Heparanase inhibitors restrain mesothelioma

Our plain-English summary of Heparanase inhibitors restrain mesothelioma, by M. Lapidot, U. Barash, I. Vlodavsky, et al (Oncotarget, 2018).

The study

• Authors: M. Lapidot, U. Barash, I. Vlodavsky, H. Pass
• Journal: Oncotarget
• Published: 2018;9(96):36830-36832
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This short article is a 'Research Perspective' in which the authors summarized their own earlier study, published in 2018 in the Journal of the National Cancer Institute (Barash, Lapidot and colleagues). It gave no new methods or patient numbers. Heparanase is an enzyme that breaks down heparan sulfate, part of the material surrounding cells. In the mouse experiments, human mesothelioma cells (the MSTO-211H line) were injected into the abdomen of immune-deficient mice. Tumor growth was reported to be markedly reduced by the heparanase-blocking drugs PG545 and defibrotide, by silencing the heparanase gene, and in mice lacking heparanase. PG545 was described as significantly more effective than the chemotherapy drug cisplatin at slowing tumor growth and prolonging the mice's survival. In patients, those whose tumors stained strongly for heparanase survived less than those whose tumors were negative (p = 0.04), and a heparanase H-score above 90 was associated with reduced survival. Heparanase levels in plasma or effusion samples were reported to sort samples as malignant or benign. The authors concluded that heparanase inhibitors should be examined in mesothelioma clinical trials, and wrote that further studies are needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Research perspective (short commentary) summarizing the authors' previously published study, which used mouse experiments and patient tumor and fluid samples
• Who was studied: In the summarized study: immune-deficient (SCID) mice injected in the abdomen with MSTO-211H human mesothelioma cells, and mesothelioma patients whose tumors were stained for heparanase. No patient numbers, locations or dates are given.
• Exposure: Not an asbestos exposure study. Treatments tested were the heparanase inhibitors PG545 (pixatimod) and defibrotide, compared with the chemotherapy drug cisplatin or a control (PBS), plus heparanase gene silencing and heparanase-null mice.
• Main results:
  • In mice, mesothelioma tumor growth was markedly reduced by heparanase-inhibiting compounds, by heparanase gene silencing, and when tumor cells were injected into heparanase-null mice
  • In mice, PG545 was significantly more effective than cisplatin at inhibiting tumor growth and prolonging survival
  • In mice, defibrotide showed similar potency
  • Mesothelioma patients with strong heparanase tumor staining survived less than patients whose tumors were negative for heparanase (p = 0.04, strong vs. negative)
  • In patients, a heparanase H-score above 90 (from immunostaining of tumor specimens) was associated with reduced survival
  • Heparanase levels measured by ELISA were reported to categorize plasma or effusion samples as malignant or benign
• The authors' conclusion: The authors concluded that heparanase appears to be a master regulator of the aggressive behavior of malignant mesothelioma and a prime target for therapy, encouraging clinical testing of heparanase inhibitors
• Limitations the authors state:
  • The authors state that further studies are needed

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Prognosis, Metastasis, Angiogenesis, Inflammation, Chemotherapy, Pleural Effusion, Clinical Trial.

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