Poster Presentation 30th Lorne Cancer Conference 2018

Targeting microtubule dynamics with eribulin as a potential therapeutic strategy in the treatment of fallopian-tube/ovarian carcinosarcoma (#172)

Gwo Yaw Ho 1 2 3 , Elizabeth Kyran 3 , Elizabeth Lieschke 3 , Kathy Barber 3 , Olga Kondraschova 3 , Cassandra Vandenberg 3 , Orla McNally 1 , Anne Hamilton 1 2 , Holly Barker 3 , Kirsty Shield-Artin 3 , Ronny Drapkin 4 , David Bowtell 2 5 , Matthew Wakefield 3 , Clare Scott 2 3
  1. Royal Women’s Hospital, Melbourne, VIC, Australia
  2. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  3. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  4. Penn Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA
  5. Australian Ovarian Cancer Study, Melbourne, VIC, Australia

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 HMGA24which 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.

  1. George, E. M. et al. Carcinosarcoma of the ovary: Natural history, patterns of treatment, and outcome. Gynecologic Oncology 131, 42–45 (2013)
  2. Berton-Rigaud, D. et al. Gynecologic Cancer InterGroup (GCIG) Consensus Review for Uterine and Ovarian Carcinosarcoma. International Journal of Gynecological Cancer 24, S55–S60 (2014)
  3. Zhao, S. et al. Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial? mesenchymal transition. Proceedings of the National Academy of Sciences 113, 12238–12243 (2016)
  4. Mahajan, A. et al. HMGA2: A biomarker significantly overexpressed in high-grade ovarian serous carcinoma. Mod Pathol 23, 673–681 (2010)
  5. Helland, Å. et al. Deregulation of MYCN, LIN28B and LET7 in a Molecular Subtype of Aggressive High-Grade Serous Ovarian Cancers. PLoS ONE 6, e18064–20 (2011)