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

Gwo Yaw Ho; Cassandra J Vandenberg; Ratana Lim; Elizabeth L Christie; Dale W Garsed; Elizabeth Lieschke; Ksenija Nesic; Olga Kondrashova; Gayanie Ratnayake; Marc Radke; Jocelyn S Penington; Amandine Carmagnac; Valerie Heong; Elizabeth L Kyran; Fan Zhang; Nadia Traficante; Australian Ovarian Cancer Study; Ruby Huang; Alexander Dobrovic; Elizabeth M Swisher; Orla McNally; Damien Kee; Matthew J Wakefield; Anthony T Papenfuss; David D L Bowtell; Holly E Barker; Clare L Scott

doi:10.1177/17588359231208674

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

Ther Adv Med Oncol. 2023 Nov 22:15:17588359231208674. doi: 10.1177/17588359231208674. eCollection 2023.

Authors

Gwo Yaw Ho^{1

2

3

4}, Cassandra J Vandenberg^{1

2}, Ratana Lim¹, Elizabeth L Christie^{5

6}, Dale W Garsed^{5

6}, Elizabeth Lieschke^{1

2}, Ksenija Nesic^{1

2}, Olga Kondrashova^{1

2

7}, Gayanie Ratnayake³, Marc Radke⁸, Jocelyn S Penington¹, Amandine Carmagnac¹, Valerie Heong¹, Elizabeth L Kyran¹, Fan Zhang⁹, Nadia Traficante^{5

6}; Australian Ovarian Cancer Study; Ruby Huang¹⁰, Alexander Dobrovic⁹, Elizabeth M Swisher⁸, Orla McNally^{3

6

11}, Damien Kee^{1

6

12}, Matthew J Wakefield^{1

11}, Anthony T Papenfuss^{1

2

5

6}, David D L Bowtell^{5

6}, Holly E Barker^{1

2}, Clare L Scott^{1

2

3

6

11}

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
² Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
³ The Royal Women's Hospital, Parkville, VIC, Australia.
⁴ School of Clinical Sciences, Monash University, Clayton Road, Clayton, VIC 3168, Australia.
⁵ Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
⁶ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.
⁷ QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
⁸ University of Washington, Seattle, WA, USA.
⁹ Department of Surgery, Austin Health, University of Melbourne, Heidelberg, VIC, Australia.
¹⁰ National Taiwan University, Taipei.
¹¹ Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC, Australia.
¹² Department of Medical Oncology, Austin Hospital, Heidelberg, VIC, Australia.

Abstract

Background: Despite initial response to platinum-based chemotherapy and PARP inhibitor therapy (PARPi), nearly all recurrent high-grade serous ovarian cancer (HGSC) will acquire lethal drug resistance; indeed, ~15% of individuals have de novo platinum-refractory disease.

Objectives: To determine the potential of anti-microtubule agent (AMA) therapy (paclitaxel, vinorelbine and eribulin) in platinum-resistant or refractory (PRR) HGSC by assessing response in patient-derived xenograft (PDX) models of HGSC.

Design and methods: Of 13 PRR HGSC PDX, six were primary PRR, derived from chemotherapy-naïve samples (one was BRCA2 mutant) and seven were from samples obtained following chemotherapy treatment in the clinic (five were mutant for either BRCA1 or BRCA2 (BRCA1/2), four with prior PARPi exposure), recapitulating the population of individuals with aggressive treatment-resistant HGSC in the clinic. Molecular analyses and in vivo treatment studies were undertaken.

Results: Seven out of thirteen PRR PDX (54%) were sensitive to treatment with the AMA, eribulin (time to progressive disease (PD) ⩾100 days from the start of treatment) and 11 out of 13 PDX (85%) derived significant benefit from eribulin [time to harvest (TTH) for each PDX with p < 0.002]. In 5 out of 10 platinum-refractory HGSC PDX (50%) and one out of three platinum-resistant PDX (33%), eribulin was more efficacious than was cisplatin, with longer time to PD and significantly extended TTH (each PDX p < 0.02). Furthermore, four of these models were extremely sensitive to all three AMA tested, maintaining response until the end of the experiment (120d post-treatment start). Despite harbouring secondary BRCA2 mutations, two BRCA2-mutant PDX models derived from heavily pre-treated individuals were sensitive to AMA. PRR HGSC PDX models showing greater sensitivity to AMA had high proliferative indices and oncogene expression. Two PDX models, both with prior chemotherapy and/or PARPi exposure, were refractory to all AMA, one of which harboured the SLC25A40-ABCB1 fusion, known to upregulate drug efflux via MDR1.

Conclusion: The efficacy observed for eribulin in PRR HGSC PDX was similar to that observed for paclitaxel, which transformed ovarian cancer clinical practice. Eribulin is therefore worthy of further consideration in clinical trials, particularly in ovarian carcinoma with early failure of carboplatin/paclitaxel chemotherapy.

Keywords: anti-microtubule agent; eribulin; high-grade serous ovarian cancer; homologous recombination deficiency; paclitaxel; platinum resistance; proliferative index.