DNA Repair, radiations and innovative cancer therapies

Dutreix

Marie Dutreix Team Leader Tel:

Our team develop new antitumoral therapies associated to radio- and/or chemo-therapy to fight cancer resistance to treatment while limiting adverse effects.

New small molecules named DBAit that inhibit major DNA Repair pathways

During these last years we have:

Figure 1 : inhibition de la réparation par Dbait.
Figure 1: DNA repair inhibition by DBait
  • Analyzed the mechanism of action of DBait (short double-stranded DNA mimicking double-strand break).
  • Developed derived Dbait molecules with a cholesterol (AsiDNA) to facilitate cells penetration without any transfection agent and studied the molecular mechanisms that determine the specificity of AsiDNA for tumor cells (sparing healthy tissues).
  • Demonstrated the clinical potential of the AsiDNA in a first-in-man clinical trial (in association with radiotherapy to treat melanoma in transit).
  • Developed protocols of AsiDNA in association with chemotherapy (mainly 5-FU, Carboplatin, Irinotecan, Doxorubicin) in solid tumors (colon cancer, hepatocarcinoma, breast cancer) and in association with radiotherapy or chemotherapy (etoposide, cyclophosphamide (4-HC), and vincristine sulfate) in hematologic malignancies
  • Tested protocols of AsiDNA in association with poly(ADP-ribose) polymerase inhibitors and validated the concept of the synthetic lethality induced by targeted combined therapies.

In collaboration with ONXEO (www.onxeo.com), the team prepares next clinical trial to systemically administrate AsiDNA in patients with solids tumors (planned trial start in 2019).

Identification of tumor sensitivity biomarkers to antitumoral treatment (i.e AsiDNA)

The survival of cells suffering spontaneous genetic instability, a common feature among tumor cells, depends on the efficiency of DNA repair. We have confirmed that this intrinsic characteristic of tumors and metastases is a prerequisite for the sensibility to AsiDNA to occur. We also showed that the presence of micronuclei in tumor cells from biopsies could be a good prognosis of the response to the AsiDNA treatment. The study of the feasibility and biodistribution of this biomarker in various types of tumors in clinic is in progress.

Development of new modalities of radiotherapy

  • The Ultrahigh dose-rate irradiation (FLASH)

Flash anglaisThe V. Favaudon’s team at Institut Curie published in 2014 the results of a long-standing investigation carried out in vivo, demonstrating for the first time that FLASH irradiation spares normal lung tissue from radioinduced fibrosis whilst leaving the anti-tumor efficiency unchanged.

We are currently working at decrypting and the physical, physico-chemical and biological “parameters” (optimum doses and dose-rates, oxygenation, physiological compartments, molecular and cellular pathways…) that account for normal tissue sparing from radiation toxicity. We focus our efforts to enhance our knowledge on the effects of FLASH radiation on normal tissues from both biological and technological sides and bring FLASH radiotherapy to the clinic.

  • The cold plasma

Cold atmospheric pressure plasma (CAPP) is an ionized gas obtained at atmospheric pressure and room temperature and is used for biomedical applications such as healing, sterilization and decontamination. CAPP is composed of a mixture of reactive oxygen and nitrogen species (RONS), free radicals, electric field, photons, excited atoms and molecules. Part of the team, in a strong and efficient collaboration with physicists of plasma (LPGP, Orsay) who provided us a Helium-based plasma device, exploits these properties to target and eliminate in vitro and in vivo tumor cells.

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Our fundamental projects are conducted to understand the molecular effects of the treatments in cancer cells and at the preclinical level by developing animal models and setting coherent protocols of treatments in view of future clinical applications.

These projects are part of a local network organized on the Saclay University campus the AMI NanoTheRad (https://www.universite-parissaclay.fr/fr/recherche/projet/nanotherad#presentation-3553) and a European network ITN-Radiate (www.radiate.eu).

Key publications

Year of publication 2019

Charles Fouillade, Sandra Curras-Alonso, Lorena Giuranno, Eddy Quelennec, Sophie Heinrich, Sarah Bonnet-Boissinot, Arnaud Beddok, Sophie Leboucher, Hamza Umut Karakurt, Mylène Bohec, Sylvain Baulande, Marc Vooijs, Pierre Verrelle, Marie Dutreix, Arturo Londoño-Vallejo, Vincent Favaudon (2019 Dec 5)

FLASH Irradiation Spares Lung Progenitor Cells and Limits the Incidence of Radio-induced Senescence.

Clinical cancer research : an official journal of the American Association for Cancer Research : DOI : 10.1158/1078-0432.CCR-19-1440
Wael Jdey, Maria Kozlak, Sergey Alekseev, Sylvain Thierry, Pauline Lascaux, Pierre-Marie Girard, Françoise Bono, Marie Dutreix (2019 Jul 31)

AsiDNA Treatment Induces Cumulative Antitumor Efficacy with a Low Probability of Acquired Resistance.

Neoplasia (New York, N.Y.) : 863-871 : DOI : S1476-5586(19)30213-1

Year of publication 2018

Annalisa Patriarca, Charles Fouillade, Michel Auger, Frédéric Martin, Frédéric Pouzoulet, Catherine Nauraye, Sophie Heinrich, Vincent Favaudon, Samuel Meyroneinc, Rémi Dendale, Alejandro Mazal, Philip Poortmans, Pierre Verrelle, Ludovic De Marzi (2018 Nov 1)

Experimental set-up for FLASH proton irradiation of small animals using a clinical system

International Journal of Radiation Oncology • Biology • Physics : 102 : 619-626 : DOI : 10.1016/j.ijrobp.2018.06.403

Year of publication 2017

Biau J., Chautard E., De Koning L., Court F., Pereira B., Verrelle P., Dutreix M. (2017 Jul 1)

Predictive biomarkers of resistance to hypofractionated radiotherapy in high grade glioma

RADIATION ONCOLOGY : 12 : 123 : DOI : 10.1186/s13014-017-0858-0

Year of publication 2016

Wael Jdey, Sylvain Thierry, Christophe Russo, Flavien Devun, Muthana Al Abo, Patricia Noguiez-Hellin, Jian-Sheng Sun, Emmanuel Barillot, Andrei Zinovyev, Inna Kuperstein, Yves Pommier, Marie Dutreix (2016 Aug 26)

Drug Driven Synthetic Lethality: bypassing tumor cell genetics with a combination of Dbait and PARP inhibitors.

Clinical cancer research : an official journal of the American Association for Cancer Research : DOI : clincanres.1193.2016
C Le Tourneau, B Dreno, Y Kirova, J J Grob, T Jouary, C Dutriaux, L Thomas, C Lebbé, L Mortier, P Saiag, M F Avril, E Maubec, P Joly, P Bey, J M Cosset, J S Sun, B Asselain, F Devun, M E Marty, M Dutreix (2016 May 4)

First-in-human phase I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma.

British journal of cancer : 1199-205 : DOI : 10.1038/bjc.2016.120
All publications