Physical Poster + E-Poster Presentation 34th Lorne Cancer Conference 2022

The microtubule inhibitor eribulin demonstrates efficacy in platinum resistant and refractory high-grade serous ovarian cancer patient derived xenograft models (#244)

Cassandra Vandenberg 1 2 , Gwo Yaw Ho 1 2 3 4 , Ratana Lim 1 , Elizabeth Christie 5 , Dale Garsed 5 , Jocelyn Penington 1 , Ksenija Nesic 1 2 , Gayanie Ratnayake 3 , Kathy Barber 1 , Silvia Stoev 1 , Elizabeth Lieschke 1 , Olga Kondrashova 1 2 , Amandine Carmagnac 1 , Elizabeth Kyran 1 , Elizabeth Swisher 6 , Orla McNally 3 , Matthew Wakefield 1 2 , Anthony Papenfuss 1 2 5 , David Bowtell 5 , Holly Barker 1 2 , Clare Scott 1 2 3 5
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. University of Melbourne, Melbourne, VIC, Australia
  3. The Royal Women's Hospital, Parkville, VIC, Australia
  4. Monash University, Clayton, VIC, Australia
  5. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  6. University of Washington, Seattle, WA, USA

Up to 80% of women with stage III or IV high grade serous ovarian cancer (HGSOC) have disease which is responsive to platinum-based chemotherapy, and 50% of these harbor defects in Homologous Recombination (HR) DNA repair and are likely to be sensitive to PARP inhibitor therapy (PARPi). However, ~15% of women have de novo platinum refractory disease, and eventually all recurrent HGSOC acquire resistance to the drugs available for treatment following exposure to multiple lines of therapy. We have generated and characterised a cohort of fourteen platinum resistant or refractory HGSOC patient-derived xenograft (PDX) models derived from chemo-naïve or post-treatment tumour samples (prior exposure to chemotherapy and/or PARPi), recapitulating the population of women with aggressive treatment-resistant HGSOC. Six PDX models had germline or somatic mutations in BRCA1 or BRCA2, with four of these models derived from patients who had received PARPi as part of their treatment regimen.

Despite their platinum resistant/refractory phenotype, three PDX models were extremely sensitive to the anti-microtubule chemotherapeutic agents (AMA), paclitaxel, vinorelbine and eribulin, whilst nine PDX exhibited improved responses to AMA compared with platinum-based chemotherapy. Two PDX models with prior chemotherapy/PARPi exposure were refractory to AMA, one of which harbored the SLC25A40-ABCB1 fusion, known to upregulate drug efflux via MDR1. Additional genomic profiling of the cohort revealed multiple oncogenic events correlated with a poor prognosis, including PIK3CA aberrations in three models, MYC amplifications in five models and CCNE1 amplifications in four models. Unexpectedly, these poor prognostic events were more common in the models that exhibited greater sensitivity to the microtubule inhibitors. Our data indicates the well-tolerated AMA eribulin is worthy of re-consideration in HGSOC. This cohort of PDX models is a robust and powerful preclinical tool to explore novel therapeutics for these women with aggressive and treatment resistant tumours and to study mechanisms of drug response/resistance.