Publications by authors named "Françoise Degoul"

44 Publications

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

Relevance of the combination of external beam radiotherapy with the hypoxia-activated prodrug ICF05016 in an experimental model of extraskeletal myxoid chondrosarcoma.

Invest New Drugs 2021 Apr 18;39(2):295-303. Epub 2020 Sep 18.

Clermont Auvergne University, UMR 1240 INSERM IMoST, 58 rue Montalembert, F-63000, Clermont Ferrand, France.

Currently, there is no gold standard treatment for Extraskeletal Myxoid Chondrosarcomas (EMC) making wide margin surgical resection the most effective alternative treatment. Nevertheless, in previous preclinical studies our lab demonstrated the potential of the hypoxia-activated prodrug (HAP) ICF05016 on EMC murine model inoculated with the H-EMC-SS human cell line. The aim of this study was to assess, in vivo, the relevance of the combination of this HAP with External Beam Radiotherapy (EBR). Firstly EMC-bearing mice were treated with 6 Gy or 12 Gy of EBR (single 6 MV photon). Then for combination of HAP and EBR, animals received 6 doses of ICF05016 (46.8 μmol/kg, intravenously) at 4-day intervals, with 6 Gy EBR performed 24 h after the 3rd dose of HAP. Animals were monitored throughout the study for clinical observations (tumour growth, side effects) and survival studies were performed. From tumour samples, PCNA, Ki-67 and p21 expressions were used as markers of proliferation and cell cycle arrest. Statistical significances were determined using Kruskall-Wallis and log rank tests. The radiosensitivity of the EMC model was demonstrated at 12 Gy with significant inhibition of tumour growth. Then, the HAP strategy potentiated EBR efficacy at a lower dose (6 Gy) by improving survival without generating side effects. Thus, results of this study showed the potential interest of ICF05016 for the combination with EBR in the management of EMC.
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http://dx.doi.org/10.1007/s10637-020-01002-4DOI Listing
April 2021

Optimization of IEDDA bioorthogonal system: Efficient process to improve trans-cyclooctene/tetrazine interaction.

Eur J Med Chem 2020 Oct 15;203:112574. Epub 2020 Jul 15.

Université Clermont Auvergne, Imagerie Moléculaire et Stratégies Théranostiques, BP 184, F-63005, Clermont-Ferrand, France; Inserm, U 1240, F-63000, Clermont-Ferrand, France; Centre Jean Perrin, F-63011, Clermont-Ferrand, France. Electronic address:

The antibody pretargeting approach for radioimmunotherapy (RIT) using inverse electron demand Diels-Alder cycloaddition (IEDDA) constitutes an emerging theranostic approach for solid cancers. However, IEDDA pretargeting has not reached clinical trial. The major limitation of the IEDDA strategy depends largely on trans-cyclooctene (TCO) stability. Indeed, TCO may isomerize into the more stable but unreactive cis-cyclooctene (CCO), leading to a drastic decrease of IEDDA efficiency. We have thus developed both efficient and reproducible synthetic pathways and analytical follow up for (PEGylated) TCO derivatives, providing high TCO isomeric purity for antibody modification. We have set up an original process to limit the isomerization of TCO to CCO before the mAbs' functionalization to allow high TCO/tetrazine cycloaddition.
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http://dx.doi.org/10.1016/j.ejmech.2020.112574DOI Listing
October 2020

Tspan8 Drives Melanoma Dermal Invasion by Promoting ProMMP-9 Activation and Basement Membrane Proteolysis in a Keratinocyte-Dependent Manner.

Cancers (Basel) 2020 May 21;12(5). Epub 2020 May 21.

Centre de Génétique et de Physiologie Moléculaires et Cellulaires, CNRS UMR5534, Université de Lyon, F-69003 Lyon, France.

Melanoma is the most aggressive skin cancer with an extremely challenging therapy. The dermal-epidermal junction (DEJ) degradation and subsequent dermal invasion are the earliest steps of melanoma dissemination, but the mechanisms remain elusive. We previously identified Tspan8 as a key actor in melanoma invasiveness. Here, we investigated Tspan8 mechanisms of action during dermal invasion, using a validated skin-reconstruct-model that recapitulates melanoma dermal penetration through an authentic DEJ. We demonstrate that Tspan8 is sufficient to induce melanoma cells' translocation to the dermis. Mechanistically, Tspan8 melanoma cells cooperate with surrounding keratinocytes within the epidermis to promote keratinocyte-originated proMMP-9 activation process, collagen IV degradation and dermal colonization. This concurs with elevated active MMP-3 and low TIMP-1 levels, known to promote MMP-9 activity. Finally, a specific Tspan8-antibody reduces proMMP-9 activation and dermal invasion. Overall, our results provide new insights into the role of keratinocytes in melanoma dermal colonization through a cooperative mechanism never reported before, and establish for the first time the pro-invasive role of a tetraspanin family member in a cell non-autonomous manner. This work also displays solid arguments for the use of Tspan8-blocking antibodies to impede early melanoma spreading and therefore metastasis.
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http://dx.doi.org/10.3390/cancers12051297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281247PMC
May 2020

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

Antibody Pretargeting Based on Bioorthogonal Click Chemistry for Cancer Imaging and Targeted Radionuclide Therapy.

Bioconjug Chem 2020 02 6;31(2):159-173. Epub 2020 Jan 6.

Université Clermont Auvergne , Imagerie Moléculaire et Stratégies Théranostiques , BP 184, F-63005 Clermont-Ferrand , France.

Bioorthogonal click chemistry-employing antibody-conjugated -cyclooctenes (TCO) and tetrazine (Tz)-based radioligands able to covalently bind -appeared recently as a potential alternative to circumvent the hematotoxicity induced by radioimmunotherapy of solid tumors. This Review focuses on the recent advances concerning TCO/Tz pretargeting in both cancer imaging and targeted-radionuclide therapy for prospective clinical transfer. We exhaustively identified 25 PubMed publications reporting preclinical imaging and 5 therapy studies with full mAbs as targeting vectors, since its first application in 2010. The fast, safe, modulable, and specific TCO/Tz pretargeting showed high potential as a theranostic tool to get more personalized and precise cancer care. The recent optimizations reported here highlighted a possible first clinical evaluation of IEDDA pretargeting in the coming years.
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00761DOI Listing
February 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

Pretargeted radioimmunotherapy and SPECT imaging of peritoneal carcinomatosis using bioorthogonal click chemistry: probe selection and first proof-of-concept.

Theranostics 2019 19;9(22):6706-6718. Epub 2019 Sep 19.

Université Clermont Auvergne, Imagerie Moléculaire et Stratégies Théranostiques, BP 184, F-63005 Clermont-Ferrand, France. Inserm, U 1240, F-63000 Clermont-Ferrand, France. Centre Jean Perrin, F-63011 Clermont-Ferrand, France.

: Pretargeted radioimmunotherapy (PRIT) based upon bioorthogonal click chemistry has been investigated for the first time in the context of peritoneal carcinomatosis using a CEA-targeting 35A7 mAb bearing -cyclooctene (TCO) moieties and several Lu-labeled tetrazine (Tz) radioligands. Starting from three Tz probes containing PEG linkers of varying lengths between the DOTA and Tz groups (. PEG = 3, 7, or 11, respectively, for Tz-, Tz-, and Tz-), we selected [Lu]Lu-Tz as the most appropriate for pretargeted SPECT imaging and demonstrated its efficacy in tumor growth control. An orthotopic model of peritoneal carcinomatosis (PC) was obtained following the intraperitoneal (i.p.) injection of A431-CEA-Luc cells in nude mice. Tumor growth was assessed using bioluminescence imaging. Anti-CEA 35A7 mAb was grafted with 2-3 TCO immunoglobulin. Pretargeted SPECT imaging and biodistribution experiments were performed to quantify the activity concentrations of [Lu]Lu-Tz- in tumors and non-target organs to determine the optimal Tz probe for the PRIT of PC. The pharmacokinetic profiles of [Lu]Lu-Tz- alone were determined using both SPECT imaging and biodistribution experiments. These data revealed that [Lu]Lu-Tz- was cleared both the renal and hepatic systems while [Lu]Lu-Tz- and [Lu]Lu-Tz- were predominantly excreted the renal system. In addition, these results illuminated that the longer the PEG linker, the more rapidly the Tz radioligand was cleared from the peritoneal cavity. The absorbed radiation dose corresponding to pretargeting with 35A7-TCO followed 24 h later by [Lu]Lu-Tz- was higher for tumors following the administration of [Lu]Lu-Tz- (. 0.59 Gy/MBq) compared to either [Lu]Lu-Tz- (. 0.25 Gy/MBq) and [Lu]Lu-Tz- (. 0.18 Gy/MBq). In a longitudinal PRIT study, we showed that the i.p. injection of 40 MBq of [Lu]Lu-Tz- 24 hours after the systemic administration of 35A7-TCO significantly slowed tumor growth compared to control mice receiving only saline or 40 MBq of [Lu]Lu-Tz- alone. measurement of the peritoneal carcinomatosis index (PCI) confirmed that PRIT significantly reduced tumor growth (PCI = 15.5 ± 2.3 after PRIT 30.0 ± 2.3 and 30.8 ± 1.4 for the NaCl and [Lu]Lu-Tz- alone groups, respectively). : Our results clearly demonstrate the impact of the length of PEG linkers upon the biodistribution profiles of Lu-labeled Tz radioligands. Furthermore, we demonstrated for the first time the possibility of using bioorthogonal chemistry for both the pretargeted SPECT and PRIT of peritoneal carcinomatosis.
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http://dx.doi.org/10.7150/thno.35461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771248PMC
October 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

Targeting the Tetraspanins with Monoclonal Antibodies in Oncology: Focus on Tspan8/Co-029.

Cancers (Basel) 2019 Feb 3;11(2). Epub 2019 Feb 3.

Université Clermont Auvergne, INSERM U1240, Imagerie Moléculaire et Stratégies Théranostiques, F-63000 Clermont Ferrand, France.

Tetraspanins are exposed at the surface of cellular membranes, which allows for the fixation of cognate antibodies. Developing specific antibodies in conjunction with genetic data would largely contribute to deciphering their biological behavior. In this short review, we summarize the main functions of Tspan8/Co-029 and its role in the biology of tumor cells. Based on data collected from recently reported studies, the possibilities of using antibodies to target Tspan8 in immunotherapy or radioimmunotherapy approaches are also discussed.
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http://dx.doi.org/10.3390/cancers11020179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406856PMC
February 2019

TIP60: an actor in acetylation of H3K4 and tumor development in breast cancer.

Epigenomics 2018 11 16;10(11):1415-1430. Epub 2018 Oct 16.

Department of Oncogenetics, Centre Jean Perrin, CBRV, 28 Place Henri-Dunant, 63001, Clermont-Ferrand, France.

Aim: The acetyltransferase TIP60 is reported to be downregulated in several cancers, in particular breast cancer, but the molecular mechanisms resulting from its alteration are still unclear.

Materials & Methods: In breast tumors, H3K4ac enrichment and its link with TIP60 were evaluated by chromatin immunoprecipitation-qPCR and re-chromatin immunoprecipitation techniques. To assess the biological roles of TIP60 in breast cancer, two cell lines of breast cancer, MDA-MB-231 (ER-) and MCF-7 (ER+) were transfected with shRNA specifically targeting TIP60 and injected to athymic Balb-c mice.

Results: We identified a potential target of TIP60, H3K4. We show that an underexpression of TIP60 could contribute to a reduction of H3K4 acetylation in breast cancer. An increase in tumor development was noted in sh-TIP60 MDA-MB-231 xenografts and a slowdown of tumor growth in sh-TIP60 MCF-7 xenografts.

Conclusion: This is evidence that the underexpression of TIP60 observed in breast cancer can promote the tumorigenesis of ER-negative tumors.
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http://dx.doi.org/10.2217/epi-2018-0004DOI Listing
November 2018

Radiation dosimetry of [ I]ICF01012 in rabbits: Application to targeted radionuclide therapy for human melanoma treatment.

Med Phys 2018 Nov 24;45(11):5251-5262. Epub 2018 Sep 24.

Université Clermont Auvergne, CNRS/IN2P3, Laboratoire de Physique de Clermont, UMR6533, 4 Avenue Blaise Pascal TSA 60026, CS 60026 63178, Aubière Cedex, France.

Purpose: Dosimetry for melanoma-targeted radionuclide therapy (TRT) with [ I]ICF01012, a melanin ligand, has been previously evaluated in mice bearing melanomas. In this study, activity distribution and dosimetry are performed on healthy rabbits (Fauve de Bourgogne) using SPECT-CT imaging and ex vivo measurements.

Material And Methods: Ex vivo biodistribution (i.v. injection: 370 kBq/kg, n = 2 per point) is performed on blood, eyes, brain, lung, liver, kidneys, heart, stomach, and spleen. Dosimetry calculations follow the MIRD formalism: S values are calculated from CT images using the GATE Monte Carlo platform and activity distributions are obtained from SPECT-CT imaging (i.v. injection: 37 MBq/kg n = 3 per point). A specific study is presented to assess dose to human retina.

Results: Time-integrated activities based on SPECT-CT are in accordance with ex vivo measurements except for spleen. Doses to liver and eyes are the most significant, with respectively, 6.38 ± 0.50 Gy/GBq (evaluated through SPECT-CT imaging) and 45.8 ± 7.9 Gy/GBq (evaluated through ex vivo measurements). Characterization of ocular [ I]ICF01012 biodistribution in rabbits and quantification of melanin allowed to assess a dose of 3.07 ± 0.70 Gy/GBq to human retina.

Conclusion: This study sustains [ I]ICF01012 as a good candidate for melanoma TRT and open perspectives for personalized dosimetry calculation during phase I clinical transfer.
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http://dx.doi.org/10.1002/mp.13165DOI Listing
November 2018

Proteoglycan-targeting applied to hypoxia-activated prodrug therapy in chondrosarcoma: first proof-of-concept.

Oncotarget 2017 Nov 27;8(56):95824-95840. Epub 2017 Sep 27.

Université Clermont Auvergne, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Clermont-Ferrand, France.

Due to its abundant chondrogenic matrix and hypoxic tissue, chondrosarcoma is chemo- and radio-resistant. Our group has developed a proteoglycan targeting strategy by using a quaternary ammonium (QA) function as a carrier of DNA alkylating agents to chondrosarcoma environment. Here, we assessed the relevance of this strategy applied to hypoxia-activated prodrugs, by conjugating a QA to 2-nitroimidazole phosphoramidate. This derivative, named as , was evaluated respectively to its non-QA equivalent and to a QA-conjugated but non-hypoxia activated. Firstly binding to aggrecan was confirmed from dissociation constant determined by Surface Plasmon Resonance. , in HEMC-SS chondrosarcoma cells cultured in monolayer and in spheroids, showed higher cytotoxic activity in hypoxia versus normoxia, and led to a strong accumulation of cells in S phase and apoptosis. , a HEMC-SS xenograft model was implanted on SCID mice and characterized for hypoxia by photoacoustic imaging as well as proteoglycan content. When HEMC-SS bearing mice were given at 47 μmol/kg according to a q4d x 6 schedule, a significant 62.1% inhibition of tumor growth was observed, without associated hematological side effects. Mechanistic studies of treated tumors highlighted decrease in mitotic index associated to increase in both p21 and p53S15 markers. Interestingly, treatment induced an increase of DNA damages as measured by γH2AX predominantly found in pimonidazole-positive hypoxic areas. These preclinical results are the first to demonstrate the interest of addressing hypoxia-activated prodrugs selectively to proteoglycan of chondrogenic tumor tissue, as a promising therapeutic strategy.
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http://dx.doi.org/10.18632/oncotarget.21337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707064PMC
November 2017

Antibody PEGylation in bioorthogonal pretargeting with trans-cyclooctene/tetrazine cycloaddition: in vitro and in vivo evaluation in colorectal cancer models.

Sci Rep 2017 11 2;7(1):14918. Epub 2017 Nov 2.

Université Clermont Auvergne, INSERM U1240, Imagerie Moléculaire et Stratégies Théranostiques, F-63000, Clermont Ferrand, France.

Bioorthogonal chemistry represents a challenging approach in pretargeted radioimmunotherapy (PRIT). We focus here on mAb modifications by grafting an increase amount of trans-cyclooctene (TCO) derivatives (0 to 30 equivalents with respect to mAb) bearing different polyethylene glycol (PEG) linkers between mAb and TCO (i.e. PEG (1), PEG (2) and PEG (3)) and assessing their functionality. We used colorectal xenograft (HT29/Ts29.2) and peritoneal carcinomatosis (A431-CEA-Luc/35A7) as tumor cells/mAbs models and fluorescent tetrazines (TZ). MALDI-TOF MS shows that grafting with 2,3 increases significantly the number of TCO per mAb compared with no PEG. In vitro immunofluorescence showed that Ts29.2 and 35A7 labeling intensity is correlated with the number of TCO when using 1,3 while signals reach a maximum at 10 equivalents when using 2. Under 10 equivalents conditions, the capacity of resulting mAbs-1-3 for antigen recognition is similar when reported per grafted TCO and comparable to mAbs without TCO. In vivo, on both models, pretargeting with mAbs-2,3 followed by TZ injection induced a fluorescent signal two times lower than with mAbs-1. These findings suggest that while PEG linkers allow a better accessibility for TCO grafting, it might decrease the number of reactive TCO. In conclusion, mAb-1 represents the best candidate for PRIT.
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http://dx.doi.org/10.1038/s41598-017-15051-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668303PMC
November 2017

Doxycycline and its quaternary ammonium derivative for adjuvant therapies of chondrosarcoma.

Cancer Chemother Pharmacol 2017 Sep 13;80(3):517-526. Epub 2017 Jul 13.

Centre Jean Perrin, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Université Clermont Auvergne, 63000, Clermont-Ferrand, France.

Purpose: This study was conducted during the development of innovative treatment targeting the microenvironment of chondrosarcoma. In this context, MMP inhibitors were conjugated with a quaternary ammonium (QA) function as a targeting ligand to proteoglycans of chondrosarcoma extracellular matrix. Here we report the proof of concept of this strategy applied to the MMP13 inhibitor, doxycycline (Dox).

Methods: A quaternary ammonium derivative of the MMP13 inhibitor doxycycline (QA-Dox) was synthesized, and its anticancer activity was evaluated in the Swarm rat chondrosarcoma (SRC) model compared with the parent drug doxycycline, in vitro and in vivo. In vivo, dox and QA-Dox efficiency was assessed at equimolar doses according to a q4dx4 schedule by monitoring tumour volume by MRI and PG-targeted scintigraphy. Molecular mechanism (MMP13 expression, proteoglycan level) and histology studies were performed on tumours.

Results: The link of QA targeting function to Dox maintained the MMP13 inhibitory activity in vitro. Interestingly, the bacteriostatic activity was lost. SRC cells incubated with both drugs were blocked in S and G2 M phases. Tumour growth inhibition (confirmed by histology) was observed for both Dox and QA-Dox. Undesirable blood effects (leukocyte decrease) were reduced when Dox was targeted to tumour tissue using the QA function.

Conclusions: In the SRC model, the MMP13 inhibitor Dox and its QA derivative are promising as adjuvant therapies for chondrosarcoma management.
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http://dx.doi.org/10.1007/s00280-017-3377-7DOI Listing
September 2017

Development and characterization of a human three-dimensional chondrosarcoma culture for in vitro drug testing.

PLoS One 2017 13;12(7):e0181340. Epub 2017 Jul 13.

Université Clermont Auvergne, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Clermont-Ferrand, France.

It has been suggested that chemoresistance of chondrosarcoma (CHS), the cartilage tumor, is caused by the phenotypic microenvironmental features of the tumor tissue, mainly the chondrogenic extracellular matrix (ECM), and hypoxia. We developed and characterized a multicellular tumor spheroid (MCTS) of human chondrosarcoma HEMC-SS cells to gain insight into tumor cell biology and drug response. At Day 7, HEMC-SS spheroids exhibited a homogeneous distribution of proliferative Ki-67 positive cells, whereas in larger spheroids (Day 14 and Day 20), proliferation was mainly localized in the periphery. In the core of larger spheroids, apoptotic cells were evidenced by TUNEL assay, and hypoxia by pimonidazole staining. Interestingly, VEGF excretion, evidenced by ELISA on culture media, was detectable from Day 14 spheroids, and increased as the spheroids grew in size. HEMC-SS spheroids synthesized a chondrogenic extracellular matrix rich in glycosaminoglycans and type-2 collagen. Finally, we investigated the sensitivity of Day 7 and Day 14 chondrosarcoma MCTS to hypoxia-activated prodrug TH-302 and doxorubicin compared with their 2D counterparts. As expected, TH-302 exhibited higher cytotoxic activity on larger hypoxic spheroids (Day 14) than on non-hypoxic spheroids (Day 7), with multicellular resistance index (MCRI) values of 7.7 and 9.1 respectively. For doxorubicin, the larger-sized spheroids exhibited higher drug resistance (MCRI of 5.0 for Day 7 and 18.3 for Day 14 spheroids), possibly due to impeded drug penetration into the deep layer of spheroids, evidenced by its auto-fluorescence property. We have developed a model of human chondrosarcoma MCTS that combines an ECM rich in glycosaminoglycans with a high hypoxic core associated with VEGF excretion. This model could offer a more predictive in vitro chondrosarcoma system for screening drugs targeting tumor cells and their microenvironment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181340PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509331PMC
September 2017

Tetraspanin 8 (TSPAN 8) as a potential target for radio-immunotherapy of colorectal cancer.

Oncotarget 2017 Mar;8(13):22034-22047

INSERM, U 1240, 63005 Clermont-Ferrand, France.

Tetraspanin 8 (TSPAN8) overexpression is correlated with poor prognosis in human colorectal cancer (CRC). A murine mAb Ts29.2 specific for human TSPAN8 provided significant efficiency for immunotherapy in CRC pre-clinical models. We therefore evaluate the feasability of targeting TSPAN8 in CRC with radiolabeled Ts29.2. Staining of tissue micro-arrays with Ts29.2 revealed that TSPAN8 espression was restricted to a few human healthy tissues. DOTA-Ts29.2 was radiolabeled with 111In or 177Lu with radiochemical purities >95%, specific activity ranging from 300 to 600 MBq/mg, and radioimmunoreactive fractions >80%. The biodistribution of [111In]DOTA-Ts29.2 in nude mice bearing HT29 or SW480 CRC xenografts showed a high specificity of tumor localization with high tumor/blood ratios (HT29: 4.3; SW480-TSPAN8: 3.9 at 72h and 120h post injection respectively). Tumor-specific absorbed dose calculations for [177Lu]DOTA-Ts29.2 was 1.89 Gy/MBq, establishing the feasibility of using radioimmunotherapy of CRC with this radiolabeled antibody. A significant inhibition of tumor growth in HT29 tumor-bearing mice treated with [177Lu]DOTA-Ts29.2 was observed compared to control groups. Ex vivo experiments revealed specific DNA double strand breaks associated with cell apoptosis in [177Lu]DOTA-Ts29.2 treated tumors compared to controls. Overall, we provide a proof-of-concept for the use of [111In/177Lu]DOTA-Ts29.2 that specifically target in vivo aggressive TSPAN8-positive cells in CRC.
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http://dx.doi.org/10.18632/oncotarget.15787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400644PMC
March 2017

Tetraspanin 8 is a novel regulator of ILK-driven β1 integrin adhesion and signaling in invasive melanoma cells.

Oncotarget 2017 Mar;8(10):17140-17155

Université de Lyon, Lyon, France.

Melanoma is well known for its propensity for lethal metastasis and resistance to most current therapies. Tumor progression and drug resistance depend to a large extent on the interplay between tumor cells and the surrounding matrix. We previously identified Tetraspanin 8 (Tspan8) as a critical mediator of melanoma invasion, whose expression is absent in healthy skin. The present study investigated whether Tspan8 may influence cell-matrix anchorage and regulate downstream molecular pathways leading to an aggressive behavior. Using silencing and ectopic expression strategies, we showed that Tspan8-mediated invasion of melanoma cells resulted from defects in cell-matrix anchorage by interacting with β1 integrins and by interfering with their clustering, without affecting their surface or global expression levels. These effects were associated with impaired phosphorylation of integrin-linked kinase (ILK) and its downstream target Akt-S473, but not FAK. Specific blockade of Akt or ILK activity strongly affected cell-matrix adhesion. Moreover, expression of a dominant-negative form of ILK reduced β1 integrin clustering and cell-matrix adhesion. Finally, we observed a tumor-promoting effect of Tspan8 in vivo and a mutually exclusive expression pattern between Tspan8 and phosphorylated ILK in melanoma xenografts and human melanocytic lesions. Altogether, the in vitro, in vivo and in situ data highlight a novel regulatory role for Tspan8 in melanoma progression by modulating cell-matrix interactions through β1 integrin-ILK axis and establish Tspan8 as a negative regulator of ILK activity. These findings emphasize the importance of targeting Tspan8 as a means of switching from low- to firm-adhesive states, mandatory to prevent tumor dissemination.
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http://dx.doi.org/10.18632/oncotarget.15084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370029PMC
March 2017

Theranostic Approach for Metastatic Pigmented Melanoma Using ICF15002, a Multimodal Radiotracer for Both PET Imaging and Targeted Radionuclide Therapy.

Neoplasia 2017 01 14;19(1):17-27. Epub 2016 Dec 14.

UMR 990 INSERM/Université d'Auvergne, F-63005 Clermont-Ferrand, France. Electronic address:

Purpose: This work reports, in melanoma models, the theranostic potential of ICF15002 as a single fluorinated and iodinated melanin-targeting compound.

Methods: Studies were conducted in the murine syngeneic B16BL6 model and in the A375 and SK-MEL-3 human xenografts. ICF15002 was radiolabeled with fluorine-18 for positron emission tomography (PET) imaging and biodistribution, with iodine-125 for metabolism study, and iodine-131 for targeted radionuclide therapy (TRT). TRT efficacy was assessed by tumor volume measurement, with mechanistics and dosimetry parameters being determined in the B16BL6 model. Intracellular localization of ICF15002 was characterized by secondary ion mass spectrometry (SIMS).

Results: PET imaging with [F]ICF15002 evidenced tumoral uptake of 14.33±2.11%ID/g and 4.87±0.93%ID/g in pigmented B16BL6 and SK-MEL-3 models, respectively, at 1 hour post inoculation. No accumulation was observed in the unpigmented A375 melanoma. SIMS demonstrated colocalization of ICF15002 signal with melanin polymers in melanosomes of the B16BL6 tumors. TRT with two doses of 20 MBq [I]ICF15002 delivered an absorbed dose of 102.3 Gy to B16BL6 tumors, leading to a significant tumor growth inhibition [doubling time (DT) of 2.9±0.5 days in treated vs 1.8±0.3 in controls] and a prolonged median survival (27 days vs 21 in controls). P53S15 phosphorylation and P21 induction were associated with a G2/M blockage, suggesting mitotic catastrophe. In the human SK-MEL-3 model, three doses of 25 MBq led also to a DT increase (26.5±7.8 days vs 11.0±3.8 in controls) and improved median survival (111 days vs 74 in controls).

Conclusion: Results demonstrate that ICF15002 fulfills suitable properties for bimodal imaging/TRT management of patients with pigmented melanoma.
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http://dx.doi.org/10.1016/j.neo.2016.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5157796PMC
January 2017

Proteoglycans as Target for an Innovative Therapeutic Approach in Chondrosarcoma: Preclinical Proof of Concept.

Mol Cancer Ther 2016 11 29;15(11):2575-2585. Epub 2016 Aug 29.

Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.

To date, surgery remains the only option for the treatment of chondrosarcoma, which is radio- and chemoresistant due in part to its large extracellular matrix (ECM) and poor vascularity. In case of unresectable locally advanced or metastatic diseases with a poor prognosis, improving the management of chondrosarcoma still remains a challenge. Our team developed an attractive approach of improvement of the therapeutic index of chemotherapy by targeting proteoglycan (PG)-rich tissues using a quaternary ammonium (QA) function conjugated to melphalan (Mel). First of all, we demonstrated the crucial role of the QA carrier for binding to aggrecan by surface plasmon resonance. In the orthotopic model of Swarm rat chondrosarcoma, an in vivo biodistribution study of Mel and its QA derivative (Mel-QA), radiolabeled with tritium, showed rapid radioactivity accumulation in healthy cartilaginous tissues and tumor after [H]-Mel-QA injection. The higher T/M ratio of the QA derivative suggests some advantage of QA-active targeting of chondrosarcoma. The antitumoral effects were characterized by tumor volume assessment, in vivo Tc-NTP 15-5 scintigraphic imaging of PGs, H-HRMAS NMR spectroscopy, and histology. The conjugation of a QA function to Mel did not hamper its in vivo efficiency and strongly improved the tolerability of Mel leading to a significant decrease of side effects (hematologic analyses and body weight monitoring). Thus, QA conjugation leads to a significant improvement of the therapeutic index, which is essential in oncology and enable repeated cycles of chemotherapy in patients with chondrosarcoma. Mol Cancer Ther; 15(11); 2575-85. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0003DOI Listing
November 2016

Targeting DNA repair by coDbait enhances melanoma targeted radionuclide therapy.

Oncotarget 2016 Mar;7(11):12927-36

Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France.

Radiolabelled melanin ligands offer an interesting strategy for the treatment of disseminated pigmented melanoma. One of these molecules, ICF01012 labelled with iodine 131, induced a significant slowing of melanoma growth. Here, we have explored the combination of [131I]ICF01012 with coDbait, a DNA repair inhibitor, to overcome melanoma radioresistance and increase targeted radionuclide therapy (TRT) efficacy. In human SK-Mel 3 melanoma xenograft, the addition of coDbait had a synergistic effect on tumor growth and median survival. The anti-tumor effect was additive in murine syngeneic B16Bl6 model whereas coDbait combination with [131I]ICF01012 did not increase TRT side effects in secondary pigmented tissues (e.g. hair follicles, eyes). Our results confirm that DNA lesions induced by TRT were not enhanced with coDbait association but, the presence of micronuclei and cell cycle blockade in tumor shows that coDbait acts by interrupting or delaying DNA repair. In this study, we demonstrate for the first time, the usefulness of DNA repair traps in the context of targeted radionuclide therapy.
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http://dx.doi.org/10.18632/oncotarget.7340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914332PMC
March 2016

Annexin A1 localization and its relevance to cancer.

Clin Sci (Lond) 2016 Feb;130(4):205-20

Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France INSERM, U 990, F-63000 Clermont-Ferrand, France.

Annexin A1 (ANXA1) is a Ca(2+)-regulated phospholipid-binding protein involved in various cell processes. ANXA1 was initially widely studied in inflammation resolution, but its overexpression was later reported in a large number of cancers. Further in-depth investigations have revealed that this protein could have many roles in cancer progression and act at different levels (from cancer initiation to metastasis). This is partly due to the location of ANXA1 in different cell compartments. ANXA1 can be nuclear, cytoplasmic and/or membrane associated. This last location allows ANXA1 to be proteolytically cleaved and/or to become accessible to its cognate partners, the formyl-peptide receptors. Indeed, in some cancers, ANXA1 is found at the cell surface, where it stimulates formyl-peptide receptors to trigger oncogenic pathways. In the present review, we look at the different locations of ANXA1 and their association with the deregulated pathways often observed in cancers. We have specifically detailed the non-classic pathways of ANXA1 externalization, the significance of its cleavage and the role of the ANXA1-formyl-peptide receptor complex in cancer progression.
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http://dx.doi.org/10.1042/CS20150415DOI Listing
February 2016

Radiolabeled dendritic probes as tools for high in vivo tumor targeting: application to melanoma.

J Mater Chem B 2015 Mar 24;3(12):2560-2571. Epub 2015 Feb 24.

Institut de Physique et Chimie des Matériaux de Strasbourg (IPCMS), UMR CNRS-Université de Strasbourg 7504, 23 rue du loess, BP 43, 67034 Strasbourg Cedex 2, France.

In bioimaging, targeting allows refining the diagnosis by improving the sensitivity and especially the specificity for an earlier diagnosis. Two In-radiolabeled dendritic nanoprobes (DPs) (In-2, In-3) and their model counterparts (In-1, In-4) are designed and assessed for in vitro and in vivo tumor targeting efficiency in a murine melanoma models. Tumor uptake is correlated to dendrimer multivalency and reaches values as high as 12.7 ± 1.6% ID g at 4 h post intravenous injection for In-3vs. 1.5 ± 0.5% ID g for the unfunctionalized DP, and over 11% ID g for any tumor weight whatsoever.
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http://dx.doi.org/10.1039/c5tb00235dDOI Listing
March 2015

Synthesis, radiolabeling and preliminary in vivo evaluation of multimodal radiotracers for PET imaging and targeted radionuclide therapy of pigmented melanoma.

Eur J Med Chem 2015 Mar 21;92:818-38. Epub 2015 Jan 21.

Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, F-63000 Clermont-Ferrand, France; Inserm, U 990, F-63000 Clermont-Ferrand, France; Centre Jean Perrin, F-63011 Clermont-Ferrand, France. Electronic address:

Melanin pigment represents an attractive target to address specific treatment to melanoma cells, such as cytotoxic radionuclides. However, less than half of the patients have pigmented metastases. Hence, specific marker is required to stratify this patient population before proceeding with melanin-targeted radionuclide therapy. In such a context, we developed fluorinated analogues of a previously studied melanin-targeting ligand, N-(2-diethylaminoethyl)-6-iodoquinoxaline-2-carboxamide (ICF01012). These latter can be labeled either with (18)F or (131)I/(125)I for positron emission tomography imaging (melanin-positive patient selection) and targeted radionuclide therapy purposes. Here we describe the syntheses, radiosyntheses and preclinical evaluations on melanoma-bearing mice model of several iodo- and fluoro(hetero)aromatic derivatives of the ICF01012 scaffold. After preliminary planar gamma scintigraphic and positron emission tomography imaging evaluations, [(125)I]- and [(18)F]-N-[2-(diethylamino)ethyl]-4-fluoro-3-iodobenzamides ([(125)I]4, [(18)F]4) were found to be chemically and biologically stable with quite similar tumor uptakes at 1 h p.i. (9.7 ± 2.6% ID/g and 6.8 ± 1.9% ID/g, respectively).
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http://dx.doi.org/10.1016/j.ejmech.2015.01.034DOI Listing
March 2015

[¹²³I]ICF01012 melanoma imaging and [¹³¹I]ICF01012 dosimetry allow adapted internal targeted radiotherapy in preclinical melanoma models.

Eur J Dermatol 2015 Jan-Feb;25(1):29-35

Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, BP 10448, Inserm, U 990, F-63000 Clermont-Ferrand, France.

Background: Melanin-targeting radiotracers are interesting tools for imaging and treatment of pigmented melanoma metastases. However, variation of the pigment concentration may alter the efficiency of such targeting.

Objectives: A clear assessment of both tumor melanin status and dosimetry are therefore prerequisites for internal radiotherapy of disseminated melanoma.

Materials & Methods: The melanin tracer ICF01012 was labelled with iodine-123 for melanoma imaging in pigmented murine B16F0 and human SK-Mel 3 melanomas.

Results: In vivo imaging showed that the uptake of [(123)I]ICF01012 to melanomas correlated significantly with melanin content. Schedule treatment of 3 × 25 MBq [(131)I]ICF01012 significantly reduced SK-Mel 3 tumor growth and significantly increased the median survival in treated mice. For this protocol, the calculated delivered dose was 53.2 Gy.

Conclusion: Radio-iodinated ICF01012 is a good candidate for both imaging and therapeutic purposes for patients with metastatic pigmented melanomas.
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http://dx.doi.org/10.1684/ejd.2014.2481DOI Listing
January 2016

Annexin A1 in primary tumors promotes melanoma dissemination.

Clin Exp Metastasis 2014 Oct 6;31(7):749-60. Epub 2014 Jul 6.

Clermont-Ferrand Université, Université d'Auvergne, INSERM U990, Imagerie Moléculaire et Thérapie Vectorisée, BP 184, 63000, Clermont-Ferrand, France.

Metastatic melanoma is one of the most aggressive forms of skin cancer and has a poor prognosis. We have previously identified Annexin A1 (ANXA1) as a potential murine melanoma-spreading factor that may modulate cell invasion by binding to formyl peptide receptors (FPRs). Here, we report that (1) in a B16Bl6 spontaneous metastasis model, a siRNA-induced decrease in tumoral ANXA1 expression significantly reduced tumoral MMP2 activity and number of lung metastases; (2) in a retrospective study of 61 patients, metastasis-free survival was inversely related to ANXA1 expression levels in primary tumors (HR 3.15 [1.03-9.69], p = 0.045); (3) in human melanoma cell lines, ANXA1 level was positively correlated with in vitro invasion capacity whereas normal melanocytes contained low ANXA1 levels, and (4) the ANXA1 N-terminal peptide ANXA12-26 stimulated MMP2 activity after interaction with FPRs and significantly stimulated the in vitro invasion of melanomas by acting on FPRs. These findings identify ANXA1 as a proinvasive protein in melanoma that holds promise as a potential prognostic marker and therapeutic target.
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http://dx.doi.org/10.1007/s10585-014-9665-2DOI Listing
October 2014

Small rigid platforms functionalization with quaternary ammonium: targeting extracellular matrix of chondrosarcoma.

Nanomedicine 2014 Nov 25;10(8):1887-95. Epub 2014 Jun 25.

Institut Lumière Matière, UMR 5306 Université Lyon1-CNRS, Université de Lyon, 69622 Villeurbanne cédex, France; Hospices Civils de Lyon, Hôpital Edouard Herriot, 69000 Lyon, France.

Unlabelled: This work takes place in the "cartilage targeting strategy", consisting in using the quaternary ammonium (QA) function as a vector to proteoglycans (PGs) of extracellular matrix (ECM). The objective was to demonstrate that QA could address gadolinium based small rigid platforms (SRP) to PG-rich tumors. SRP were functionalized with QA, radiolabeled with (111)Indium and evaluated for biodistribution in vivo, respectively to non functionalized SRP, in two experimental models: (i) the HEMCSS human xenograft model; (ii) the Swarm rat chondrosarcoma (SRC) orthotopic model. The contribution of cellular uptake to tumoral accumulation of nano-objects was also determined from in vitro binding. In the SRC model expressing a highly and homogeneously distributed PG content, tumor accumulation and retention of SRP@QA were increased by 40% as compared to non-functionalized SRP. When considering the radiosensitizing potential of gadolinium based SRP, these results provide hopes for the radiobiological approach of highly resistant tumor such as chondrosarcoma.

From The Clinical Editor: In this study, gadolinium-based complexing DOTA-surfaced small polysiloxane nanoparticles were functionalized with quaternary ammonium derivatives that target the extracellular matrix of chondrosarcoma. The authors demonstrate in a rat model that the use of these constructs results in a 40% increase of tumor accumulation and retention compared to non-functionalized (and otherwise same) platforms. Similar approaches would be welcome additions to the clinical armamentarium addressing chondrosarcoma.
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http://dx.doi.org/10.1016/j.nano.2014.06.011DOI Listing
November 2014