Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours

Gregorc, Vanesa; Citterio, Giovanni; Vitali, Giordano; Spreafico, Anna; Scifo, Paola; Borri, Anna; Donadoni, Giovanni; Rossoni, G.; Corti, Angelo; Caligaris-Cappio, Federico; Maschio, Alessandro Del; Esposito, Antonio; Cobelli, Francesco De; Dell’Acqua, Flavio; Troysi, Antonella; Bruzzi, Paolo; Lambiase, A.; Bordignon, Claudio

doi:10.1016/j.ejca.2009.10.005

Cited by 48 publications

(47 citation statements)

References 22 publications

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“…NGR peptides have been used by different investigators to deliver cytokines, chemotherapeutic drugs, liposomes, anti-angiogenic compounds, viruses, imaging agents and DNA complexes to tumor neovasculature, in order to improve their therapeutic or imaging properties (reviewed by . For example, the CNGRCG peptide, fused to the N-terminus of TNF- (NGR-TNF), and the GNGRAHA-peptide, fused to the C-terminus of tissue factor, are currently tested in several phase I, II and III clinical studies (Bieker et al, 2009;Gregorc et al, 2010a;Gregorc et al, 2010b;van Laarhoven et al, 2010;. The rationale for using these peptides is the observation that NGR can recognize a membrane-bound form of aminopeptidase N (CD13) that is expressed by angiogenic vessels (Curnis et al, 2002;Pasqualini et al, 2000).…”

Section: Pharmacological Implications and Therapeutic Opportunities Fmentioning

confidence: 99%

Isoaspartate-dependent molecular switches for integrin–ligand recognition

Corti¹,

Curnis²

2011

Journal of Cell Science

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Formation of isoAsp in ECM proteins and its functional effects Formation of isoAsp and ECM protein damageThe formation of isoAsp residues at Asn or Asp residues in proteins is generally considered a degradation reaction as a consequence of protein aging. IsoAsp formation has been shown to occur in ECM proteins, including collagen types I and III, in fibronectin, in -crystallin and in the ECM of the mammalian brain (Lanthier and Desrosiers, 2004;Lindner and Helliger, 2001; Reissner and Aswad, SummaryIntegrins are cell-adhesion receptors that mediate cell-extracellular-matrix (ECM) and cell-cell interactions by recognizing specific ligands. Recent studies have shown that the formation of isoaspartyl residues (isoAsp) in integrin ligands by asparagine deamidation or aspartate isomerization could represent a mechanism for the regulation of integrin-ligand recognition. This spontaneous posttranslational modification, which might occur in aged proteins of the ECM, changes the length of the peptide bond and, in the case of asparagine, also of the charge. Although these changes typically have negative effects on protein function, recent studies suggested that isoAsp formation at certain Asn-Gly-Arg (NGR) sites in ECM proteins have a gain-of-function effect, because the resulting isoAsp-Gly-Arg (isoDGR) sequence can mimic Arg-Gly-Asp (RGD), a well-known integrin-binding motif. Substantial experimental evidence suggests that the NGR-to-isoDGR transition can occur in vitro in natural proteins and in drugs containing this motif, thereby promoting integrin recognition and cell adhesion. In this Commentary, we review these studies and discuss the potential effects that isoAsp formation at NGR, DGR and RGD sites might have in the recognition of integrins by natural ligands and by drugs that contain these motifs, as well as their potential biological and pharmacological implications.

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Section: Pharmacological Implications and Therapeutic Opportunities Fmentioning

confidence: 99%

Isoaspartate-dependent molecular switches for integrin–ligand recognition

Corti¹,

Curnis²

2011

Journal of Cell Science

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“…Administration of 1 mg of CgA, i.p., generated circulating levels of about 3 to 5 nmol/L at the time of NGR-TNF administration in our murine models. This dose was selected to achieve circulating levels similar to those observed in subpopulation of patients with nonneuroendocrine tumors (11,12,31,37). For example, although serum CgA in the blood of normal subjects is about 1 nmol/L (21), increased levels of CgA, up to 4 to 8 nmol/L have been detected in the sera of a subgroup of patients with NSCLC, despite the lack of neuroendocrine differentiation, with important prognostic implication (37).…”

Section: Discussionmentioning

confidence: 99%

“…For example, although serum CgA in the blood of normal subjects is about 1 nmol/L (21), increased levels of CgA, up to 4 to 8 nmol/L have been detected in the sera of a subgroup of patients with NSCLC, despite the lack of neuroendocrine differentiation, with important prognostic implication (37). Considering that the combination of NGR-TNF and chemotherapy is currently under investigation in patients with NSCLC, hepatocellular carcinoma, or other nonneuroendocrine tumors (9)(10)(11)(12)(13)(14), the results showing inhibitory activity of CgA in animal models of nonneuroendocrine tumors might be clinically relevant. A growing body of evidence suggest that administration of proton pump inhibitors, which are drugs commonly used in the treatment of acid peptic disorders, can enhance 2 to 3 times, and in certain patients even up to 10 times, the circulating levels of CgA, depending on the time of administration (32,33).…”

Section: Discussionmentioning

confidence: 99%

“…NGR-TNF can also induce, at later time points, vascular damage and inflammatory/immune responses (4,8). Phase I and II clinical studies with low-dose NGR-TNF, alone and in combination with chemotherapy, showed manageable toxicity profile and evidence of disease control, particularly in subpopulations of patients with hepatocellular carcinoma and pleural mesothelioma (9)(10)(11)(12)(13)(14). A randomized double-blind phase III study of NGR-TNF (in combination with chemotherapy or supportive care) started in 2010 in patients with malignant pleural mesothelioma (http://www.…”

Section: Introductionmentioning

confidence: 99%

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Chromogranin A Restricts Drug Penetration and Limits the Ability of NGR-TNF to Enhance Chemotherapeutic Efficacy

Dondossola¹,

Gasparri²,

Colombo³

et al. 2011

Cancer Research

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“…No objective responses were observed, but of 6 patients with stable disease who received 6 or more cycles, 5 were treated with low doses (21). An additional trial aiming to further explore the low-dose range (from 0.2 to 1.6 mg/m 2 ) selected 0.8 mg/m 2 as the optimal biological dose based on dynamic imaging changes, soluble TNF-Rs kinetics, safety, and preliminary activity (22). To overcome the counterregulatory mechanism of the shedding of soluble TNF-a-receptors noted at higher doses and given the apparent similar preclinical and clinical activity between low and high doses, only the low-dose range previously tested in the single-agent trial (ref.…”

Section: Introductionmentioning

confidence: 99%

Phase I Study of NGR-hTNF, a Selective Vascular Targeting Agent, in Combination with Cisplatin in Refractory Solid Tumors

Gregorc

Braud

Pas

et al. 2011

Clinical Cancer Research

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Purpose: NGR-hTNF exploits the tumor-homing peptide asparagine-glycine-arginine (NGR) for selectively targeting TNF-a 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 mg/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 ¼ 4) and 0.4 mg/m 2 (n ¼ 3). One DLT (grade 3 infusion-related reaction) was observed at 0.8 mg/m 2 . This dose cohort was expanded to six patients without further DLTs.No DLTs were noted also at 1.6 mg/m 2 (n ¼ 3). NGR-hTNF exposure increased dose-proportionally without apparent PK interactions with cisplatin. No shedding of sTNF-Rs was detected up to 0.8 mg/m 2 . At the dose level of 0.8 mg/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 mg/m 2 with cisplatin 80 mg/m 2 showed favorable toxicity profile and promising antitumor activity.

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Defining the optimal biological dose of NGR-hTNF, a selective vascular targeting agent, in advanced solid tumours

Cited by 48 publications

References 22 publications

Isoaspartate-dependent molecular switches for integrin–ligand recognition

Isoaspartate-dependent molecular switches for integrin–ligand recognition

Chromogranin A Restricts Drug Penetration and Limits the Ability of NGR-TNF to Enhance Chemotherapeutic Efficacy

Phase I Study of NGR-hTNF, a Selective Vascular Targeting Agent, in Combination with Cisplatin in Refractory Solid Tumors

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