Procyon's Anti-metastatic agent
Procyon Biopharma from Montreal, Canada, has reported further results on the mechanism of action of PCK3145, the company's lead Phase II compound for the treatment of metastatic hormone-refractory prostate cancer (HRPC).
Procyon Biopharma from Montreal, Canada, has reported further results on the mechanism of action of PCK3145, the company's lead Phase II compound for the treatment of metastatic hormone-refractory prostate cancer (HRPC).
The latest research work on the mechanism of action of PCK3145 was conducted under the supervision of Dr. Richard Beliveau, director, Laboratory of Molecular Medicine, Hopital Sainte-Justine and Universite du Quebec àMontreal in collaboration with Procyon.
The new findings indicate that PCK3145 interferes with Vascular Endothelial Growth Factor (VEGF) signaling pathway which is critical to angiogenesis and subsequent metastasis. 'In light of the positive Phase IIa data on PCK3145 in metastatic HRPC and the scientific literature suggesting the utility of plasma levels of MMP-9 as a prognostic marker for other types of cancers such as for breast, colon, lung and ovarian cancers, we needed to further understand the mechanism of action of PCK3145,' said Hans Maeder, president and ceo of Procyon. 'While further research is ongoing, the confirmation of a VEGF receptor associated cell signaling induced by PCK3145 is clinically very important as it establishes a targeted "hit-and-run" mode of action for the peptide,' he added.
Angiogenesis, the formation of new blood vessels, is an integral part of normal physiological and developmental processes as well as several pathologies, ranging from tumour growth and metastasis to inflammation and ocular diseases. Under normal physiological conditions, humans or animals only undergo angiogenesis in very specific restricted situations. However, persistent, unregulated angiogenesis occurs in a multiplicity of disease states. The control of angiogenesis has been found to be altered in certain disease states and, in many cases, the pathological damage associated with the disease is related to the uncontrolled angiogenesis. Angiogenesis is prominent in solid tumour formation and metastasis. A primary tumour cannot expand without a blood supply to provide nutrients. Therefore, inhibition of angiogenesis could lead to the reduction of tumor growth and metastasis.
PCK3145 has been previously shown to potentially inhibit cancer cell growth and metastasis. Dr Beliveau's team and Procyon's scientitists have now found that PCK3145 specifically antagonised in a dose-dependent manner the VEGF-induced Extracellular signal-Regulated Kinase (ERK) phosphorylation as well as phosphorylation of the VEGFR-2 in Human Umbilical Vein Endothelial Cells (HUVECs). These anti-VEGF effects of PCK3145 suggest that PCK3145 inhibits intracellular signaling through the Mitogen-Activated Protein Kinase (MAPK) cascade. These data indicate that PCK3145 acts through cell signaling pathways such as VEGF signaling axis in endothelial cells. Further work is underway to identify additional signaling pathways as well as to identify the receptor for PCK3145. The company expects to report these data soon.
'The antiangiogenic properties of this peptide could be highly beneficial as a novel therapy for patients with various cancers,' said Dr Richard Beliveau, director, Laboratory of Molecular Medicine, Hopital Sainte-Justine and Universite du Quebec àMontreal. 'These findings are certainly very encouraging in pursuing the PCK3145 development and helping us focusing on the evaluation of angiogenic tumor markers in Procyon's preclinical and clinical program,' he added.
About PCK3145
PCK3145 is a synthetic 15-mer peptide based on the sequence of the native PSP94, a naturally occurring protein synthesised primarily in the prostate and found in large quantities in the seminal fluid. A multiple ascending dose, open-label, Phase IIa study showed that PCK3145 is safe and was well-tolerated at all dose levels tested. Moreover, the Phase IIa trial confirmed the potential modulating effect of PCK3145 on the levels of MMP-9 - matrix metalloproteinase-9 - a gelatinase B enzyme involved in extracellular matrix degradation and tumour invasion (metastasis). A substantial reduction in MMP-9 level was observed in all patients with elevated MMP-9 levels at baseline. In patients with normal baseline MMP-9 levels, no change was observed after the first cycle. The Company is currently in the midst of filing an Investigational New Drug (IND) dossier with the Food and Drug Administration (FDA) in order to initiate a North American Phase IIb trial next year to demontrate efficacy in man.