020 Apr 07]