Abstract 5353: Efficacy of an innovative, enzyme-activated doxorubicin prodrug in patient-derived dedifferentiated liposarcoma and synovial sarcoma xenograft models

Abstract

Abstract Background and objective: Dedifferentiated liposarcoma (DDLPS) and synovial sarcoma (SynSa) are aggressive malignant tumors of mesenchymal origin. Prognosis of advanced disease is poor with low response rates to first-line single agent doxorubicin (doxo) treatment, which is regarded as standard of care in metastatic disease. We evaluated the efficacy of PhAc-ALGP-doxorubicin (ALGP-doxo), a prodrug which is metabolized to doxo by peptidases present in the tumor microenvironment and/or tumor cells, in one SynSa and two DDLPS patient-derived xenografts. Methods: NMRI mice (n = 24) were transplanted subcutaneously on both flanks with human DDLPS (models UZLX-STS3 and UZLX-STS5) or SynSa (UZLX-STS7). Mice were randomized to three treatment groups: control (vehicle), doxo (0.03 mmol/kg for UZLX-STS3; 0.04 mmol/kg for UZLX-STS5 and UZLX-STS7) or ALGP-doxo (1.2 mmol/kg). Treatments were administered using intraperitoneal osmotic pumps, continuously releasing drugs for 7 days. Afterwards, half of mice from each group were sacrificed and tumors were collected. Remaining mice were monitored for another 14 days and tumors were collected on day 21. Treatment efficacy was assessed by tumor volume, hematoxylin and eosin (H&E) staining, immunohistochemistry for proliferation [phospho-histone H3 (pHH3), Ki-67] and apoptosis [cleaved caspase 3 (CC3)] and by Western blotting (WB). Statistical analysis was performed with Wilcoxon and Mann-Withney U-test, defining p<0.05 as statistically significant. Results: While the tumor volume in the control and doxo group increased steadily, in UZLX-STS3 and UZLX-STS5 ALGP-doxo caused tumor volume stabilization. Moreover, in UZLX-STS7 the average relative tumor volume decreased to 60.1% on day 7 and to 4.6% on day 21 under ALGP-doxo treatment. Long-lasting therapeutic effects of ALGP-doxo even after treatment withdrawal were observed in all three models tested. Compared to the control and doxo group, ALGP-doxo induced a significant decrease in proliferation and a significant increase in apoptotic activity on day 7 in all three models. It was also observed on day 21 in UZLX-STS3 and UZLX-STS5, while in UZLX-STS7 tumor tissue was replaced by fibroblasts. WB with tumor samples collected on day 7 showed expression of cleaved PARP in ALGP-doxo treated samples of UZLX-STS7, but not in the control or doxo group, and decreased pHH3 levels in the ALGP-doxo treated tumors of UZLX-STS5 and UZLX-STS7. Conclusion: ALGP-doxo shows considerably higher anti-tumor activity than doxo in patient-derived DDLPS and SynSa xenografts. The delivery of a 30-40 fold higher dose of ALGP-doxo than doxo is tolerated without significant side effects, while comparable dose of doxo is lethal. The prodrug and its activation by the tumor or the microenvironment warrants further testing in anthracycline-sensitive and -resistant preclinical models of human malignancies. Citation Format: Jasmien Cornillie, Agnieszka Wozniak, Lise Vreys, Haifu Li, Thomas Van Looy, Jasmien Wellens, Ulla Vanleeuw, André Trouet, Peter Pokreisz, Daphne Hompes, Maria Debiec-Rychter, Raf Sciot, Patrick Schöffski. Efficacy of an innovative, enzyme-activated doxorubicin prodrug in patient-derived dedifferentiated liposarcoma and synovial sarcoma xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5353. doi:10.1158/1538-7445.AM2015-5353