Heparanase inhibitors restrain mesothelioma
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Moshe Lapidot1, Uri Barash1, Israel Vlodavsky1 and Harvey Pass2
1 Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel
2 Department of Cardiothoracic Surgery, Langone Medical Center, New York University School of Medicine, New York, USA
Moshe Lapidot, email: email@example.com
Keywords: mesothelioma; heparanase; PG545; defibrotide; therapies
Received: September 20, 2018 Accepted: October 06, 2018 Published: December 07, 2018
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.
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