作者: So, Remmick ; Vanderhyden, Barbara ; Garson, Kenneth ; Yan, Fu J. ; Chaparro, Luisa E. Sancen ; Chabot, Jaclyn ; Sokoll, Kenneth K. ; Aguirre, Miranda Gonzalez

AbstractBackground: Liposomes, vesicular structures in the nano - micrometer range, have been widely studied as drug delivery vehicles. Liposomes can self-assemble in aqueous solutions and are normally comprised of lipids organized in concentric bilayers that enclose an internal aqueous volume, unique in their ability to accommodate a wide variety of therapeutic or diagnostic compounds. Novel liposomal compositions of peptide GAP-107B8, have recently been developed and their inhibitory effect on cell proliferation in cancer cell lines has been studied. Protein kinase B, Akt, has been implicated in certain cancer functions, including cell motility and invasion, hormone independence, chemotherapy and radiation resistance. Abnormalities in Akt are associated with certain breast, pancreatic, colorectal, gastric and ovarian cancers. The present work shows that an important mechanism of action for GAP-107B8 peptide formulations is through modification of protein kinase pathways. Objectives: 1) To optimize GAP-107B8 liposomal formulations, 2) To evaluate the efficacy of GAP-107B8 liposomal formulations towards inhibiting proliferation in ovarian cancer cell lines and 3) To gather information on the inhibitory mechanism of action in ovarian cancer cells. Methods: Optimization of the lipid components in the liposomes including lipid identity and ratio in relation to extent of peptide-liposome association was determined by IEC, liposome size and charge. Cell proliferation was measured in A2780cp and OCC-1 ovarian cancer cell lines with liposomal peptide formulations (24 and 72 hrs). Immunoblotting experiments were executed on cancer cell line lysates treated with peptide to explore inhibitory effects on signaling targets. Results: Peptide association ranged from 80-100% for liposomal formulations prepared with two lipid components in varying ratios (formulation 2A and 2B) as opposed to a single lipid component (formulation 1 - 30%). Treatment of ovarian cancer cells with liposomal formulations 2A, 2B and 3 showed significant inhibition on cell proliferation when compared to control groups. Densitometry results showed a 50% reduction in pAkt levels (relative to Akt levels) when ovarian cells were treated with peptide for 1 hour (similar inhibitory effect found after peptide treatment for 4, 8, 14 and 30 hours). Conclusions: A lipid based delivery system for GAP-107B8 peptide was developed in which lipid ratio played an important role for an enhanced peptide-associated liposomal formulation. Proliferation results indicate that administration of peptides in liposome formulations generally results in improved potency in a time dependent manner. All formulations exhibited greater potency after 72 hrs in comparison to earlier time points. GAP-107B8 was found to be a peptide-based inhibitor of protein kinase B (Akt) with a strong potential for anti-cancer properties.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2907. doi:1538-7445.AM2012-2907

2011-04-15·Cancer Research

Abstract 2592: Therapeutic testing of a novel inhibitor GAP-107B8 on ovarian cancer cells

作者: Yan, Fu J. ; Garson, Kenneth ; Vanderhyden, Barbara C. ; Chabot, Jaclyn M.

AbstractBackground: Ovarian cancer is the most fatal gynaecologic disease in the western world. In 2010 in the United States, an estimated 21,880 women will develop ovarian cancer and an estimated 13,850 women will succumb to this disease. Current treatments are limited to surgery and chemotherapy, but the disease often recurs highlighting the need for novel cancer therapeutics. We are currently evaluating the efficacy of a novel therapeutic, GAP-107B8 (PharmaGap Inc, Ottawa) using in vitro and in vivo models. GAP-107B8 was designed as a protein kinase C (PKC) inhibitor. The PKC family of serine/threonine kinases are involved in cellular proliferation, differentiation, apoptosis and cell polarity. One PKC isoform, PKC iota, has recently been identified as a human oncogene and has been shown to be overexpressed in epithelial ovarian cancers and is thus a potential therapeutic target for ovarian cancer. Objectives: 1) To test the novel inhibitor GAP-107B8 on ovarian cancer cell lines to determine its effects on cell proliferation, cell cycle progression and apoptosis; and 2) To determine the therapeutic potential of GAP-107B8 in xenograft models of two different ovarian cancer cell lines. Methods: Three ovarian cancer cell lines were treated with three different concentrations of GAP-107B8 and screened using high throughput assays to measure the proliferation of cells in adherent cultures. Apoptosis was measured by TUNEL staining, PARP cleavage and cell cycle analysis. Tumor burden was assessed in mice receiving subcutaneous implants of two ovarian cancer cell lines, followed by daily intra-tumoral injections of GAP-107B8. Results: GAP-107B8 caused a significant reduction in cell proliferation in 3 ovarian cancer cell lines tested (86% to 95%; p<0.001), including a cell line resistant to standard chemotherapy. In vivo, intra-tumoral treatment with GAP-107B8 resulted in a 45% reduction in average tumor size in the A2780cp-derived tumours (n=6/group, p<0.01) and 75% in the HEY-derived tumors (n=3/group, p<0.001). Cell killing may be mediated by apoptosis based on the observation of TUNEL staining 30 hours after treatment of cells in vitro with GAP-107B8. Apoptosis was confirmed by flow cytometry and PARP cleavage. GAP-107B8 also inhibited progression of cells through the cell cycle by blocking or delaying progression of cells through G2/M into the G1 phase.Conclusion: The novel inhibitor GAP-107B8 displays good efficacy in vitro in suppressing the proliferation of ovarian cancer cell lines. Cytotoxicity may be manifested in perturbations of the cell cyle and induction of apoptosis. Finally, GAP-107B8 showed therapeutic efficacy in ovarian cancer xenograft models.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2592. doi:10.1158/1538-7445.AM2011-2592

2011-04-15·Cancer Research

Abstract 1687: A novel PKC inhibitor: Inhibition of cell proliferation in cancer cell lines and pharmacokinetics in Sprague-Dawley rats

作者: Gonzalez-Aguirre, Miranda ; Sokoll, Kenneth K. ; Chabot, Jaclyn M. ; Mojica, Jorge R.

AbstractBackground: Cancer treatment by conventional chemotherapy is hindered by toxic side effects and the frequent development of multi-drug resistance by cancer cells. Cytotoxic peptides are a promising class of drugs that avoid the shortcomings of conventional chemotherapy because certain peptides exhibit selective cytotoxicity against a broad spectrum of human cancer cells (Mader J.S. and Hoskin D.W., 2006). Protein kinase C (PKC) is a family of kinases involved in the transduction of signals for cell proliferation, differentiation, angiogenesis, migration and apoptosis. PKC has been implicated in tumorigenesis (Griner E.M. and Kazanietz M.G., 2007). PharmaGap based its anticancer therapy strategy on the use of proprietary computer modelling for the design of novel cytotoxic peptide candidates for select PKC peptides in order to develop novel drugs targeting PKC. Objective: 1) To test novel GAP-107B8 peptide-based PKC inhibitors’ capability to inhibit cell proliferation in various cancer cell lines; and 2) To gather information about the pharmacokinetics of an inhibitor in a rodent model. Methods: Cell proliferation was measured in LS513 colon, A2780cp ovarian, and ES-2 ovarian cancer cell lines after treatment with different peptides (concentrations in the micromolar range) up to 48 hours. Proliferation was measured using CyQuant Assay and data was normalized to untreated controls. Pharmacokinetic data was obtained from a bolus study and from a 2 hour continuous infusion study performed in Sprague-Dawley rats. Single bolus doses ranged from 1.0 to 5.5 mg/kg. Blood sampling was obtained over 120 minutes following administration. Doses for the 2 hour continuous infusion study ranged from 10 to 40 mg/kg. Blood sampling was obtained prior to infusion start, and up to 120 minutes post-infusion. Plasma was used for all subsequent pharmacokinetic analyses. Results: In different screenings, a peptide dose-response inhibition on cell proliferation was observed in all cell lines tested. In one screening study, at the highest peptide concentration after a 48 hour incubation, the peptide decreased proliferation by 67%, 71%, and 28% in LS513, A2780cp, and ES-2 cells respectively. Another screening showed decreased proliferation by 92%, 92%, and 75% in LS513, A2780cp, and ES-2 cells respectively. From the bolus study it was found that the pharmacokinetic profiles of the cytotoxic peptide were similar for all doses and for both genders. Elimination appeared to be biphasic, and plasma half-life values were dose dependent. Exposure, based on AUC0-t, increased in a dose related fashion (pseudo linear) for both genders. Conclusions: Novel PKC inhibitors have been found to inhibit cell proliferation of various cancer cell lines. The first pharmacokinetic data for these novel inhibitors was obtained after a bolus and an infusion study.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1687. doi:10.1158/1538-7445.AM2011-1687

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