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

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.

Figure 1.

Characterization of a cohort of HGSC PDX representative of the patient population. (a) Overall survival of HGSC patients in TCGA (n = 488) compared to the patients from which the PDX cohort was derived (n = 13). Median overall survival, from the date of diagnosis to the date of death or last known follow-up, for the TCGA cohort was 44 months and for our 13 cases was 42.0 months. Cases in the chemo-naïve cohort were predominantly platinum-resistant or refractory and two individuals were too unwell to receive chemotherapy, consistent with the reduced median OS. (b) Representative images of tumour sections stained with H&E, PAX8 and p53 for each PDX model. Scale bars represent 100 μm. (c) Summary of HR genes altered in the PDX models. HGSC, high-grade serous ovarian cancer; PDX, patient-derived xenograft; TCGA, The Cancer Genome Atlas.

Figure 2.

HGSC PDX models mostly displayed improved responses to anti-microtubule agents compared to cisplatin. (a) In vivo treatment of mice bearing chemo-naïve HGSC PDX tumours with DPBS (vehicle control), cisplatin (4 mg/kg), paclitaxel (25 mg/kg), vinorelbine (15 mg/kg) and eribulin (1 mg/kg). (b) In vivo treatment of mice bearing post-chemotherapy/PARPi HGSC PDX tumours with DPBS (vehicle control), cisplatin (4 mg/kg), paclitaxel (25 mg/kg), vinorelbine (15 mg/kg) and eribulin (1 mg/kg). A number of mice and p values for each model and treatment are shown in Table 2. Tumour volumes for individual mice are indicated by dotted lines with the solid line representing the mean. Shaded area = 95% confidence interval. Time to PD and harvest (TTH) are shown in Table 2. DPBS, Dulbecco’s phosphate-buffered saline; HGSC, high-grade serous ovarian cancer; PD, progressive disease; PDX, patient-derived xenograft; PARPi, TTH, time to harvest.

Figure 3.

HGSC PDX models with markers of increased proliferation exhibit increased sensitivity to anti-microtubule agents. (a) Summary of drug response, protein expression and gene alterations in PDX models. (b) Expression of Cyclin E1, MYC and MDR1 in tumours from each HGSC PDX model as determined by Western Blot analysis. Samples are ordered left to right based on sensitivity to eribulin, with the most sensitive models on the left (a representative blot is shown; a lane was removed as indicated by the vertical line). β-actin was used as a loading control. (c) Expression of ABCB1 and the SLC25A40-ABCB1 fusion transcript as determined by qPCR analysis. A patient-derived cell line AOCS18.5, previously shown to be positive for the SLC25A40-ABCB1 fusion, was used as a positive control. (d) Representative images of tumour sections stained with Ki-67 for each PDX model. Scale bars represent 100 μm. (e) Quantification of Ki-67 staining in PDX tumours (grey dots, with mean and SD; across the PDX cohort, the Ki-67 range was 26–92% with an overall mean of 61%; using a cutoff of >60% for high (dashed line), eight PRR PDX models (not including the platinum-sensitive model, #183) had high Ki-67), baseline tumours (red dots) and associations with time to PD for treatment with three AMAs (paclitaxel, vinorelbine and eribulin) in vivo (orange violin plots). HGSC, high-grade serous ovarian cancer; PDX, patient-derived xenograft; PRR, platinum-resistant or refractory.