A New Synthesized Dicarboxylated Oxy-Heparin Efficiently Attenuates Tumor Growth and Metastasis

Our plain-English summary of A New Synthesized Dicarboxylated Oxy-Heparin Efficiently Attenuates Tumor Growth and Metastasis, by L. Li, U. Barash, N. Ilan, et al (Cells, 2024).

The study

• Authors: L. Li, U. Barash, N. Ilan, M. Farhoud, X. Zhang, I. Vlodavsky, J.P. Li
• Journal: Cells
• Published: 2024;13(3)
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Heparanase (Hpa1) is expressed by tumor cells and cells of the tumor microenvironment and functions to remodel the extracellular matrix (ECM) and regulate the bioavailability of ECM-bound factors that support tumor growth. Heparanase expression is upregulated in human carcinomas, sarcomas, and hematological malignancies, correlating with increased tumor metastasis, vascular density, and shorter postoperative survival of cancer patients, and encouraging the development of heparanase inhibitors as anti-cancer drugs. Among these are heparin/HS mimetics, the only heparanase-inhibiting compounds that are being evaluated in clinical trials. We have synthesized dicarboxylated oxy-heparins (DCoxHs) containing three carboxylate groups per split residue (DC-Hep). The resulting lead compound (termed XII) was upscaled, characterized, and examined for its effectiveness in tumor models. Potent anti-tumorigenic effects were obtained in models of pancreatic carcinoma, breast cancer, mesothelioma, and myeloma, yielding tumor growth inhibition (TGI) values ranging from 21 to 70% and extending the survival time of the mice. Of particular significance was the inhibition of spontaneous metastasis in an orthotopic model of breast carcinoma following resection of the primary tumor. It appears that apart from inhibition of heparanase enzymatic activity, compound XII reduces the levels of heparanase protein and inhibits its cellular uptake and activation. Heparanase-dependent and -independent effects of XII are being investigated. Collectively, our pre-clinical studies with compound XII strongly justify its examination in cancer patients.

In plain English

This was a laboratory and animal study, not of asbestos exposure or of people. The authors made a modified heparin, compound XII, designed to block heparanase, an enzyme linked to tumor growth. In test-tube assays it blocked the enzyme. They gave it daily (20 to 160 mg/kg) to mice with pancreatic, breast, mesothelioma or myeloma tumors. In mice injected in the abdomen with human mesothelioma cells (6 to 7 per group), compound XII and the chemotherapy drug cisplatin each reduced imaged tumor growth by a comparable 60 to 80%, though cisplatin had no effect at the first measurement. Median survival was 65 days with compound XII and 71 days with cisplatin, versus 48 days in untreated mice. In a mouse breast cancer model, lung spread after primary tumor removal was nearly completely blocked. Compound XII did not work in one pancreatic tumor model (PA1644). The authors concluded the results support a first human safety trial. They cautioned that isogenic mice lack human cancers' genetic diversity, and that mouse tumor environment, immunity and metabolism differ from those of humans, affecting drug response.

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: Preclinical laboratory and animal experiments: enzyme assays, mouse tumor models, and rat studies of blood levels and clotting
• Who was studied: Mice bearing human or mouse tumors: pancreatic, breast, mesothelioma (human MSTO-211H cells, 2 million injected intraperitoneally into NOD/SCID mice, 6 to 7 per group) and myeloma. Groups were usually 6 to 10 mice. Sprague-Dawley rats were also used for pharmacokinetic and coagulation tests.
• Exposure: No asbestos exposure was studied. The treatment was compound XII, a dicarboxylated oxy-heparin heparanase inhibitor, given daily at 20 to 160 mg/kg. It was compared with vehicle and, in some experiments, with gemcitabine, docetaxel, paclitaxel or cisplatin.
• Main results:
  • Mesothelioma mice: compound XII or cisplatin alone gave a comparable 60 to 80% inhibition of tumor growth by imaging signal. Cisplatin showed no effect on Day 10.
  • Mesothelioma mice: median survival was 65 days with compound XII versus 48 days in untreated mice (p = 0.0264).
  • Mesothelioma mice: median survival was 71 days with cisplatin versus 48 days in untreated mice (p = 0.017).
  • Mia PaCa-2 pancreatic tumor mice: tumor growth was inhibited 21% at 20 mg/kg of compound XII.
  • PA1233 pancreatic patient-derived tumor model: tumor growth inhibition was 39.68% with 80 mg/kg of compound XII.
  • Compound XII was not effective in the PA1644 pancreatic tumor model.
  • 4T1 breast cancer mice: compound XII reduced primary tumor weight by about 30% (p = 0.009).
  • 4T1 breast cancer mice: after the primary tumor was removed, lung metastasis was nearly completely inhibited with compound XII.
  • 4T1 breast cancer survival model: median survival was 44 to 49 days with compound XII versus 38.5 days with vehicle.
  • Mia PaCa-2 tumors: compound XII at 20 mg/kg/day produced a 50% decrease in heparanase protein.
  • Rats: compound XII caused a dose-dependent prolongation of aPTT, a clotting time, without obvious bleeding.
• The authors' conclusion: The authors concluded that their results provide a strong rationale for a phase I clinical trial of compound XII's safety and maximal tolerated dose in cancers including mesothelioma, myeloma, breast carcinoma and pancreatic carcinoma.
• Limitations the authors state:
  • Isogenic mice have limited genetic diversity and do not represent the genetic variety of human cancers.
  • The tumor microenvironment, immune system and metabolism of mice differ significantly from those of humans, which affects how a tumor responds to a drug.
  • The anti-tumor effects cannot be attributed solely to heparanase inhibition, because the compound likely binds other proteins.

Topics

Medical terms in this study, explained in our Lexicon: Metastasis, Tumor Microenvironment, Carcinoma, Sarcoma, Clinical Trial, Mesothelioma, Myeloma.

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