Safety and Tolerability of PCK3145, a Synthetic Peptide Derived from Prostate Secretory Protein 94 (PSP94) in Metastatic Hormone-Refractory Prostate Cancer

Hawkins, Robert E.; Daigneault, Luc; Cowan, Richard; Griffiths, Richard W.; Panchal, Chandra J.; Armstrong, Anne; Fenemore, Jackie; Irvine, A. H.; Sereda, Kasia; Dulude, Hélène

doi:10.3816/cgc.2005.n.016

Cited by 14 publications

(10 citation statements)

References 24 publications

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“…22 ABT-510 (modified peptide derived from the TSR domain of angiogenesis inhibitor protein thrombospondin-1) and PCK3145 (antiangiogenic peptide derived from the prostate secretary protein) are peptide based drugs that are in Phase II clinical trials. [23][24][25][26] Our observations show that the GAGE positive tumor cell lines are more sensitive to the lethal effects of peptide#1, however GAGE-null cell lines are resistant to the cell killing induced by peptide#1 at lower doses. This feature of the peptide could be very important for targeting GAGE expressing tumor cells for cell death.…”

Section: Methodsmentioning

confidence: 62%

Rational drug design: A GAGE derived peptide kills tumor cells

Kular

Yehiely²,

Deiss

2010

Cancer Biology & Therapy

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Section: Methodsmentioning

confidence: 62%

Rational drug design: A GAGE derived peptide kills tumor cells

Kular

Yehiely²,

Deiss

2010

Cancer Biology & Therapy

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“…In fact, the recently conducted phase IIa dose escalating clinical trial demonstrated that PCK3145 was safe and well tolerated in all doses (from 5 to 80 mg/m 2 ) in patients with metastatic HRPC. A downregulation in levels of circulating plasma MMP-9 ranging from 34 to 90% in patients having an elevated level of MMP-9 (above 100 lg/l) at study entry was also observed after the treatment with PCK3145 [6,7]. This in vivo PCK3145 activity suggests a biological effect possibly related to the control of MMP-9 mediated metastasis and prompted us to further explore the PCK3145 mechanism of action.…”

Section: Discussionmentioning

confidence: 73%

“…In the recent phase IIa clinical trial in HRPC, PCK3145 was shown to reduce the levels of circulating MMP-9 plasma levels ranging from 34 to 90% in patients having elevated level of MMP-9 (above 100 lg/l) at study entry [6,7]. In order to investigate the effect of PCK3145 on MMP-9 secretion in vitro, we treated serum-starved HT-1080 fibrosarcoma cells with increasing doses of PCK3145 for 24 and 48 h. Doses of PCK3145 were found not to be cytotoxic as assessed by the measurement of the pro-apoptotic caspase-3 activity (not shown).…”

Section: Pck3145 Inhibits Mmp-9 Secretion From Ht-1080 Cellsmentioning

confidence: 99%

“…In previous studies using the Dunning rat R-3327 MLL xenograft model, we have shown that PSP94 can reduce experimental skeletal metastases and prostate cancer growth in vivo [4], and that the amino acid 31-45 region of PSP94 (PCK3145) was sufficient to elicit PSP94-mediated anti-tumor effects [5]. More recently, a phase IIa clinical trial indicated that PCK3145 down-regulated the levels of plasma matrix metalloproteinase (MMP)-9 in patients with HRPC that had elevated levels (>100 lg/l) at baseline, while those with levels below 100 lg/l remained low [6,7]. Such efficacy in reducing the levels of plasma MMP-9 in patients receiving PCK3145 suggests a biological effect possibly targeting the control of tumor-related ECM degradation and metastasis processes.…”

Section: Introductionmentioning

confidence: 99%

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A PSP94-derived Peptide PCK3145 inhibits MMP-9 Secretion and Triggers CD44 Cell Surface Shedding: Implication in Tumor Metastasis

Annabi

Bouzeghrane

Currie

et al. 2005

Clin Exp Metastasis

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Our data suggest that PCK3145 may antagonize tumor cell metastatic processes by inhibiting both MMP-9 secretion and its potential binding to its cell surface docking receptor CD44. Such mechanism may involve RhoA signaling and increase in MT1-MMP-mediated CD44 shedding. Together with its beneficial effects in clinical trials, this is the first demonstration of PCK3145 acting as a MMP secretion inhibitor.

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“…It inhibits tumour angiogenesis by suppressing VEGF signalling and inhibits tumour metastasis by repressing MMP-9 secretion [131][132][133]. It was safe and well tolerated at all doses tested.…”

Section: Antiangiogenic Peptides In Clinical Trialsmentioning

confidence: 93%

Developing Antiangiogenic Peptide Drugs for Angiogenesis-Related Diseases

Sulochana

Ge²

2007

CPD

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Angiogenesis is regulated by stimulators and inhibitors and involve multiple biological processes including endothelial cell proliferation, migration, cell-cell and cell-matrix adhesion, assembly into tube structures as well as apoptosis. Designing and developing peptides for therapeutic application to inhibit angiogenesis is an important area in antiangiogenic drug development. Small peptides have advantages over proteins for therapeutic application, due to their stability, solubility, increased bio-availability and lack of immune response in the host cell. Endogenous protein angiogenesis stimulators and inhibitors hold vital information for designing antiangiogenic peptides for drug development. These proteins function through their interaction with extracellular matrix molecules, cell surface receptors, proteases, as well as growth factors and cytokines. Conserved domains such as thrombospondin type 1 repeats (TSRs), kringle domains as well as critical amino acid residues present in these domains are involved in their functions. By exploiting these properties, several small peptides have been designed, synthetically made and being tested for therapeutic efficacy. Peptides derived from type 1 repeat of thrombospondin, alpha 4 and beta 1 chains of laminin, arginine rich N terminus of endostatin, leucine rich repeat 5 of decorin, pigment epithelium derived factor and N terminal of parathyroid hormone are examples of small antiangiogenic peptides derived from endogenous proteins. Such bioactive peptides are further modified physico-chemically to increase their potency and stability. In addition, phage-display library screening and combinatorial approach are also in use to identify novel antiangiogenic peptides targeting tumour and various proteins. This review will provide a comprehensive summary of the current status of the antiangiogenic peptides and their relevance for drug designing and development. Several critical issues that need to be resolved in translating this concept into clinical practice are also discussed.

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Safety and Tolerability of PCK3145, a Synthetic Peptide Derived from Prostate Secretory Protein 94 (PSP94) in Metastatic Hormone-Refractory Prostate Cancer

Cited by 14 publications

References 24 publications

Rational drug design: A GAGE derived peptide kills tumor cells

Rational drug design: A GAGE derived peptide kills tumor cells

A PSP94-derived Peptide PCK3145 inhibits MMP-9 Secretion and Triggers CD44 Cell Surface Shedding: Implication in Tumor Metastasis

Developing Antiangiogenic Peptide Drugs for Angiogenesis-Related Diseases

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