Periodic Reporting for period 1 - HEPARANIB (Small molecule heparanase inhibitors as anti-metastatic cancer drugs)
Berichtszeitraum: 2023-06-01 bis 2024-11-30
One of the major challenges in oncology today is the persistent growth and spread of cancer, even when diagnosed and treated early. Compounding this problem is cancer’s ability to adapt and develop resistance to treatment. As a result, primary therapies, often developed at great cost and effort, become less effective than intended. This often leads to unresectable tumors and metastatic disease, reducing treatment options and patient outcomes.
A key mechanism enabling this resilience is the overexpression of heparanase, an enzyme that degrades the extracellular matrix (ECM). This degradation releases growth factors and signaling molecules, triggering cascades that drive cancer cell proliferation, invasion, and metastasis. Moreover, heparanase overexpression is linked to the development of drug resistance, further complicating treatment.
Targeting heparanase offers a promising therapeutic strategy. Inhibiting this enzyme restores the integrity of the ECM, disrupting the tumor microenvironment and resulting in reduced tumor growth, metastasis, and angiogenesis. This underscores the enzyme’s central role in cancer progression and highlights the potential of heparanase inhibitors as effective anticancer therapeutics.
To address this need, researchers at Leiden University have developed a proprietary library of rationally designed heparanase inhibitors. These compounds are based on the enzyme’s natural substrate, heparan sulfate, and are designed to covalently bind to its active site, causing irreversible inhibition. Among these, the lead compound VL166 has demonstrated significant efficacy in reducing cancer aggression in preclinical in vivo murine models.
A key mechanism enabling this resilience is the overexpression of heparanase, an enzyme that degrades the extracellular matrix (ECM). This degradation releases growth factors and signaling molecules, triggering cascades that drive cancer cell proliferation, invasion, and metastasis. Moreover, heparanase overexpression is linked to the development of drug resistance, further complicating treatment.
Targeting heparanase offers a promising therapeutic strategy. Inhibiting this enzyme restores the integrity of the ECM, disrupting the tumor microenvironment and resulting in reduced tumor growth, metastasis, and angiogenesis. This underscores the enzyme’s central role in cancer progression and highlights the potential of heparanase inhibitors as effective anticancer therapeutics.
To address this need, researchers at Leiden University have developed a proprietary library of rationally designed heparanase inhibitors. These compounds are based on the enzyme’s natural substrate, heparan sulfate, and are designed to covalently bind to its active site, causing irreversible inhibition. Among these, the lead compound VL166 has demonstrated significant efficacy in reducing cancer aggression in preclinical in vivo murine models.
To strengthen our science case and by building on our in vivo data in mouse models for metastatic breast cancer, lung cancer and multiple myeloma, we have designed a suitable route of synthesis to prepare sufficient quantities of clinical grade material; synthesized reference compounds; and performed initial ADME studies. The outcomes of these studies will be kept confidential until all necessary IP is protected.
Even with an early diagnosis and good treatment options available, cancer continues to grow, spread and resist treatment. Treatments that are initially effective, become less effective over time eventually leading to unresectable tumors and metastasized cancer. Heparanase inhibitors could provide a novel solution to this problem. Inhibition of heparanase reduces growth, metastasis and drug-resistance. Combining these inhibitors with first-line treatments could lead to overall better outcomes, i.e. more cancer free patients. Furthermore, since the overexpression of heparanase is shared by the majority (~90%) of cancers, inhibition of heparanase could become a general anti-cancer tool widely used.
To achieve such an impact additional funding will be needed to further develop these inhibitors.
To achieve such an impact additional funding will be needed to further develop these inhibitors.