Heparanase inhibitors restrain mesothelioma

Abstract

Malignant mesothelioma is a highly aggressive form of cancer with poor prognosis due to lack of markers for early diagnosis and resistance to conventional therapies. Heparanase, the sole heparan sulfate (HS) degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, metastasis, angiogenesis, and inflammation. Heparanase accomplishes this by degrading HS and thereby facilitating cell invasion and regulating the bioavailability of heparin-binding proteins. Applying pre-clinical and clinical models of human mesothelioma and potent inhibitors of heparanase enzymatic activity (PG545, Defibrotide) we investigated the significance of heparanase in the pathogenesis of mesothelioma. We found that mesothelioma tumor growth was markedly attenuated by heparanase gene silencing and by heparanase inhibitors. Furthermore, heparanase inhibitors were more potent in vivo than conventional chemotherapy. Clinically, heparanase levels in patients' pleural effusions could distinguish between malignant and benign effusions, and heparanase H-score (immunostaining of tumor specimens) above 90 was associated with reduced patient survival. These results strongly imply that heparanase plays an important role in mesothelioma tumor progression, thus encouraging the use of heparanase inhibitors in combination with existing drugs as a new therapeutic modality in mesothelioma clinical trials.

Keywords: PG545; defibrotide; heparanase; mesothelioma; therapies.

Figure 1. Heparanase a valid target in the pathogenesis of mesothelioma

A. Tumor growth. Luciferase-labeled MSTO-211H human mesothelioma cells (2×10⁶) were inoculated i.p into SCID mice. Mice were treated with PG545 (400 mg/mouse; once a week), cisplatin (once/2 weeks; 3 mg/kg), or control vehicle (PBS) and tumor development was inspected by IVIS. Quantification of the luciferase intensities is shown graphically in the lower right panel. B. Survival. The effect of PG545 and cisplatin on the survival of mice is plotted as Kaplan–Meier curves. Note that PG545 is significantly more effective than cisplatin in inhibiting orthotopic mesothelioma tumor growth and prolonged survival of the mice. C. Defibrotide. Luciferase-labeled MSTO-211H human mesothelioma cells (0.5×10⁶) were inoculated i.p into SCID mice. Mice were treated with defibrotide (8 mg/mouse; twice a day), PG545 (400 mg/mouse; once a week) or control vehicle (PBS) and tumor development was inspected by IVIS over time. D. Kaplan–Meier survival analysis of patients according to their heparanase staining intensities. Mesothelioma patients endowed with strong heparanase staining survive less than patients that are found negative for heparanase (p = 0.04 for strong vs. negative).