Background: Fallopian tube (FT) or ovarian carcinosarcoma (FT/OCS) is an aggressive, drug-resistant rare cancer1. FT/OCS is a rare variant of high grade serous OC2 and shares TP53 gene dysfunction3 and over-expression of HMGA24, which is elevated in the C5 HGSOC subgroup5.
Method: We generated a genetically engineered mouse model (GEMM) with p53 dysfunction (SV40 TAg) and over-expression of the C5/MYCN-pathway (lsl-lin28b transgene), both directed by the doxycycline-inducible PAX8 promoter to the FT. Following activation, FT were transplanted into ovarian bursae of recipient mice. Tumour with histologic features of FT/OCS developed 5 months post-transplantation and was expanded in NodscidIlr2-gamma mice. An OCS patient-derived xenograft (PDX) model was generated. In vivo response to standard therapies for FT/OCS (cisplatin, paclitaxel or peglated doxorubicin) and novel therapeutic approaches for C5 HGSOC (microtubule inhibitors, vinorelbine and eribulin) were tested.
Result: The GEMM FT/OCS had limited response to cisplatin, paclitaxel or pegylated doxorubicin with median time to harvest (TTH) of 18d vs 15d for vehicle (p = 0.025); 36d vs 15d; p = 0.01 and 29d vs 15d; p = 0.08, respectively. However, the FT/OCS had durable responses and significant regressions following vinorelbine or eribulin (TTH 81d vs 15d; p < 0.001; 46d vs 15d; p < 0.001). Durable response was also seen in the OCS PDX.
Conclusion: As expected, FT/OCS GEMM and PDX responded poorly to standard chemotherapy. Impressive single agent activity for the microtubule inhibitors, vinorelbine and eribulin, support eribulin as a worthy candidate for human clinical trials in this rare cancer.