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Small Molecule Therapeutics

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

Caroline Peyrode, Valérie Weber, Aurélien Voissière, Aurélie Maisonial-Besset, Aurélien Vidal, Philippe Auzeloux, Vincent Gaumet, Michèle Borel, Marie-Mélanie Dauplat, Mercedes Quintana, Françoise Degoul, Françoise Rédini, Jean-Michel Chezal and Elisabeth Miot-Noirault
Caroline Peyrode
Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.INSERM, UMR990, Clermont-Ferrand, France.
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  • For correspondence: caroline.peyrode@udamail.fr
Valérie Weber
Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.INSERM, UMR990, Clermont-Ferrand, France.
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Aurélien Voissière
Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.INSERM, UMR990, Clermont-Ferrand, France.
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Aurélie Maisonial-Besset
Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.INSERM, UMR990, Clermont-Ferrand, France.
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Aurélien Vidal
Arronax, Saint-Herblain, France.
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Philippe Auzeloux
Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.INSERM, UMR990, Clermont-Ferrand, France.
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Vincent Gaumet
Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.INSERM, UMR990, Clermont-Ferrand, France.
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Michèle Borel
Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.INSERM, UMR990, Clermont-Ferrand, France.
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Marie-Mélanie Dauplat
CLCC Jean-Perrin, Clermont-Ferrand, France.
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Mercedes Quintana
Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.INSERM, UMR990, Clermont-Ferrand, France.
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Françoise Degoul
Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.INSERM, UMR990, Clermont-Ferrand, France.
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Françoise Rédini
INSERM, UMR S957, Nantes Atlantique Université, Nantes, France.
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Jean-Michel Chezal
Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.INSERM, UMR990, Clermont-Ferrand, France.
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Elisabeth Miot-Noirault
Clermont Université, Université d'Auvergne, Imagerie Moléculaire et Thérapie Vectorisée, Clermont-Ferrand, France.INSERM, UMR990, Clermont-Ferrand, France.
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DOI: 10.1158/1535-7163.MCT-16-0003
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Abstract

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 [3H]-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 99mTc-NTP 15-5 scintigraphic imaging of PGs, 1H-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); 1–11. ©2016 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Received January 9, 2016.
  • Revision received August 1, 2016.
  • Accepted August 3, 2016.
  • ©2016 American Association for Cancer Research.
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Published OnlineFirst October 18, 2016
doi: 10.1158/1535-7163.MCT-16-0003

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Proteoglycans as Target for an Innovative Therapeutic Approach in Chondrosarcoma: Preclinical Proof of Concept
Caroline Peyrode, Valérie Weber, Aurélien Voissière, Aurélie Maisonial-Besset, Aurélien Vidal, Philippe Auzeloux, Vincent Gaumet, Michèle Borel, Marie-Mélanie Dauplat, Mercedes Quintana, Françoise Degoul, Françoise Rédini, Jean-Michel Chezal and Elisabeth Miot-Noirault
Mol Cancer Ther October 18 2016 DOI: 10.1158/1535-7163.MCT-16-0003

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Proteoglycans as Target for an Innovative Therapeutic Approach in Chondrosarcoma: Preclinical Proof of Concept
Caroline Peyrode, Valérie Weber, Aurélien Voissière, Aurélie Maisonial-Besset, Aurélien Vidal, Philippe Auzeloux, Vincent Gaumet, Michèle Borel, Marie-Mélanie Dauplat, Mercedes Quintana, Françoise Degoul, Françoise Rédini, Jean-Michel Chezal and Elisabeth Miot-Noirault
Mol Cancer Ther October 18 2016 DOI: 10.1158/1535-7163.MCT-16-0003
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Molecular Cancer Therapeutics
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