Publications by authors named "Jacques Rouanet"

7 Publications

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Efficacy of Targeted Radionuclide Therapy Using [I]ICF01012 in 3D Pigmented BRAF- and NRAS-Mutant Melanoma Models and In Vivo NRAS-Mutant Melanoma.

Cancers (Basel) 2021 Mar 20;13(6). Epub 2021 Mar 20.

INSERM U1240, University of Clermont Auvergne, 58 rue Montalembert, 63000 Clermont-Ferrand, France.

Purpose: To assess the efficiency of targeted radionuclide therapy (TRT), alone or in combination with MEK inhibitors (MEKi), in melanomas harboring constitutive MAPK/ERK activation responsible for tumor radioresistance.

Methods: For TRT, we used a melanin radiotracer ([I]ICF01012) currently in phase 1 clinical trial (NCT03784625). TRT alone or combined with MEKi was evaluated in three-dimensional melanoma spheroid models of human BRAF SK-MEL-3, murine NRAS 1007, and WT B16F10 melanomas. TRT in vivo biodistribution, dosimetry, efficiency, and molecular mechanisms were studied using the C57BL/6J-NRAS 1007 syngeneic model.

Results: TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant spheroids. NRAS spheroids were highly radiosensitive towards [I]ICF01012-TRT. In mice bearing NRAS 1007 melanoma, [I]ICF01012 induced a significant extended survival (92 vs. 44 days, < 0.0001), associated with a 93-Gy tumor deposit, and reduced lymph-node metastases. Comparative transcriptomic analyses confirmed a decrease in mitosis, proliferation, and metastasis signatures in TRT-treated vs. control tumors and suggest that TRT acts through an increase in oxidation and inflammation and P53 activation.

Conclusion: Our data suggest that [I]ICF01012-TRT and MEKi combination could be of benefit for advanced pigmented BRAF-mutant melanoma care and that [I]ICF01012 alone could constitute a new potential NRAS-mutant melanoma treatment.
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http://dx.doi.org/10.3390/cancers13061421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003594PMC
March 2021

Benzamide derivative radiotracers targeting melanin for melanoma imaging and therapy: Preclinical/clinical development and combination with other treatments.

Pharmacol Ther 2021 Mar 1;224:107829. Epub 2021 Mar 1.

Université Clermont Auvergne, INSERM, Imagerie Moléculaire et Stratégies Théranostiques, UMR1240, 58 Rue Montalembert, 63005 Clermont-Ferrand, Cedex, France. Electronic address:

Cutaneous melanoma arises from proliferating melanocytes, cells specialized in the production of melanin. This property means melanin can be considered as a target for monitoring melanoma patients using nuclear imaging or targeted radionuclide therapy (TRT). Since the 1970s, many researchers have shown that specific molecules can interfere with melanin. This paper reviews some such molecules: benzamide structures improved to increase their pharmacokinetics for imaging or TRT. We first describe the characteristics and biosynthesis of melanin, and the main features of melanin tracers. The second part summarizes the preclinical and corresponding clinical studies on imaging. The last section presents TRT results from ongoing protocols and discusses combinations with other therapies as an opportunity for melanoma non-responders or patients resistant to treatments.
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http://dx.doi.org/10.1016/j.pharmthera.2021.107829DOI Listing
March 2021

Immune checkpoint inhibitors reverse tolerogenic mechanisms induced by melanoma targeted radionuclide therapy.

Cancer Immunol Immunother 2020 Oct 23;69(10):2075-2088. Epub 2020 May 23.

UMR1240 INSERM, Université Clermont Auvergne, 58, rue Montalembert, BP 184, 63005, Clermont-Ferrand, France.

In line with the ongoing phase I trial (NCT03784625) dedicated to melanoma targeted radionuclide therapy (TRT), we explore the interplay between immune system and the melanin ligand [I]ICF01012 alone or combined with immunotherapy (immune checkpoint inhibitors, ICI) in preclinical models. Here we demonstrate that [I]ICF01012 induces immunogenic cell death, characterized by a significant increase in cell surface-exposed annexin A1 and calreticulin. Additionally, [I]ICF01012 increases survival in immunocompetent mice, compared to immunocompromised (29 vs. 24 days, p = 0.0374). Flow cytometry and RT-qPCR analyses highlight that [I]ICF01012 induces adaptive and innate immune cell recruitment in the tumor microenvironment. [I]ICF01012 combination with ICIs (anti-CTLA-4, anti-PD-1, anti-PD-L1) has shown that tolerance is a main immune escape mechanism, whereas exhaustion is not present after TRT. Furthermore, [I]ICF01012 and ICI combination has systematically resulted in a prolonged survival (p < 0.0001) compared to TRT alone. Specifically, [I]ICF01012 + anti-CTLA-4 combination significantly increases survival compared to anti-CTLA-4 alone (41 vs. 26 days; p = 0.0011), without toxicity. This work represents the first global characterization of TRT-induced modifications of the antitumor immune response, demonstrating that tolerance is a main immune escape mechanism and that combining TRT and ICI is promising.
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http://dx.doi.org/10.1007/s00262-020-02606-8DOI Listing
October 2020

'Aberrant localisation of Annexin A1 is associated with metastatic outcome in thin melanomas'.

Australas J Dermatol 2020 May 23;61(2):e254-e256. Epub 2019 Oct 23.

UMR990 INSERM, Université d'Auvergne, Clermont-Ferrand, France.

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http://dx.doi.org/10.1111/ajd.13174DOI Listing
May 2020

Targeted Radionuclide Therapy Decreases Melanoma Lung Invasion by Modifying Epithelial-Mesenchymal Transition-Like Mechanisms.

Transl Oncol 2019 Nov 14;12(11):1442-1452. Epub 2019 Aug 14.

UMR 1240 INSERM, University of Clermont Auvergne, Clermont-Ferrand, France. Electronic address:

Melanin-radiolabeled molecules for targeted radionuclide therapy (TRT) provide a promising approach for the treatment of pigmented melanoma. Among these radiolabeled molecules, the iodinated melanin-specific binding molecule ([I]ICF01012) has shown a significant antitumor effect on metastatic melanoma preclinical models. We report herein that [I]ICF01012 decreases the epithelial-mesenshymal transition-like (EMT-like) markers in both in vivo and in vitro three-dimensional (3D) melanoma spheroid models. [I]ICF01012 spheroids irradiation resulted in reduced clonogenic capacity of all pigmented spheroids accompanied by increased protein expression levels of phosphorylated H2A.X, p53 and its downstream target p21. In addition, [I]ICF01012 treatment leads to a significant increase of cell pigmentation as demonstrated in SK-MEL3 human xenograft model. We also showed that [I]ICF01012 decreases the size and the number of melanoma lung colonies in the syngeneic murine B16BL6 in vivo model assessing its potentiality to kill circulating tumor cells. Taken together, these results indicate that [I]ICF01012 reduces metastatic capacity of melanoma cells presumably through EMT-like reduction and cell differentiation induction.
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http://dx.doi.org/10.1016/j.tranon.2019.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704444PMC
November 2019

Determination of eumelanin and pheomelanin in melanomas using solid-phase extraction and high performance liquid chromatography-diode array detection (HPLC-DAD) analysis.

J Chromatogr B Analyt Technol Biomed Life Sci 2019 Apr 11;1113:60-68. Epub 2019 Mar 11.

UMR 1240 INSERM UCA, 58 Rue Montalembert, 63005 Clermont-Ferrand Cedex, France. Electronic address:

Determination of eumelanin and pheomelanin in melanomas that exhibit different pigmentation was carried using a solid-phase extraction (SPE) preparation method based on weak anion exchange chemistry. This extraction significantly enhanced the chromatographic profile obtained by reverse phase high performance liquid chromatography-diode array detection (RP-HPLC-DAD). The SPE method was developed using aqueous standards of melanin markers: thiazole-2,4,5-tricarboxylic acid (TTCA), thiazole-4,5-dicarboxylic acid (TDCA), pyrrole-2,3-dicarboxylic acid (PDCA) and pyrrole-2,3,5-tricarboxylic acid (PTCA) and non-pigmented cell lines spiked with those markers. An excellent average recovery, above 90%, was obtained for the four markers with a relative standard deviation below 7%. We have also optimized the stationary phase and the mobile phase (phosphate concentration and pH) to improve sensitivity and to reduce the analysis time. Elution of the four markers is achieved in 5 min and total analysis of biological samples is completed in 15 min. The quantification limits for TDCA, TTCA, PDCA and PTCA are 60, 50, 47 and 48 ng/mL respectively. Furthermore, DAD detection improves the marker identification in complex matrices through the analysis of UV spectra. We have successfully applied this method to melanoma tumors and cells. Murine B16BL6 tumor are highly pigmented with mostly eumelanin (98.1% of eumelanin) while human SK-MEL-3 tumor contain about 30% pheomelanin. B16BL6 and B16F10 are eumelanic cells lines and NHEM melanocytes contain about 24% of pheomelanin.
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http://dx.doi.org/10.1016/j.jchromb.2019.03.010DOI Listing
April 2019