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A potential therapy to reduce the side effects of a chemotherapy

Press release | 15 Nov 2022 - 18h01 | By INSERM PRESS OFFICE
Cancer | Neurosciences, cognitives sciences, neurology and psychiatry

Convergent effect of cisplatin and KW6002 on DNA double-strand breaks in lung tumor cells. Blue corresponds to cell nuclei and red to a protein that marks DNA damage © Dewaeles et al

Cisplatin is a chemotherapy indicated to fight tumors in many types of cancer. However, it does have major side effects – especially kidney toxicity, that can lead to acute kidney failure. In addition, patients treated with cisplatin also often report high levels of neuropathic pain. Scientists from Inserm, Université de Lille, University Hospital Lille, CNRS and Institut Pasteur de Lille within the CANTHER and Lille Neuroscience & Cognition laboratories, in collaboration with researchers from Michigan State University (USA), have identified a drug that could be a game changer for patients. Istradefylline, which is already approved for Parkinson’s disease, could not only reduce the harmful effects of cisplatin but also improve its anti-tumor properties. These findings will now need to be confirmed in a clinical trial. The study is published in The Journal of Clinical Investigation.

Cisplatin is a chemotherapy used to treat several types of cancer, in particular lung, ovarian and testicular cancers. While its anti-tumor efficacy has been proven, cisplatin promotes side effects. These include intense pain (peripheral neuropathy) and kidney damage, leading to acute kidney failure in one third of cases. Currently, there is no effective solutions to limit side effects for patients exposed to cisplatin.

An international work conducted by Christelle Cauffiez, David Blum and Geoffroy Laumet[1] have now identified a molecule that reduces cisplatin-induced side effects, while preserving or even potentiating its anti-tumor properties.  

 

A Parkinson’s disease drug

The scientists focused on a drug called istradefylline, which is already approved in the USA and Japan for the treatment of Parkinson’s disease. Biologically, this compound blocks the adenosine receptors receptors at the surface of cells.

Blum’s team, which is working on neurodegenerative diseases, had previously observed an increased density of these receptors in the brains of patients with dementia, a phenomenon involved in the development of these diseases. Interestingly, a comparable increase of adenosine receptors was also observed by Cauffiez’s team in the kidneys, under exposure to cisplatin.

With this in mind, the scientists decided to join forces with Laumet’s lab, a specialist of  cisplatin-induced neuropathic pain, to test the impact of istradefylline to mitigate the harmful effects of cisplatin.

 

Findings to confirm in a clinical trial

Their experiments, conducted on animal and cellular models, indeed pointed towards a beneficial role of istradefylline. In mice exposed to cisplatin, the molecule not only reduced kidney damages but also prevented neuropathic pain.

In addition, cisplatin’s ability to reduce tumor growth was increased in the animals receiving istradefylline – an effect subsequently confirmed in cell models.

Before considering the widespread application of this therapeutic approach to patients with cancer, these findings must however first be consolidated by organizing a rigorous clinical trial. The fact that istradefylline is already used in humans to treat another disease already constitutes an interesting perspective.

“In fact, we already have a lot of clinical data showing that this molecule is safe. While it is necessary to conduct a clinical study to test its efficacy in reducing the side effects of the chemotherapy, the possibility of therapeutic repositioning is a promising perspective for improving patient care in the short term,” the researchers point out.

 

[1] from the CANTHER laboratory (Inserm/Institut Pasteur de Lille/CNRS/Université de Lille/University Hospital Lille), the Lille Neuroscience & Cognition laboratory (Inserm/Université de Lille/University Hospital Lille) and the Department of Physiology of Michigan State University

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Researcher Contact

David Blum

Inserm Research Director

Lille Neuroscience & Cognition laboratory

Inserm/University Hospital Lille/Université de Lille

Email: david.blum@inserm.fr

 

Christelle Cauffiez

CANTHER laboratory

Université de Lille/Inserm/University Hospital Lille/CNRS/Institut Pasteur de Lille

Email: christelle.cauffiez@univ-lille.fr

 

Geoffroy Laumet

Laboratory of Neuroimmunology of Pain

Department of Physiology, Michigan State University

laumetge@msu.edu

Telephone numbers provided upon request

Press Contact

presse@inserm.fr

Sources

Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin anti-tumor effects

 

Edmone Dewaeles1,2, Kévin Carvalho2,3, Sandy Fellah1, Jaewon Sim4, Nihad Boukrout1
,Raphaelle Caillierez2,3, Hariharan Ramakrishnan4, Cynthia Van der Hauwaert 1,5, Jhenkruthi
Vijaya Shankara2,3 , Nathalie Martin1 Noura Massri 4 Agathe Launay2,3 , Joseph K. Folger 4 ,8
Clémentine de Schutter1, Romain Larrue1,6 , Ingrid Loison1, Marine Goujon1, Matthieu Jung7, Stéphanie Le Gras7, Victoria Gomez-Murcia2,3, Emilie Faivre2,3, Julie Lemaire1, Anne Garat 6,10, Nicolas Beauval6,8, Patrice Maboudou9, Viviane Gnemmi1,10, Jean-Baptiste Gibier 1, Luc Buée2,3 , Corinne Abbadie1 , Francois Glowacki 1,11 , Nicolas Pottier1,6 , Michael Perrais1, Rodrigo A. Cunha12,13,Jean-Sébastien Annicotte14,15, Geoffroy Laumet4, David Blum2,3, Christelle Cauffiez1

 

  1. Univ. Lille, Inserm, CNRS, CHU Lille, UMR9020-U1277 – CANTHER – Cancer

Heterogeneity, Plasticity and Resistance to Therapies, F-59000, Lille, France

  1. Univ. Lille, Inserm, CHU Lille, UMR-S1172 LilNCog – Lille Neuroscience & Cognition, F 59000 Lille, France
  2. Alzheimer and Tauopathies, LabEx DISTALZ, France
  3. Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
  4. Département de la Recherche en Santé, CHU Lille, F-59000, Lille, France.
  5. CHU Lille, Service de Toxicologie et Génopathies, F-59000 Lille, France
  6. University of Strasbourg, CNRS UMR 7104, Inserm U1258 – GenomEast Platform – IGBMC Institut de Génétique et de Biologie Moléculaire et Cellulaire, F-67404 Illkirch, France.
  7. Univ. Lille, CHU Lille, Institut Pasteur de Lille, ULR 4483 – IMPECS – IMPact de

 l’Environnement Chimique sur la Santé humaine, F-59000 Lille, France

  1. CHU Lille, Service de Biochimie Automatisée, Protéines et Biologie Prédictive, F-59000 Lille, France
  2. CHU Lille, Service d’Anatomopathologie, F-59000 Lille, France
  3. CHU Lille, Service de Néphrologie, F-59000 Lille, France
  4. CNC – Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Faculty of Medicine Building-Polo 1, 3004-504, Coimbra, Portugal
  5. Faculty of Medicine, University of Coimbra, 3004-504, Coimbra, Portugal
  6. Univ. Lille, INSERM, CNRS, CHU Lille, Institut Pasteur de Lille, Inserm U1283-UMR8199 – EGID, F-59000 Lille, France Lille
  7. Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167 – RID-AGE-Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, F-59000 Lille, France.

Journal of Clinical Investigation, novembre 2022

DOI : https://doi.org/10.1172/JCI152924

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