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

Gregorc, Vanesa; Braud, Filippo de; Pas, Tommaso Martino De; Scalamogna, R.; Citterio, Giovanni; Milani, Alessandra; Boselli, Sabrina; Catania, Chiara; Donadoni, Giovanni; Rossoni, G.; Ghio, Domenico; Spitaleri, Gianluca; Ammannati, Cristina; Colombi, Scialini; Caligaris-Cappio, Federico; Lambiase, A.; Bordignon, Claudio

doi:10.1158/1078-0432.ccr-10-1376

Cited by 52 publications

(32 citation statements)

References 25 publications

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“…TNFα from CICs may directly contribute to oncogene activation, DNA damage, or formation of epithelial mesenchymal transition (EMT) [34], although TNFα is also involved in asthma, chronic bronchitis, or COPD [35]. The combination of cisplatin with a vascular agent selectively targeting TNFα showed favorable toxicity profile and promising anti-tumor activity in patients with lung cancer [34]. Cancer cell proliferation, survival, angiogenesis, invasion, or metastasis increased through TNFα-induced NF-κB activation [33].…”

Section: Roles Of Cytokines In Cancer-related Inflammationmentioning

confidence: 99%

Targeting roles of inflammatory microenvironment in lung cancer and metastasis

Shi

Wang

Hou

et al. 2015

Cancer Metastasis Rev

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Inflammatory cells and mediators are essential components in tumor microenvironment and play decisive roles in the initiation, proliferation, survival, promotion, invasion, or metastasis of lung cancer. Clinical and epidemiologic studies suggested a strong association between inflammation and lung cancer and an influence of immune surveillances and tumor responses to chemotherapeutic drugs, although roles of inflammation in lung cancer remain unclear. The present review outlined roles of inflammation in lung cancer, with particular focus on inflammatory components, types, biomarkers, or principal mechanisms by which the inflammation contributes to the development of lung cancer. The cancer-associated inflammatory cells (CICs) should be furthermore defined and include cancer-specific and interacted cells with inflammatory or inflammation-like characteristics, e.g., innate or adaptive immune cells and cancer tissue cells. We also discuss targeting potentials of inflammation in the prevention and treatment of lung cancer. The diversity of cancer-related inflammatory microenvironment is instrumental to design novel therapeutic approaches for lung cancer.

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Section: Roles Of Cytokines In Cancer-related Inflammationmentioning

confidence: 99%

Targeting roles of inflammatory microenvironment in lung cancer and metastasis

Shi

Wang

Hou

et al. 2015

Cancer Metastasis Rev

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“…23,28,29 Our final aim was to address the most accurate strategy to predict cisplatin sensitivity/resistance after short-time treatments with doses around the peak plasma concentration achieved in Pt-treated cancer patients. 30 …”

Section: Introductionmentioning

confidence: 99%

Cisplatin resistance in cell models: evaluation of metallomic and biological predictive biomarkers to address early therapy failure

et al. 2017

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Cisplatin, one of the most extensively used metallodrugs in cancer treatment, presents the important drawback of patient resistance. This resistance is the consequence of different processes including those preventing the formation of DNA adducts and/or their quick removal. Thus, a tool for the accurate detection and quantitation of cisplatin-induced adducts might be valuable for predicting patient resistance. To prove the validity of such an assumption, highly sensitive plasma mass spectrometry (ICP-MS) strategies were applied to determine DNA adduct levels and intracellular Pt concentrations. These two metal-relative parameters were combined with an evaluation of biological responses in terms of genomic stability (with the Comet assay) and cell cycle progression (by flow cytometry) in four human cell lines of different origins and cisplatin sensitivities (A549, GM04312, A2780 and A2780cis), treated with low cisplatin doses (5, 10 and 20 mM for 3 hours). Cell viability and apoptosis were determined as resistance indicators. Univariate linear regression analyses indicated that quantitation of cisplatin-induced G-G intra-strand adducts, measured 1 h after treatment, was the best predictor for viability and apoptosis in all of the cell lines. Multivariate linear regression analyses revealed that the prediction improved when the intracellular Pt content or the Comet data were included in the analysis, for all sensitive cell lines and for the A2780 and A2780cis cell lines, respectively. Thus, a reliable cisplatin resistance predictive model, which combines the quantitation of adducts by HPLC-ICP-MS, and their repair, with the intracellular Pt content and induced genomic instability, might be essential to identify early therapy failure. Significance to metallomicsKnowledge about cisplatin as a chemotherapy drug is extensive, including information about the several processes that contribute to its resistance, the main problem of using this chemical. However, this knowledge and information does not yet allow the early identification of resistant tumors/patients, one of the most desired aims of clinicians. In this work we have developed a model that might allow the early detection of chemical resistance and, more importantly, might do so mostly regardless of the resistance mechanism involved, because it determines the dynamics of adduct induction/repair, considering chemical influx/efflux and induced genomic instability.

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“…[3][4][5][6][7][8][9] It shows antitumor activity at low dose (0.8 mg/sqm) and has a very low toxicity profile rendering it suitable for long-term maintenance treatment.…”

mentioning

confidence: 99%

The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

et al. 2015

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NGR-TNF is a vascular targeting agent in advanced clinical development, coupling tumor necrosis factor-a (TNF) with the CNGRCG peptide, which targets a CD13 isoform specifically expressed by angiogenic vessels. Antitumor efficacy of NGR-TNF has been described in different transplantation tumor models. Nevertheless, the mechanism underlying its activity is not fully understood. In the wild type and in the immunodeficient (RAG ¡/¡ ) RIP1-Tag2 models of multistage pancreatic carcinogenesis, we demonstrate that CD13 is highly expressed on endothelial cells of hyperplastic and angiogenic islets, whereas its expression is down regulated in tumors where it partially colocalize with pericytes. In vivo CNGRCG peptides coupled to fluorescent nanoparticles (quantum dots) bind to CD13 and colocalize with anti-CD31, in pancreatic islets. At early stage, low doses of NGR-murine (m)TNF have a direct cytotoxic effect inducing endothelial cell apoptosis, reducing vessel density and eventually inhibiting the development of angiogenic islets. At a later stage, NGRmTNF is able to reduce tumor growth inducing vascular normalization, exclusively when treatment is carried out in the immunocompetent mice. Interestingly, NGR-mTNF-treated tumors from these mice are characterized by CD8 C T cell infiltration. At molecular level, overexpression of genes involved in vessels normalization was detected only in NGRmTNF-treated tumors from immunocompetent mice.These findings identified a new mechanism of action of NGR-mTNF, providing support for the development of new therapeutic strategies combining chemotherapy or active/adoptive immunotherapies to low dose NGR-TNF treatment.

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

Cited by 52 publications

References 25 publications

Targeting roles of inflammatory microenvironment in lung cancer and metastasis

Targeting roles of inflammatory microenvironment in lung cancer and metastasis

Cisplatin resistance in cell models: evaluation of metallomic and biological predictive biomarkers to address early therapy failure

The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

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