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13 pages, 1759 KB

Open AccessArticle

Prognosis of Coronary Atherosclerotic Burden in Non-Ischemic Dilated Cardiomyopathies

by Marjorie Canu, Léa Margerit, Ismail Mekhdoul, Alexis Broisat, Laurent Riou, Loïc Djaileb, Clémence Charlon, Adrien Jankowski, Michele Magnesa, Caroline Augier, Stéphanie Marlière, Muriel Salvat, Charlotte Casset, Marion Maurin, Carole Saunier, Daniel Fagret, Catherine Ghezzi, Gerald Vanzetto and Gilles Barone-Rochette

J. Clin. Med. 2021, 10(10), 2183; https://doi.org/10.3390/jcm10102183 - 18 May 2021

Cited by 7 | Viewed by 3940

Abstract

Background: Atherosclerosis is associated with a worse prognosis in many diseases such as ischemic cardiomyopathy, but its impact in non-ischemic dilated cardiomyopathy (dCMP) is lesser known. Our aim was to study the prognostic impact of coronary atherosclerotic burden (CAB) in patients with dCMP. Methods: Consecutive patients with dCMP and left ventricular (LV) dysfunction diagnosed by concomitant analysis of invasive coronary angiography (ICA) and CMR imaging were identified from registry-database. CAB was measured by Gensini score. The primary composite endpoint was the occurrence of major adverse cardiovascular events (MACE) defined as cardiovascular (CV) mortality, non-fatal MI and unplanned myocardial revascularization. The results of 139 patients constituting the prospective study population (mean age 59.4 ± 14.7 years old, 74% male), average LV ejection fraction was 31.1 ± 11.02%, median Gensini score was 0 (0–3), and mid-wall late gadolinium enhancement (LGE) was the most frequent LGE pattern (42%). Over a median follow-up of 2.8 years, 9% of patients presented MACE. Patients with MACE had significantly higher CAB compared to those who were free of events (0 (0–3) vs. 3.75 (2–15), p < 0.0001). CAB remained the significant predictor of MACE on multivariate logistic analysis (OR: 1.12, CI: 1.01–1.23, p = 0.02). Conclusion: High CAB may be a new prognostic factor in dCMP patients. Full article

(This article belongs to the Special Issue The Treatment of Coronary Artery Disease and the Impact of This on All Cardiomyopathies)

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11 pages, 3069 KB

Open AccessArticle

In Vivo Biodistribution and Efficacy Evaluation of NeoB, a Radiotracer Targeted to GRPR, in Mice Bearing Gastrointestinal Stromal Tumor

by Christopher Montemagno, Florian Raes, Mitra Ahmadi, Sandrine Bacot, Marlène Debiossat, Julien Leenhardt, Jean Boutonnat, Francesca Orlandi, Donato Barbato, Mattia Tedesco, Catherine Ghezzi, Pascale Perret and Alexis Broisat

Cancers 2021, 13(5), 1051; https://doi.org/10.3390/cancers13051051 - 2 Mar 2021

Cited by 19 | Viewed by 4653

Abstract

NeoB is a radiotracer targeting the gastrin-releasing peptide receptor (GRPR), a G-protein–coupled receptor expressed in various cancers. The aim of the present study was to evaluate the biodistribution and efficacy of this new therapeutic agent in Gastrointestinal Stromal Tumors (GIST). Eighty-two SCID mice bearing GIST-882 tumors were employed. [¹⁷⁷Lu]Lu-NeoB biodistribution was evaluated up to seven days by organ sampling (200 pmol/0.8 MBq, i.v.). For efficacy evaluation, mice received either saline, 400 pmol or 800 pmol of [¹⁷⁷Lu]Lu-NeoB (37MBq, 1/w, 3 w, i.v.). SPECT/CT imaging was performed at 24 h, and tumor volume was determined up to 100 days. Elevated and specific [¹⁷⁷Lu]Lu-NeoB uptake was found in the GIST tumor, as demonstrated by in vivo competition (19.1 ± 3.9 %ID/g vs. 0.3 ± 0.1 %ID/g at 4h). [¹⁷⁷Lu]Lu-NeoB tumor retention (half-life of 40.2 h) resulted in elevated tumor-to-background ratios. Tumor volumes were significantly reduced in both treated groups (p < 0.01), even leading to complete tumor regression at the 400 pmol dose. [¹⁷⁷Lu]Lu-NeoB exhibited excellent pharmacokinetics with elevated and prolonged tumor uptake and low uptake in non-target organs such as pancreas. The potential of this new theragnostic agent in different indications, including GIST, is under evaluation in the FIH [¹⁷⁷Lu]Lu-NeoB clinical trial. Full article

(This article belongs to the Special Issue Molecular Imaging and Radio-Nuclide Therapy in Cancers)

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18 pages, 1263 KB

Open AccessReview

From Malignant Progression to Therapeutic Targeting: Current Insights of Mesothelin in Pancreatic Ductal Adenocarcinoma

by Christopher Montemagno, Shamir Cassim, Jacques Pouyssegur, Alexis Broisat and Gilles Pagès

Int. J. Mol. Sci. 2020, 21(11), 4067; https://doi.org/10.3390/ijms21114067 - 6 Jun 2020

Cited by 31 | Viewed by 7420

Abstract

Pancreatic ductal adenocarcinoma (PDAC), accounting for 90% of all pancreatic tumors, is a highly devastating disease with poor prognosis and rising incidence. The lack of available specific diagnostics tests and the limited treatment opportunities contribute to this pejorative issue. Over the last 10 years, a growing interest pointing towards mesothelin (MSLN) as a promising PDAC-associated antigen has emerged. The limited expression of MSLN in normal tissues (peritoneum, pleura and pericardium) and its overexpression in 80 to 90% of PDAC make it an attractive candidate for therapeutic management of PDAC patients. Moreover, its role in malignant progression related to its involvement in tumor cell proliferation and resistance to chemotherapy has highlighted the relevance of its targeting. Hence, several clinical trials are investigating anti-MSLN efficacy in PDAC. In this review, we provide a general overview of the different roles sustained by MSLN during PDAC progression. Finally, we also summarize the different MSLN-targeted therapies that are currently tested in the clinic. Full article

(This article belongs to the Special Issue Pancreatic Ductal Adenocarcinoma: Precursors and Variants)

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10 pages, 4269 KB

Open AccessArticle

Improved Detection of Molecular Markers of Atherosclerotic Plaques Using Sub-Millimeter PET Imaging

by Jessica Bridoux, Sara Neyt, Pieterjan Debie, Benedicte Descamps, Nick Devoogdt, Frederik Cleeren, Guy Bormans, Alexis Broisat, Vicky Caveliers, Catarina Xavier, Christian Vanhove and Sophie Hernot

Molecules 2020, 25(8), 1838; https://doi.org/10.3390/molecules25081838 - 16 Apr 2020

Cited by 16 | Viewed by 4234

Abstract

Since atherosclerotic plaques are small and sparse, their non-invasive detection via PET imaging requires both highly specific radiotracers as well as imaging systems with high sensitivity and resolution. This study aimed to assess the targeting and biodistribution of a novel fluorine-18 anti-VCAM-1 Nanobody (Nb), and to investigate whether sub-millimetre resolution PET imaging could improve detectability of plaques in mice. The anti-VCAM-1 Nb functionalised with the novel restrained complexing agent (RESCA) chelator was labelled with [¹⁸F]AlF with a high radiochemical yield (>75%) and radiochemical purity (>99%). Subsequently, [¹⁸F]AlF(RESCA)-cAbVCAM1-5 was injected in ApoE^−/− mice, or co-injected with excess of unlabelled Nb (control group). Mice were imaged sequentially using a cross-over design on two different commercially available PET/CT systems and finally sacrificed for ex vivo analysis. Both the PET/CT images and ex vivo data showed specific uptake of [¹⁸F]AlF(RESCA)-cAbVCAM1-5 in atherosclerotic lesions. Non-specific bone uptake was also noticeable, most probably due to in vivo defluorination. Image analysis yielded higher target-to-heart and target-to-brain ratios with the β-CUBE (MOLECUBES) PET scanner, demonstrating that preclinical detection of atherosclerotic lesions could be improved using the latest PET technology. Full article

(This article belongs to the Special Issue Radiopharmaceuticals for PET Imaging - Issue A)

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8 pages, 1313 KB

Open AccessBrief Report

^99mTc-A1 as a Novel Imaging Agent Targeting Mesothelin-Expressing Pancreatic Ductal Adenocarcinoma

by Christopher Montemagno, Shamir Cassim, Dimitry Trichanh, Clara Savary, Jacques Pouyssegur, Gilles Pagès, Daniel Fagret, Alexis Broisat and Catherine Ghezzi

Cancers 2019, 11(10), 1531; https://doi.org/10.3390/cancers11101531 - 10 Oct 2019

Cited by 18 | Viewed by 5329

Abstract

Mesothelin is a membrane-associated protein overexpressed in pancreatic ductal adenocarcinoma (PDAC). Some mesothelin-targeted therapies are in clinical development but the identification of patients eligible for such therapies is still challenging. The objective of this study was to perform the imaging of mesothelin in mice models of PDAC with a technetium-labeled anti-mesothelin single-domain antibody (^99mTc-A1). Methods: The Cancer Genomic Atlas (TCGA) database was used to determine the prognostic role of mesothelin in PDAC. ^99mTc-A1 was evaluated both in vitro in PDAC cells (SW1990 and AsPC-1) and in vivo in an experimental model of mesothelin-expressing PDAC (AsPC-1) in mice. Results: TCGA analysis showed that PDAC patients with high mesothelin expression had a shorter overall survival (P = 0.00066). The binding of ^99mTc-A1 was 2.1-fold greater in high-mesothelin-expressing AsPC-1 cells when compared to moderate-mesothelin-expressing SW1990 cells (p < 0.05). In vivo, the ^99mTc-A1 uptake was 3.5-fold higher in AsPC-1-derived tumors as compared to a technetium-labeled irrelevant antibody (^99mTc-Ctl) (p < 0.01). Conclusions: ^99mTc-A1 accurately allows imaging of mesothelin-expressing experimental PDAC tumors. Our experiments paved the way for the development of a companion test for mesothelin-targeted therapies. Full article

(This article belongs to the Special Issue Role of Medical Imaging in Cancers)

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13 pages, 2649 KB

Open AccessArticle

In Vivo Assessment of VCAM-1 Expression by SPECT/CT Imaging in Mice Models of Human Triple Negative Breast Cancer

by Christopher Montemagno, Laurent Dumas, Pierre Cavaillès, Mitra Ahmadi, Sandrine Bacot, Marlène Debiossat, Audrey Soubies, Loic Djaïleb, Julien Leenhardt, Nicolas De Leiris, Maeva Dufies, Gilles Pagès, Sophie Hernot, Nick Devoogdt, Pascale Perret, Laurent Riou, Daniel Fagret, Catherine Ghezzi and Alexis Broisat

Cancers 2019, 11(7), 1039; https://doi.org/10.3390/cancers11071039 - 23 Jul 2019

Cited by 7 | Viewed by 6268

Abstract

Recent progress in breast cancer research has led to the identification of Vascular Cell Adhesion Molecule-1 (VCAM-1) as a key actor of metastatic colonization. VCAM-1 promotes lung-metastases and is associated with clinical early recurrence and poor outcome in triple negative breast cancer (TNBC). Our objective was to perform the in vivo imaging of VCAM-1 in mice models of TNBC. The Cancer Genomic Atlas (TCGA) database was analyzed to evaluate the prognostic role of VCAM-1 in TNBC. MDA-MB-231 (VCAM-1+) and control HCC70 (VCAM-1-) TNBC cells were subcutaneously xenografted in mice and VCAM-1 expression was assessed in vivo by single-photon emission computed tomography (SPECT) imaging using ^99mTc-cAbVCAM1-5. Then, MDA-MB-231 cells were intravenously injected in mice and VCAM-1 expression in lung metastasis was assessed by SPECT imaging after 8 weeks. TCGA analysis showed that VCAM-1 is associated with a poor prognosis in TNBC patients. In subcutaneous tumor models, ^99mTc-cAbVCAM1-5 uptake was 2-fold higher in MDA-MB-231 than in HCC70 (p < 0.01), and 4-fold higher than that of the irrelevant control (p < 0.01). Moreover, ^99mTc-cAbVCAM1-5 uptake in MDA-MB-231 lung metastases was also higher than that of ^99mTc-Ctl (p < 0.05). ^99mTc-cAbVCAM1-5 is therefore a suitable tool to evaluate the role of VCAM-1 as a marker of tumor aggressiveness of TNBC. Full article

(This article belongs to the Special Issue Role of Medical Imaging in Cancers)

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11 pages, 2177 KB

Open AccessArticle

Biodistribution, Stability, and Blood Distribution of the Cell Penetrating Peptide Maurocalcine in Mice

by Pascale Perret, Mitra Ahmadi, Laurent Riou, Sandrine Bacot, Julien Pecher, Cathy Poillot, Alexis Broisat, Catherine Ghezzi and Michel De Waard

Int. J. Mol. Sci. 2015, 16(11), 27730-27740; https://doi.org/10.3390/ijms161126054 - 19 Nov 2015

Cited by 15 | Viewed by 6531

Abstract

Maurocalcine (MCa) is the first natural cell penetrating peptide to be discovered in animal venom. In addition to the fact that it represents a potent vector for the cell penetration of structurally diverse therapeutic compounds, MCa also displays several distinguishing features that make it a potential peptide of choice for clinical and biotechnological applications. The aim of the present study was to gain new information about the properties of MCa in vivo in order to delineate the future potential applications of this vector. For this purpose, two analogues of this peptide with (Tyr-MCa) and without (Lin-Tyr-MCa) disulfide bridges were synthesized, radiolabeled with ¹²⁵I, and their in vitro stabilities were first evaluated in mouse blood. The results indicated that ¹²⁵I-Tyr-MCa was stable in vitro and that the disulfide bridges conferred a competitive advantage for the stability of peptide. Following in vivo injection in mice, ¹²⁵I-Tyr-MCa targeted peripheral organs with interesting quantitative differences and the main route of peptide elimination was renal. Full article

(This article belongs to the Special Issue Cell-Penetrating Peptides)

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