Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer
Robert A Weinberg,
Benjamin G Neel
Posted 07 Apr 2020
bioRxiv DOI: 10.1101/2020.04.06.028597 (published DOI: 10.1158/2159-8290.CD-20-0455)
Posted 07 Apr 2020
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 lentivirus gene transduction and/or CRISPR/Cas9 mutagenesis, we generated combinations seen in patients. Detailed analysis of homologous recombination (HR)-proficient (Tp53-/-;Ccne1OE;Akt2OE;KrasOE), HR-deficient (Tp53-/-;Brca1-/-;MycOE) 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-/-;Ccne1OE;Akt2OE;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.
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