PG545, a heparan sulfate mimetic, reduces heparanase expression in vivo, blocks spontaneous metastases and enhances overall survival in the 4T1 breast carcinoma model.

PG545 is a clinically relevant heparan sulfate (HS) mimetic which, in addition to possessing anti-angiogenic properties, also acts as a heparanase inhibitor which may differentiate its mechanism(s) of action from approved angiogenesis inhibitors. The degradation of HS by heparanase has been strongly implicated in cell dissemination and the metastatic process. Thus, the anti-metastatic activity of PG545 has been linked to the enzymatic function of heparanase – the only endoglycosidase known to cleave HS, an important component of the extracellular matrix (ECM) which represents a potential avenue for therapeutic intervention for certain metastatic cancer indications. Recent concerns raised about the paucity of overall survival as an endpoint in mouse models of clinically relevant metastasis led us to examine the effect of PG545 on the progression of both primary tumor growth and the spontaneously metastasizing disease in the 4T1 syngeneic breast carcinoma model in a non-surgical and surgical (mastectomy) setting. PG545 significantly inhibited primary tumor growth but importantly also inhibited lung metastasis in treated mice, an effect not observed with the tyrosine kinase inhibitor sorafenib. Importantly, PG545 significantly enhanced overall survival compared to vehicle control and the sorafenib group, suggesting PG545’s inhibitory effect on heparanase is indeed a critical attribute to induce anti-metastatic activity. In addition to blocking a common angiogenic signalling pathway in tumor cells, the expression of heparanase in the primary tumor and lung was also significantly reduced by PG545 treatment. These results support the ongoing development of PG545 and highlight the potential utility in metastatic disease settings.

[1]  Gang Wang,et al.  Mutual enhancement between heparanase and vascular endothelial growth factor: a novel mechanism for melanoma progression. , 2011, Cancer letters.

[2]  A. Jemal,et al.  Cancer statistics, 2011 , 2011, CA: a cancer journal for clinicians.

[3]  C. L. Chu,et al.  M402, a Novel Heparan Sulfate Mimetic, Targets Multiple Pathways Implicated in Tumor Progression and Metastasis , 2011, PloS one.

[4]  G. Sledge,et al.  Rethinking the metastatic cascade as a therapeutic target , 2011, Nature Reviews Clinical Oncology.

[5]  P. Carmeliet,et al.  Antiangiogenic therapy, hypoxia, and metastasis: risky liaisons, or not? , 2011, Nature Reviews Clinical Oncology.

[6]  Jiannis Ragoussis,et al.  Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization , 2011, Nature Medicine.

[7]  L. Borsig,et al.  Sulfated hexasaccharides attenuate metastasis by inhibition of P-selectin and heparanase. , 2011, Neoplasia.

[8]  Robert S. Kerbel,et al.  Antiangiogenic therapy: impact on invasion, disease progression, and metastasis , 2011, Nature Reviews Clinical Oncology.

[9]  T. Gonda,et al.  PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models , 2011, British Journal of Cancer.

[10]  P. Gunaratne,et al.  MicroRNA-1258 suppresses breast cancer brain metastasis by targeting heparanase. , 2011, Cancer research.

[11]  F. Zunino,et al.  SST0001, a Chemically Modified Heparin, Inhibits Myeloma Growth and Angiogenesis via Disruption of the Heparanase/Syndecan-1 Axis , 2011, Clinical Cancer Research.

[12]  Neha S. Gandhi,et al.  Heparin/heparan sulphate-based drugs. , 2010, Drug discovery today.

[13]  R. Sanderson,et al.  Proteoglycans in health and disease: new concepts for heparanase function in tumor progression and metastasis , 2010, The FEBS journal.

[14]  T. Gonda,et al.  The PG500 series: novel heparan sulfate mimetics as potent angiogenesis and heparanase inhibitors for cancer therapy , 2010, Investigational New Drugs.

[15]  A. Balmain,et al.  Guidelines for the welfare and use of animals in cancer research , 2010, British Journal of Cancer.

[16]  J. Sleeman,et al.  Cancer metastasis as a therapeutic target. , 2010, European journal of cancer.

[17]  Y. Hitoshi,et al.  R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. , 2010, Cancer research.

[18]  R. Kerbel,et al.  Tumor and Host-Mediated Pathways of Resistance and Disease Progression in Response to Antiangiogenic Therapy , 2009, Clinical Cancer Research.

[19]  K. Hunter,et al.  Preclinical Drug Development Must Consider the Impact on Metastasis , 2009, Clinical Cancer Research.

[20]  Qin Chen,et al.  Marine-derived oligosaccharide sulfate (JG3) suppresses heparanase-driven cell adhesion events in heparanase over-expressing CHO-K1 cells , 2009, Acta Pharmacologica Sinica.

[21]  Bob van de Water,et al.  An improved model to study tumor cell autonomous metastasis programs using MTLn3 cells and the Rag2−/− γc−/− mouse , 2009, Clinical & Experimental Metastasis.

[22]  L. Jeng,et al.  Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety and optimal dosage. , 2009, Journal of hepatology.

[23]  Masahiro Inoue,et al.  Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. , 2009, Cancer cell.

[24]  John M L Ebos,et al.  Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. , 2009, Cancer cell.

[25]  Stephen E. Jones.  Metastatic breast cancer: the treatment challenge. , 2008, Clinical breast cancer.

[26]  D. Sargent,et al.  Assessing the measure of a new drug: is survival the only thing that matters? , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  I. Vlodavsky,et al.  Heparanase induces Akt phosphorylation via a lipid raft receptor. , 2007, Biochemical and biophysical research communications.

[28]  L. Martins,et al.  Heparanase expression in circulating lymphocytes of breast cancer patients depends on the presence of the primary tumor and/or systemic metastasis. , 2007, Neoplasia.

[29]  E. Mckenzie,et al.  Heparanase: a target for drug discovery in cancer and inflammation , 2007, British journal of pharmacology.

[30]  M. Götte,et al.  Heparanase, hyaluronan, and CD44 in cancers: a breast carcinoma perspective. , 2006, Cancer research.

[31]  R. Sasisekharan,et al.  The Impact of Heparanese and Heparin on Cancer Metastasis and Angiogenesis , 2006, Pathophysiology of Haemostasis and Thrombosis.

[32]  T. Peretz,et al.  Heparanase promotes growth, angiogenesis and survival of primary breast tumors , 2006, International journal of cancer.

[33]  I. Vlodavsky,et al.  Heparanase induces vascular endothelial growth factor expression: correlation with p38 phosphorylation levels and Src activation. , 2006, Cancer research.

[34]  M. Nakajima,et al.  COX-2 induction by heparanase in the progression of breast cancer. , 2006, International journal of molecular medicine.

[35]  L. Khachigian,et al.  Early Growth Response Gene 1 (EGR1) Regulates Heparanase Gene Transcription in Tumor Cells* , 2005, Journal of Biological Chemistry.

[36]  J. O’Shaughnessy.  Extending survival with chemotherapy in metastatic breast cancer. , 2005, The oncologist.

[37]  P. Gattuso,et al.  Ductal carcinoma in situ of the breast and heparanase-1 expression: a molecular explanation for more aggressive subtypes. , 2005, Journal of the American College of Surgeons.

[38]  L. Khachigian,et al.  Regulation of Inducible Heparanase Gene Transcription in Activated T Cells by Early Growth Response 1* , 2003, Journal of Biological Chemistry.

[39]  P. Gattuso,et al.  Heparanase-1 expression is associated with the metastatic potential of breast cancer. , 2002, Surgery.

[40]  I. Pecker,et al.  The FASEB Journal express article 10.1096/fj.00-0895fje. Published online May 29, 2001. , 2022 .

[41]  J. Platt,et al.  Heparanase, a potential regulator of cell-matrix interactions. , 2000, Trends in biochemical sciences.

[42]  T. Martin,et al.  A novel orthotopic model of breast cancer metastasis to bone , 1999, Clinical & Experimental Metastasis.

[43]  T. Tsuruo,et al.  Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer. , 1996, Cancer research.

[44]  Chi-Ping Day,et al.  Preclinical therapeutic response of residual metastatic disease is distinct from its primary tumor of origin , 2012, International journal of cancer.

[45]  J. Mackey,et al.  In the end what matters most? A review of clinical endpoints in advanced breast cancer. , 2011, The oncologist.

[46]  Karthik Raman,et al.  Chemical Tumor Biology of Heparan Sulfate Proteoglycans. , 2010, Current chemical biology.

[47]  Matthew J Hayat,et al.  Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. , 2007, The oncologist.

[48]  Vito Ferro,et al.  Heparanase as a Target for Anticancer Therapeutics: New Developments and Future Prospects , 2006 .

[49]  G. Hortobagyi,et al.  Neoplasms of the Breast , 2003 .

[50]  Research Paper Mediators of Inflammation, 10, 259–267 (2001) , 2022 .