Vascular Targeting Agent

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Claudio Bordignon - One of the best experts on this subject based on the ideXlab platform.

  • anti metastatic activity of the tumor Vascular Targeting Agent ngr tnf
    Clinical & Experimental Metastasis, 2015
    Co-Authors: Paola Di Matteo, Claudio Bordignon, Barbara Valentinis, Patrizia Mangia, Elena Tiziano, Simona Porcellini, Claudio Doglioni, Francesca Sanvito, Gian Paolo Rizzardi
    Abstract:

    Tumor vessels are an attractive target for cancer therapy, including metastasis treatment. Angiogenesis inhibitors Targeting the VEGF signalling pathway have proven to be efficacious in preclinical cancer models and in clinical trials. However, angiogenesis inhibition concomitantly elicits tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased distant metastasis. Here, we investigated whether NGR-TNF, a Vascular Targeting Agent in phase III clinical development, coupling the CNGRCG angiogenic vessel-homing peptide with TNF-α, has an effect on metastasis in a model of murine breast cancer, which spontaneously metastasize to lungs, and on the growth of experimental melanoma lung metastasis. We report that NGR-TNF does not increase cancer invasiveness, as other antiangiogenics Agents do, but controls metastatic growth in both models, both when administered as primary treatment and in adjuvant settings, improving the overall survival of metastasis-bearing mice.

  • ngr tnf a novel Vascular Targeting Agent does not induce cytokine recruitment of proangiogenic bone marrow derived cells
    British Journal of Cancer, 2013
    Co-Authors: P Di Matteo, Robert S Kerbel, Claudio Bordignon, C Hackl, Christopher Jedeszko, Barbara Valentinis, Catia Traversari, Gp Rizzardi
    Abstract:

    NGR-TNF, a novel Vascular-Targeting Agent, does not induce cytokine recruitment of proangiogenic bone marrow-derived cells

  • abstract 4381 the novel direct acting Vascular Targeting Agent ngr tnf exertsin vivoantitumor activity by inducing endothelial and tumor cell death in the absence of proangiogenic bone marrow derived cell recruitment
    Cancer Research, 2012
    Co-Authors: Paola Di Matteo, Robert S Kerbel, Claudio Bordignon, C Hackl, Christopher Jedeszko, Barbara Valentinis, Catia Traversari, Simona Porcellini, Gian Paolo Rizzardi
    Abstract:

    Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Treatment with either certain chemotherapy drugs at maximum tolerated dose (e.g. paclitaxel, cyclophosphamide, 5-FU), Vascular-disrupting Agents (VDAs; e.g. fosbretabulin, Oxi4503), or local irradiation can rapidly induce mobilization and subsequent tumor homing of proangiogenic bone marrow derived cells (BMDCs), such as circulating endothelial progenitor cells (CEPs), CD11b/Tie-2-expressing monocytes (TEMs), CD11b+Gr1+ neutrophils and myeloid-derived suppressor cells (MDSCs). Increase in several growth factors and chemokines, such as SDF-1, G-CSF as well as osteopontin, contribute to the mobilization of these BMDCs that can colonize the drug treated tumors preferentially at the viable tumor rim that characteristically remains after treatment with drugs such as VDAs. This process promotes angiogenesis and rapid tumor regrowth, thus diminishing the overall antitumor activities of the aforementioned treatments. NGR-TNF, presently in advanced clinical development, is a direct-acting Vascular Targeting Agent coupling the CNGRCG peptide (NGR), homing to angiogenic blood vessels, and tumor necrosis factor alpha (TNF). Experiments performed in the Lewis lung carcinoma (LLC) model, suggested that when administrated at low doses, NGR-TNF causes a decrease of tumor blood vessels density and induces apoptosis of tumor cells without inducing cytokine-rebound and recruitment of pro-angiogenic BMDC. In order to extend these results, we investigated whether NGR-TNF fails to mobilize proangiogenic BMDC even after repeated treatments and in a highly aggressive and metastatic tumor model. LLC and 4T1 mammary gland carcinoma cells were subcutaneously implanted respectively into immunocompetent C57BL/6J or Balb/C mice. Blood was obtained by cardiac puncture or retro-orbital sinus bleeding, 4, 24 hours or 1 week after single or repeated treatments with either NGR-TNF at low and high dose or saline. Using flow cytometry CEPs were defined as CD45−/CD13+/flk-1+/CD117+/7AAD−, TEMs as CD45+/CD11b+/Tie2+ and MDSCs as CD45+/CD11b+/Gr1+ cells. At low doses, NGR-TNF exerts a control of 4T1 primary tumor growth, without inducing cytokine rebound and pro-angiogenic BMDCs mobilization. In addition, even after repeated administrations at low doses, NGR-TNF fails to mobilize or recruit to the tumor site different subtypes of BMDCs. Therefore, low doses of NGR-TNF exert an antitumor activity without inducing a reactive pro-angiogenic host response, and as such provide an explanation and the rationale for the successful use of lower dose NGR-TNF administration protocols in the clinic. 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 4381. doi:1538-7445.AM2012-4381

  • factors affecting the unexpected failure of dce mri to determine the optimal biological dose of the Vascular Targeting Agent ngr htnf in solid cancer patients
    European Journal of Radiology, 2011
    Co-Authors: Ingrid M E Desar, Claudio Bordignon, Johanna N H Timmerbonte, A Lambiase, Walter Fiedler, Sandrine Marreaud, Carla M L Van Herpen, Jack J A Van Asten, Edwin E G W Ter Voert, Arend Heerschap
    Abstract:

    Abstract Introduction To understand which factors could affect the assessment of anti-Vascular treatment by DCE-MRI, we investigated possible causes that could have hampered the selection of an optimal biological dose in humans of the Vascular targeted Agent NGR-hTNF by DCE-MRI: (1) insufficient reproducibility of DCE-MRI; (2) less specific Targeting of NGR-hTNF; (3) interference of vessel characteristics with NGR-hTNF efficacy; (4) interfering pharmacodynamic effects. Experimental In a phase I study NGR-hTNF, DCE-MRI was performed at baseline and 2 h after NGR-hTNF administration in 31 patients with advanced solid cancer. Reproducibility measurements were performed in 5 other non-treated patients with metastatic disease. Mean kep, Ktrans values and their histogram distribution were determined in metastases and healthy liver tissue. The correlation between tumour size and DCE-MRI parameters was determined. Kinetics of soluble TNF receptors and the development of anti-TNF antibodies were assessed. Results Reproducibility of the DCE-MRI technique was adequate. Mean DCE-MRI parameters did not significantly change after NGR-hTNF administration, but histogram analyses showed significant changes in metastases and healthy liver tissue in some patients. The anti-Vascular effects of NGR-hTNF were larger in smaller tumours, which have less mature neovasculature. Soluble TNF receptors were released. Conclusions The difficulty to find an optimal biological dose of NGR-TNF by DCE-MRI is likely caused by a combination of factors: (i) different profiles of early anti-Vascular effects in tumours and healthy liver tissue, (ii) dependence of the magnitude of the anti-Vascular effect of NGR-hTNF on tumour size and (iii) shedding kinetics of soluble TNFα receptors.

  • abstract 4249 ngr tnf a novel direct acting Vascular Targeting Agent does not induce cytokine rebound recruitment of pro angiogenic bone marrow derived cells
    Cancer Research, 2011
    Co-Authors: Paola Di Matteo, Robert S Kerbel, Claudio Bordignon, C Hackl, Christopher Jedeszko, Barbara Valentinis, Catia Traversari, Gian Paolo Rizzardi
    Abstract:

    NGR-TNF, presently in advanced clinical development, is a direct-acting Vascular Targeting Agent coupling the CNGRCG peptide (NGR), homing to angiogenic blood vessels, and tumour necrosis factor alpha (TNF). In order to further elucidate the mechanism of action, we investigated whether NGR-TNF mobilizes bone-marrow derived cells (BMDCs) and growth factors. Herein, treatment with either certain chemotherapy drugs at maximum tolerated dose (e.g. paclitaxel, cyclophosphamide, 5-FU), Vascular-disrupting Agents (VDAs; e.g. fosbretabulin, Oxi4503), or local irradiation can rapidly induce mobilization and subsequent tumor homing of proangiogenic BMDCs, such as circulating endothelial progenitor cells (CEPs), CD11b/Tie-2-expressing monocytes (TEMs), CD11b+Gr1+ neutrophils and myeloid-derived suppressor cells (MDSCs), and CD11b+F4/80+ macrophages. Increase in several growth factors and chemokines, such as SDF-1, G-CSF as well as osteopontin, contribute to the mobilization of BMDCs that colonize the tumour site and induce angiogenesis and rapid tumor regrowth. Lewis lung carcinoma (LLC) cells were subcutaneously implanted into immunocompetent C57BL/6J mice or into GFP+ bone marrow-chimeric mice, obtained by transplanting into lethally irradiated C57BL/6J mice bone marrow cells from UBI-GFP/BL6 donors. Blood was obtained 4 or 24 hours after treatment with either NGR-TNF, VDA, an anti-VEGFR2/flk-1 antibody or saline, by either cardiac puncture or retro-orbital sinus bleeding. Using flow cytometry (LSRII), CEPs were defined as CD45-/CD13+/flk-1+/CD117+/7AAD-, TEMs as CD45+/CD11b+/Tie2+/flk-1+ and MDSCs as CD45+/CD11b+/Gr1+ cells. Levels of circulating growth factors were assessed by ELISAs. When administrated at low doses (optimal biological dose), comparable to doses being used in clinical trials, NGR-TNF causes a decrease of tumor blood vessels density and induces apoptosis of tumor cells and tumor endothelial cells in vivo. It is worth noting that, unlike the above-mentioned treatments, NGR-TNF fails to mobilize or recruit to the tumor site different subtypes of pro-angiogenic BMDCs nor induces growth factors. Therefore, low doses of NGR-TNF exert an antitumor activity without inducing reactive a pro-angiogenic host response, which is likely an important feature for preventing/overcoming resistance and for designing combination therapeutic strategies. 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 4249. doi:10.1158/1538-7445.AM2011-4249

Vanesa Gregorc - One of the best experts on this subject based on the ideXlab platform.

  • phase i study of ngr htnf a selective Vascular Targeting Agent in combination with cisplatin in refractory solid tumors
    Clinical Cancer Research, 2011
    Co-Authors: Vanesa Gregorc, Giovanni Citterio, Giovanni Donadoni, Filippo De Braud, Tommaso De Pas, Roberto Scalamogna, Alessandra Milani, S Boselli, Chiara Catania, G Rossoni
    Abstract:

    Purpose: NGR-hTNF exploits the tumor-homing peptide asparagine-glycine-arginine (NGR) for selectively Targeting TNF-α to an aminopeptidase N overexpressed on cancer endothelial cells. Preclinical synergism with cisplatin was displayed even at low doses. This study primarily aimed to explore the safety of low-dose NGR-hTNF combined with cisplatin in resistant/refractory malignancies. Secondary aims included pharmacokinetics (PKs), pharmacodynamics, and activity. Experimental Design: NGR-hTNF was escalated using a doubling-dose scheme (0.2–0.4–0.8–1.6 μg/m 2 ) in combination with fixed-dose of cisplatin (80 mg/m 2 ), both given intravenously once every three weeks. PKs and circulating TNF-receptors (sTNF-Rs) were assessed over the first three cycles. Results: Globally, 22 patients (12 pretreated with platinum) received a range of one to ten cycles. Consistently with the low-dose range tested, maximum-tolerated dose was not reached. No dose-limiting toxicities (DLTs) were observed at 0.2 (n = 4) and 0.4 μg/m 2 (n = 3). One DLT (grade 3 infusion-related reaction) was observed at 0.8 μg/m 2 . This dose cohort was expanded to six patients without further DLTs. No DLTs were noted also at 1.6 μg/m 2 (n = 3). NGR-hTNF exposure increased dose-proportionally without apparent PK interactions with cisplatin. No shedding of sTNF-Rs was detected up to 0.8 μg/m 2 . At the dose level of 0.8 μg/m 2 , expanded to 12 patients for activity assessment, a platinum-pretreated lung cancer patient achieved a partial response lasting more than six months and five patients maintained stable disease for a median time of 5.9 months. Conclusions: The combination of NGR-hTNF 0.8 μg/m 2 with cisplatin 80 mg/m 2 showed favorable toxicity profile and promising antitumor activity. Clin Cancer Res; 17(7); 1964–72. ©2011 AACR .

  • phase ii study of ngr htnf a Vascular Targeting Agent in combination with doxorubicin in patients with relapsed small cell lung cancer sclc
    Journal of Clinical Oncology, 2010
    Co-Authors: Vanesa Gregorc, A Lambiase, A Santoro, Federico Caligariscappio, M G Vigano, Silvia Novello, Francesco Grossi, Giaj M Levra, Raffaele Cavina, Claudio Bordignon
    Abstract:

    e18043 Background: NGR-hTNF consists of tumour necrosis factor (TNF) fused to the tumour-homing peptide NGR, which selectively binds an aminopeptidase N overexpressed on tumour blood vessels. Both ...

  • phase ii study of asparagine glycine arginine human tumor necrosis factor α a selective Vascular Targeting Agent in previously treated patients with malignant pleural mesothelioma
    Journal of Clinical Oncology, 2010
    Co-Authors: Vanesa Gregorc, Armando Santoro, Giovanni Citterio, Tommaso De Pas, Giovanni Luca Ceresoli, P A Zucali, N Zilembo, Fabio De Vincenzo, Matteo Simonelli, G Rossoni
    Abstract:

    Purpose NGR-hTNF consists of human tumor necrosis factor α (hTNF-α) fused to the tumor-homing peptide asparagine-glycine-arginine (NGR) able to selectively bind an aminopeptidase N isoform overexpressed on tumor blood vessels. HyperVascularity is a prominent and poor-prognosis feature of malignant pleural mesothelioma (MPM). Currently, there are no standard options for patients with MPM who are failing a front-line pemetrexed-based regimen. We explored safety and efficacy of NGR-hTNF in this setting. Patients and Methods Eligible patients had radiologically documented tumor progression and performance status ≤ 2. Primary study aim was progression-free survival (PFS). NGR-hTNF 0.8 μg/m2 was given intravenously every 3 weeks. A subsequent cohort of patients received 0.8 μg/m2 on a weekly basis. Results In the triweekly cohort (n = 43), only one grade 3 drug-related toxicity was noted, and the most common grades 1 to 2 were short-lived chills (71%). The median PFS was 2.8 months (95% CI, 2.3 to 3.3 months). ...

  • phase ii study of asparagine glycine arginine human tumor necrosis factor alpha a selective Vascular Targeting Agent in previously treated patients with malignant pleural mesothelioma
    Journal of Clinical Oncology, 2010
    Co-Authors: Vanesa Gregorc, Armando Santoro, Giovanni Citterio, Tommaso De Pas, Giovanni Luca Ceresoli, P A Zucali, N Zilembo, Fabio De Vincenzo, Matteo Simonelli, G Rossoni
    Abstract:

    Purpose NGR-hTNF consists of human tumor necrosis factor α (hTNF-α) fused to the tumor-homing peptide asparagine-glycine-arginine (NGR) able to selectively bind an aminopeptidase N isoform overexpressed on tumor blood vessels. HyperVascularity is a prominent and poor-prognosis feature of malignant pleural mesothelioma (MPM). Currently, there are no standard options for patients with MPM who are failing a front-line pemetrexed-based regimen. We explored safety and efficacy of NGR-hTNF in this setting. Patients and Methods Eligible patients had radiologically documented tumor progression and performance status ≤ 2. Primary study aim was progression-free survival (PFS). NGR-hTNF 0.8 μg/m2 was given intravenously every 3 weeks. A subsequent cohort of patients received 0.8 μg/m2 on a weekly basis. Results In the triweekly cohort (n = 43), only one grade 3 drug-related toxicity was noted, and the most common grades 1 to 2 were short-lived chills (71%). The median PFS was 2.8 months (95% CI, 2.3 to 3.3 months). ...

  • defining the optimal biological dose of ngr htnf a selective Vascular Targeting Agent in advanced solid tumours
    European Journal of Cancer, 2010
    Co-Authors: Vanesa Gregorc, Angelo Corti, Giovanni Citterio, G Rossoni, Giovanni Donadoni, Paola Scifo, Giordano Vitali, Anna Spreafico, A Borri, Federico Caligariscappio
    Abstract:

    Abstract Background NGR-hTNF consists of human tumour necrosis factor-alpha (hTNF-α) fused to the tumour-homing peptide NGR, a ligand of an aminopeptidase N/CD13 isoform, which is overexpressed on endothelial cells of newly formed tumour blood vessels. NGR-TNF showed a biphasic dose–response curve in preclinical models. This study exploring the low-dose range aimed to define safety and optimal biological dose of NGR-hTNF. Patients and methods Pharmacokinetics, plasma biomarkers and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were evaluated at baseline and after each cycle in 16 patients enrolled at four doubling-dose levels (0.2–0.4–0.8–1.6 μg/m2). NGR-hTNF was given intravenously as 1-h infusion every 3 weeks (q3w). Tumour response was assessed q6w. Results Eighty-three cycles (median, 2; range, 1–29) were administered. Most frequent treatment-related toxicity was grade 1–2 chills (69%), occurring during the first infusions. Only one patient treated at 1.6 μg/m2 had a grade 3 drug-related toxicity (chills and dyspnoea). Both Cmax and AUC increased proportionally with dose. No shedding of soluble TNF-α receptors was observed up to 0.8 μg/m2. Seventy-five percent of DCE-MRI assessed patients showed a decrease over time of Ktrans, which was more pronounced at 0.8 μg/m2. Seven patients (44%) had stable disease for a median time of 5.9 months, including a colon cancer patient who experienced an 18-month progression-free time. Conclusion Based on tolerability, soluble TNF-receptors kinetics, anti-Vascular effect and disease control, NGR-hTNF 0.8 μg/m2 will be further developed either as single-Agent or with standard chemotherapy.

David J Chaplin - One of the best experts on this subject based on the ideXlab platform.

  • oxi4503 a novel Vascular Targeting Agent effects on blood flow and antitumor activity in comparison to combretastatin a 4 phosphate
    Anticancer Research, 2003
    Co-Authors: Jianyi Hua, David J Chaplin, Yezhou Sheng, Kevin G Pinney, Charles M Garner, Robert R Kane, Joseph A Prezioso, George R Pettit, Klaus Edvardsen
    Abstract:

    Oxi4503, which is the diphosphate prodrug of combretastatin A1, is a novel Vascular Targeting Agent from the combretastatin family. Another member of this family, Combretastatin A-4 phosphate (CA4P), is a well-characterized Vascular Targeting Agent already being evaluated in clinical trials. The potential for tumor Vascular Targeting by Oxi4503 was assessed in a mouse system. This approach aims to shut down the established tumor vasculature, leading to the development of extensive tumor cell necrosis. The Vascular effects of Oxi4503 were assessed in the s.c. implanted MDA-MB-231 adenocarcinoma and the MHEC5-T hemangio-endothelioma in SCID mice and in a range of normal tissues. Blood flow was measured by i.v. injection of fluorescence beads, while quantitative fluorescence microscopy was used to measure the spatial heterogeneity of blood flow in tumor sections. Oxi4503 induced the shutdown of tumor blood vessels in a dose-dependent pattern with an ED50 at 3 mg/kg in contrast to 43 mg/kg of CA4P. Quantitative fluorescence microscopy showed that Oxi4503 increased the spatial heterogeneity in tumor blood flow. Oxi4503 affected peripheral tumor regions less than central regions, although this was not as pronounced as seen with CA4P, where only central regions were affected. The Vascular shutdown induced by administration of Oxi4503 at a dose of 6 mg/kg resulted in extensive cell loss 24 hours following treatment, which translated into a significant effect on tumor growth. Tumor growth was completely repressed at doses above 12.5 mg/kg of Oxi4503, while doses above 25 mg/kg showed tumor regression and even complete regression in some animals. These results are promising for the use of Oxi4503 as a tumor Vascular Targeting Agent. Moreover the potent antitumor effect when administered as a single Agent suggests a different activity profile than CA4P.

  • zd6126 a novel Vascular Targeting Agent that causes selective destruction of tumor vasculature
    Cancer Research, 2002
    Co-Authors: P Davis, Gillian M. Tozer, Susan M. Galbraith, David C Blakey, Michael R L Stratford, Graeme J Dougherty, Angela L Holder, Matthew A Naylor, John Nolan, David J Chaplin
    Abstract:

    Physiological differences between tumor and normal vasculature provide a target for drug discovery. In particular, the immature nature of tumor vasculature may render it intrinsically sensitive to disruption by Agents affecting the endothelial cell cytoskeleton, including tubulin-binding Agents. In this article, we report the synthesis of a water-soluble phosphate prodrug, ZD6126, of the tubulin-binding Agent N -acetylcolchinol. In vitro studies demonstrate the comparative tubulin-binding properties of the prodrug and active drug, and show the induction of pronounced, reversible changes in endothelial cell morphology at subcytotoxic doses. Neither ZD6126 nor N -acetylcolchinol showed effects on the growth of human umbilical vein endothelial cells at concentrations below 100 μm. In contrast, changes in endothelial cell morphology were seen at much lower, noncytotoxic concentrations (0.1 μm) of ZD6126 and more pronounced effects were seen in proliferating versus confluent endothelial cell cultures. In vivo studies were carried out using a murine tumor model (CaNT) with single administration of a dose well below the maximum tolerated dose. These studies showed a large reduction in Vascular volume, induction of extensive necrosis in tumors, and a reduced tumor cell yield in a clonal excision assay, consistent with Vascular rather than cytotoxic effects. A viable rim of tumor remained after single-dose administration and minimal growth delay was observed. However, well-tolerated, multiple administration regimens led to pronounced tumor-growth delay. In the human xenograft FaDu, the growth delay given by a single dose of paclitaxel was enhanced by combination with a single dose of ZD6126, and the growth delay given by the combination was greater than the sum of the growth delays from the individual treatments. These findings show that ZD6126 is a promising antiVascular Agent for the treatment of solid tumors.

  • The development of combretastatin A4 phosphate as a Vascular Targeting Agent.
    International journal of radiation oncology biology physics, 2002
    Co-Authors: David J Chaplin, Sally A. Hill
    Abstract:

    Abstract Purpose : This overview summarizes the preclinical development of tubulin-depolymerizing Agents as Vascular Targeting Agents, leading to the identification of combretastatin A4P (CA4P). Methods and Materials : The murine tumor CaNT was implanted s.c. in the dorsum of CBA mice. Vascular function was determined after treatment using the perfusion marker Hoechst 33342 and fluorescence microscopy. Tumor cell response was assessed by using an excision assay and by measuring the delay in growth of treated tumors. Results : At doses that approximated one-half the maximum tolerated dose (MTD) in CBA mice, none of the Agents evaluated—i.e., taxol, melphalan, 5-fluorouracil, doxorubicin, cisplatin, gemcitabine, and irinotecan—induced any significant reduction in perfused Vascular volume within the tumor mass. In contrast, CA4P at a dose of 100 mg/kg, which approximates one-fifth the MTD, induced a greater than 80% reduction in Vascular function. Although colchicine did induce Vascular shutdown, this occurred only at doses approximating the MTD. Histologic evaluation demonstrated that continued growth and repopulation of the tumor mass was the result of a surviving rim of viable tumor cells at the tumor periphery. Conclusion : These results confirm the ability of CA4P to selectively compromise Vascular function in experimental tumors, inducing extensive tumor cell death at well-tolerated doses. However, despite these effects, no growth retardation is obtained when CA4P is administered alone in a single dose. The continued growth and repopulation of the tumor mass occurs from a narrow rim of viable cells at the periphery. If, as is believed, these remaining cells are the ones most sensitive to conventional cytotoxic and macromolecular approaches, CA4P and other Vascular Targeting Agents offer considerable potential for enhancing the effectiveness of existing and emerging cancer therapies.

  • Preclinical evaluation of the antitumour activity of the novel Vascular Targeting Agent Oxi 4503.
    Anticancer research, 2002
    Co-Authors: Sally A. Hill, Gillian M Toze, David J Chaplin
    Abstract:

    BACKGROUND Tubulin depolymerizing drugs, which selectively disrupt tumour neovasculature, have recently been identified. The lead drug in this class, combretastatin A4 phosphate (CA4P), has just completed Phase I clinical trial. We have continued to synthesize and evaluate a number of combretastatins, with the aim of identifying novel Agents that possess single Agent activity. In the studies presented here we provide data on our lead preclinical compound and compare its antiVascular and antitumour activity to that of CA4P in the murine breast adenocarcinoma CaNT. This compound, designated Oxi 4503, is the diphosphate prodrug form of combretastatin A1. RESULTS At a dose of 1 mg/kg Oxi 4503 induced a greater than 50% reduction in functional Vascular volume, which increased to 80% or more following doses of 10, 25 and 50 mg/kg. In contrast, CA4P induced approximately 40% Vascular shutdown at 50 mg/kg, but had no measurable effect at 10 mg/kg. In addition to these Vascular effects, Oxi 4503 at doses of 100, 200 and 400 mg/kg induced significant retardation in the growth of established CaNT tumours. No significant growth retardation was obtained with single doses of up to 400 mg/kg CA4P. CONCLUSION In summary, these studies have identified Oxi 4503 as a preclinical development candidate with more potent antiVascular and antitumour effects than CA4P when used as a single Agent.

  • mechanisms associated with tumor Vascular shut down induced by combretastatin a 4 phosphate intravital microscopy and measurement of Vascular permeability
    Cancer Research, 2001
    Co-Authors: Gillian M. Tozer, Paul R Barber, Vivien E Prise, John T Wilson, Maja Cemazar, Siqing Shan, Mark W Dewhirst, Borivoj Vojnovic, David J Chaplin
    Abstract:

    The tumor Vascular effects of the tubulin destabilizing Agent disodium combretastatinA-4 3-O-phosphate (CA-4-P) were investigated in the rat P22 tumor growing in a dorsal skin flap window chamber implanted into BD9 rats. CA-4-P is in clinical trial as a tumor Vascular Targeting Agent. In animal tumors, it can cause the shut-down of blood flow, leading to extensive tumor cell necrosis. However, the mechanisms leading to Vascular shut-down are still unknown. Tumor Vascular effects were visualized and monitored on-line before and after the administration of two doses of CA-4-P (30 and 100 mg/kg) using intravital microscopy. The combined effect of CA-4-P and systemic nitric oxide synthase (NOS) inhibition using Nω-nitro-L-arginine (L-NNA) was also assessed, because this combination has been shown previously to have a potentiating effect. The early effect of CA-4-P on tumor Vascular permeability to albumin was determined to assess whether this could be involved in the mechanism of action of the drug. Tumor blood flow reduction was extremely rapid after CA-4-P treatment, with red cell velocity decreasing throughout the observation period and dropping to<5% of the starting value by 1 h. NOS inhibition alone caused a 50% decrease in red cell velocity, and the combined treatment of CA-4-P and NOS inhibition was approximately additive. The mechanism of blood flow reduction was very different for NOS inhibition and CA-4-P. That of NOS inhibition could be explained by a decrease in vessel diameter, which was most profound on the arteriolar side of the tumor circulation. In contrast, the effects of CA-4-P resembled an acute inflammatory reaction resulting in a visible loss of a large proportion of the smallest blood vessels. There was some return of visible vasculature at 1 h after treatment, but the blood in these vessels was static or nearly so, and many of the vessels were distended. The hematocrit within larger draining tumor venules tended to increase at early times after CA-4-P, suggesting fluid loss from the blood. The stacking of red cells to form rouleaux was also a common feature, coincident with slowing of blood flow; and these two factors would lead to an increase in viscous resistance to blood flow. Tumor Vascular permeability to albumin was increased to ∼160% of control values at 1 and 10 min after treatment. This could lead to an early decrease in tumor blood flow via an imbalance between intraVascular and tissue pressures and/or an increase in blood viscosity as a result of increased hematocrit. These results suggest a mechanism of action of CA-4-P in vivo. Combination of CA-4-P with a NOS inhibitor has an additive effect, which it may be possible to exploit therapeutically.

C M L Van Herpen - One of the best experts on this subject based on the ideXlab platform.

Gian Paolo Rizzardi - One of the best experts on this subject based on the ideXlab platform.

  • anti metastatic activity of the tumor Vascular Targeting Agent ngr tnf
    Clinical & Experimental Metastasis, 2015
    Co-Authors: Paola Di Matteo, Claudio Bordignon, Barbara Valentinis, Patrizia Mangia, Elena Tiziano, Simona Porcellini, Claudio Doglioni, Francesca Sanvito, Gian Paolo Rizzardi
    Abstract:

    Tumor vessels are an attractive target for cancer therapy, including metastasis treatment. Angiogenesis inhibitors Targeting the VEGF signalling pathway have proven to be efficacious in preclinical cancer models and in clinical trials. However, angiogenesis inhibition concomitantly elicits tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased distant metastasis. Here, we investigated whether NGR-TNF, a Vascular Targeting Agent in phase III clinical development, coupling the CNGRCG angiogenic vessel-homing peptide with TNF-α, has an effect on metastasis in a model of murine breast cancer, which spontaneously metastasize to lungs, and on the growth of experimental melanoma lung metastasis. We report that NGR-TNF does not increase cancer invasiveness, as other antiangiogenics Agents do, but controls metastatic growth in both models, both when administered as primary treatment and in adjuvant settings, improving the overall survival of metastasis-bearing mice.

  • abstract 4381 the novel direct acting Vascular Targeting Agent ngr tnf exertsin vivoantitumor activity by inducing endothelial and tumor cell death in the absence of proangiogenic bone marrow derived cell recruitment
    Cancer Research, 2012
    Co-Authors: Paola Di Matteo, Robert S Kerbel, Claudio Bordignon, C Hackl, Christopher Jedeszko, Barbara Valentinis, Catia Traversari, Simona Porcellini, Gian Paolo Rizzardi
    Abstract:

    Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Treatment with either certain chemotherapy drugs at maximum tolerated dose (e.g. paclitaxel, cyclophosphamide, 5-FU), Vascular-disrupting Agents (VDAs; e.g. fosbretabulin, Oxi4503), or local irradiation can rapidly induce mobilization and subsequent tumor homing of proangiogenic bone marrow derived cells (BMDCs), such as circulating endothelial progenitor cells (CEPs), CD11b/Tie-2-expressing monocytes (TEMs), CD11b+Gr1+ neutrophils and myeloid-derived suppressor cells (MDSCs). Increase in several growth factors and chemokines, such as SDF-1, G-CSF as well as osteopontin, contribute to the mobilization of these BMDCs that can colonize the drug treated tumors preferentially at the viable tumor rim that characteristically remains after treatment with drugs such as VDAs. This process promotes angiogenesis and rapid tumor regrowth, thus diminishing the overall antitumor activities of the aforementioned treatments. NGR-TNF, presently in advanced clinical development, is a direct-acting Vascular Targeting Agent coupling the CNGRCG peptide (NGR), homing to angiogenic blood vessels, and tumor necrosis factor alpha (TNF). Experiments performed in the Lewis lung carcinoma (LLC) model, suggested that when administrated at low doses, NGR-TNF causes a decrease of tumor blood vessels density and induces apoptosis of tumor cells without inducing cytokine-rebound and recruitment of pro-angiogenic BMDC. In order to extend these results, we investigated whether NGR-TNF fails to mobilize proangiogenic BMDC even after repeated treatments and in a highly aggressive and metastatic tumor model. LLC and 4T1 mammary gland carcinoma cells were subcutaneously implanted respectively into immunocompetent C57BL/6J or Balb/C mice. Blood was obtained by cardiac puncture or retro-orbital sinus bleeding, 4, 24 hours or 1 week after single or repeated treatments with either NGR-TNF at low and high dose or saline. Using flow cytometry CEPs were defined as CD45−/CD13+/flk-1+/CD117+/7AAD−, TEMs as CD45+/CD11b+/Tie2+ and MDSCs as CD45+/CD11b+/Gr1+ cells. At low doses, NGR-TNF exerts a control of 4T1 primary tumor growth, without inducing cytokine rebound and pro-angiogenic BMDCs mobilization. In addition, even after repeated administrations at low doses, NGR-TNF fails to mobilize or recruit to the tumor site different subtypes of BMDCs. Therefore, low doses of NGR-TNF exert an antitumor activity without inducing a reactive pro-angiogenic host response, and as such provide an explanation and the rationale for the successful use of lower dose NGR-TNF administration protocols in the clinic. 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 4381. doi:1538-7445.AM2012-4381

  • abstract 4249 ngr tnf a novel direct acting Vascular Targeting Agent does not induce cytokine rebound recruitment of pro angiogenic bone marrow derived cells
    Cancer Research, 2011
    Co-Authors: Paola Di Matteo, Robert S Kerbel, Claudio Bordignon, C Hackl, Christopher Jedeszko, Barbara Valentinis, Catia Traversari, Gian Paolo Rizzardi
    Abstract:

    NGR-TNF, presently in advanced clinical development, is a direct-acting Vascular Targeting Agent coupling the CNGRCG peptide (NGR), homing to angiogenic blood vessels, and tumour necrosis factor alpha (TNF). In order to further elucidate the mechanism of action, we investigated whether NGR-TNF mobilizes bone-marrow derived cells (BMDCs) and growth factors. Herein, treatment with either certain chemotherapy drugs at maximum tolerated dose (e.g. paclitaxel, cyclophosphamide, 5-FU), Vascular-disrupting Agents (VDAs; e.g. fosbretabulin, Oxi4503), or local irradiation can rapidly induce mobilization and subsequent tumor homing of proangiogenic BMDCs, such as circulating endothelial progenitor cells (CEPs), CD11b/Tie-2-expressing monocytes (TEMs), CD11b+Gr1+ neutrophils and myeloid-derived suppressor cells (MDSCs), and CD11b+F4/80+ macrophages. Increase in several growth factors and chemokines, such as SDF-1, G-CSF as well as osteopontin, contribute to the mobilization of BMDCs that colonize the tumour site and induce angiogenesis and rapid tumor regrowth. Lewis lung carcinoma (LLC) cells were subcutaneously implanted into immunocompetent C57BL/6J mice or into GFP+ bone marrow-chimeric mice, obtained by transplanting into lethally irradiated C57BL/6J mice bone marrow cells from UBI-GFP/BL6 donors. Blood was obtained 4 or 24 hours after treatment with either NGR-TNF, VDA, an anti-VEGFR2/flk-1 antibody or saline, by either cardiac puncture or retro-orbital sinus bleeding. Using flow cytometry (LSRII), CEPs were defined as CD45-/CD13+/flk-1+/CD117+/7AAD-, TEMs as CD45+/CD11b+/Tie2+/flk-1+ and MDSCs as CD45+/CD11b+/Gr1+ cells. Levels of circulating growth factors were assessed by ELISAs. When administrated at low doses (optimal biological dose), comparable to doses being used in clinical trials, NGR-TNF causes a decrease of tumor blood vessels density and induces apoptosis of tumor cells and tumor endothelial cells in vivo. It is worth noting that, unlike the above-mentioned treatments, NGR-TNF fails to mobilize or recruit to the tumor site different subtypes of pro-angiogenic BMDCs nor induces growth factors. Therefore, low doses of NGR-TNF exert an antitumor activity without inducing reactive a pro-angiogenic host response, which is likely an important feature for preventing/overcoming resistance and for designing combination therapeutic strategies. 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 4249. doi:10.1158/1538-7445.AM2011-4249

  • abstract 4258 both ngr and tnf portions contribute to the biological activity of ngr tnf Vascular Targeting Agent in vivo
    Cancer Research, 2011
    Co-Authors: Luca Alberici, Claudio Bordignon, Barbara Valentinis, Catia Traversari, Paola Di Matteo, Simona Porcellini, Claudio Doglioni, Manuela Cota, Dan Zhou, Gian Paolo Rizzardi
    Abstract:

    Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL NGR-TNF, presently in advanced clinical development, is a direct-acting Vascular Targeting Agent coupling the CNGRCG peptide (NGR), homing to angiogenic blood vessels, and tumour necrosis factor alpha (TNF). To elucidate its mechanism of action, we investigated the NGR-TNF homing and downstream effects using doses comparable to those used in clinical trials. Targeting studies with NGR-quantum dots administered in vivo demonstrate that the binding to CD13 occurs only in neo-angiogenic tissues, sparing CD13-expressing normal tissues. NGR-TNF binding is highly specific Targeting the tumour vessel of human colon cancer specimens, whereas the binding does not occur in the normal colon tissue of the very same patients. To investigate the interaction between NGR and CD13, we incubated human primary mesangioblasts with biotinylated peptides, cross-linked with BS3 to form covalent bounds between interacting molecules, lysed the cells and pulled down biotinylated proteins by streptavidin-coated magnetic beads. Only biotinylated NGR pulls down CD13 in monomeric and dimeric forms. After CD13 immunoprecipitation, the CD13 immunoprecipitated from NGR-treated cells is biotinylated, unlike CD13 immunoprecipitated from control peptide. Depriving CD13 completely in the total lysate of cells incubated with NGR, the biotinylated bands at 150 kDa disappears. Overall these data demonstrate that biotinylated NGR directly interacts with CD13 on the cell membrane. To address whether NGR binding affects the TNF-TNFR interaction, we used TNF conjugated to an Ig Fc portion so that it can be visualised onto target cells, and we tested the ability of both TNF and NGR-hTNF to compete with this binding. Interestingly, while in NGR-non-binder cells the affinity between TNF and NGR-TNF is the same, NGR-hTNF clearly displays an higher affinity than TNF in NGR-binder cells. It is worth noting that the 1-log increase in NGR-hTNF affinity is actually due to the binding of NGR to CD13 because this is overcome with increasing amounts of free NGR. We then investigated how NGR-hTNF affects signaling pathways in human endothelial cells. Interestingly, we found that, over hTNF, NGR-hTNF impairs cell survival a) by inhibiting the activation of the pro-survival Ras pathway inducing a down-modulation of Raf, MEK, Erk, and Akt, along with preventing VEGFR2 mRNA up-regulation, and b) by activating the pro-apoptotic caspases (3, 8 and 9). Interestingly, if we stimulate endothelial cells with TNF and a neutral NGR-carrying molecule (administering them in combination, not conjugated), we observe the same impairment of the Ras signaling pathway, thus demonstrating that the engagement of CD13 has a direct effect on the signaling downstream of Ras. In conclusion, the binding of NGR to CD13 determines not only the “mere homing” of NGR-TNF but confers to NGR-hTNF specific features that significantly differentiate it from TNF. 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 4258. doi:10.1158/1538-7445.AM2011-4258

  • ngr derived isodgr is a natural recognition motif of the rgd binding site of αvβ3 integrin
    Cancer Research, 2008
    Co-Authors: Andrea Spitaleri, Claudio Bordignon, Angelo Corti, Catia Traversari, Gian Paolo Rizzardi, Silvia Mari, Flavio Curnis, Renato Longhi, Giovanna Musco
    Abstract:

    1976 NGRhTNF is a Vascular Targeting Agent in phase II clinical development exploiting a tumor homing peptide (CNGRCG) selectively binding angiogenic vessels in solid tumors, where NGRhTNF specific binding relies on dynamic interactions with TNF-receptors and aminopeptidase N (CD13). Asparagine deamidation at the NGR sequence in the 5th type I repeat of fibronectin (FN-I5) generates isoDGR, an αvβ3 integrin binding motif that regulates endothelial cell adhesion and proliferation (Curnis et al JBC 2006, 281:36466). In the present work, we analyze the structure of CisoDGRC (isoDGR), a cyclo-peptide that mimicks the FN-I5 site, as well as those of NGR, RGD or DGR-containing cyclo-peptides, by NMR and molecular dynamics (MD) studies on each peptide. These studies indicate that isoDGR has a high degree of macrocycle flexibility, yielding to a significantly greater conformational heterogeneity as compared to the other cyclo-peptides. The resulting conformers have been docked onto the αvβ3 crystallographic structure in its “RGD-bound” conformation (Xiong et al Science 2002, 296:151). Docking experiments along with MD studies on each complex peptide-receptor show that isoDGR favorably interacts with the RGD-binding site of αvβ3, both recapitulating canonical RGD/αvβ3 contacts and establishing additional polar interactions. Among these, the N-terminal cysteine flanking the isoDGR sequence points towards the binding site, contributing to receptor recognition. In contrast, NGR and DGR motives lack the fundamental pharmacophoric requirements for high receptor affinity. Consistently, MD studies do not show over time stable interactions of NGR and DGR with the αvβ3-biding site. Finally, our structural models are in accord with experimental results obtained in cell adhesion and binding assays, indicating that isoDGR and RGD, but not NGR and DGR, peptides bind to αvβ3 with similar affinity, and inhibit cell adhesion of endothelial cells.Overall, these data provide the structural basis to define isoDGR as a new natural recognition motif of αvβ3, while indicate that NGR sequence lacks the pharmacophoric features to bind αvβ3. The results also contribute to explain the functional differences of fibronectin NGR and isoDGR sequences. In this context, we argue that NGR→isoDGR transition may represent an important physiological mechanism able to work as a molecular timer for activating latent integrin-binding sites in fibronectin, with important patho-physiological implications in development, angiogenesis, inflammation, wound repair and tumor growth.

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