| Popis: |
Backgrounds: A liposomal formulation of Eribulin, E7389-LF may allow increased access to tumor tissues and has been under development for breast cancer. In a phase 1, expansion cohort as a late line treatment, objective response rate was observed to be 35.7% (Her2-negative breast cancer), and 42.9% for hormone receptor-positive (HR+ve) patients (Masuda, European Journal of Cancer, 2022). However, survival benefit and its mode of action of E7389-LF remains unclear, although E7389-LF seems more effective than Eribulin in clinic. Methods: PDX#1 is a breast cancer patient-derived xenograft (PDX) from a patient with triple negative breast cancer who later received Eribulin for 7 cycles until progression in lung metastases. PDX#2 is also a breast cancer PDX from paclitaxel-resistant HR+ve/HER2-ve breast cancer, respectively. These two PDXs were provided by the National Cancer Center J-PDX library, Japan, and were bred in NOD/Shi-scid, IL-2Rγnull (NOG) mice and observed until the onset of a mammary tumor approximately 180 and 240 mm3 in volume (Day 0). PDX tumors were randomized and monitored with tumor growth measurements. Each group received either saline, 0.34mg/kg, or 0.67 mg/kg (clinically relevant dose of E7389-LF, estimated) of Eribulin or E7389-LF at Day 0 and 7 (Experiment 1). For short-term experiments, 9 PDX#1 or 12 PDX#2 tumors were removed one week after an injection of saline, 0.67 mg/kg of Eribulin, or 0.67 mg/kg of E7389-LF (n=3/group for PDX#1, n=4/group for PDX#2), and tumors were immunohistochemically stained with anti-CD31 antibody, an endothelial cell marker, to investigate microvessel density and RNA sequencing was additionally performed (Experiment 2). Results: Table 1 summarizes the results. In Experiment 1, both E7389-LF and Eribulin showed significant antitumor activity compared with saline in a dose-dependent manner with respect to tumor growth inhibition and survival benefit, extension of tumor doubling time (earlier day with relative tumor volume >200%), in PDX#1 and #2. Tumor shrinkage was seen in PDX#1, and E7389-LF at 0.34 mg/kg, or 0.67 mg/kg were more potent than the same doses of Eribulin at Day 21 in both PDXs (p < 0.05). E7389-LF at 0.67 mg/kg also showed relative tumor growth inhibition compared with the same dose of Eribulin in PDX#2 (p < 0.05). As for survival, PDX#1 with E7389-LF at 0.67 mg/kg demonstrated significantly longer survival (p=0.03) than Eribulin at 0.67 mg/kg, while PDX#2 with E7389-LF at 0.67 mg/kg did not (p=0.10). In Experiment 2, microvessel density increased in PDX#1 after receiving eribulin and E7389-LF compared with untreated ones, with a significant difference for E7389-LF (p=0.006), and showed an increasing tendency over Eribulin (p=0.06), while microvessel density in PDX#2 did not differ between groups. Conclusions: Pre-clinical data demonstrates that E7389-LF is more potent than the same dose of Eribulin in patient-derived breast cancer xenografts. Survival benefit was observed in a PDX with a tumor shrinkage and an increase in microvessel density. Table 1. Summary of the findings. p Citation Format: Maki Tanioka, Taro Semba, Tatsunori Shimoi, Yuki Niwa, Kan Yonemori. Anti-tumor activity of a liposomal formulation of Eribulin compared with the same dose of Eribulin in patient-derived breast cancer xenografts [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-03. |
