Radiotherapy has long been a major component of localised tumour treatment. Effective and relatively inexpensive, these treatments have made significant progress over the past two decades. Major advances in imaging, dosimetry, accelerators and software now allow the adaptation of treatment to each patient. The development of new protocols combining radiation therapy with anti-tumour drugs (radio chemotherapy) further enhances the therapeutic arsenal.
Institut Curie has been a leader in the biology of radiation since the first use of ionizing radiation to treat cancer. Since 1990, our research has focused on understanding the response of tumour cells to treatment and on optimising the response. Particular emphasis was placed on signalling pathways, DNA damage repair, radio chemotherapy (cytotoxic agents, tyrosine kinase inhibitors and DNA repair), dose rate and micro fractionation studies.
Over the past decade, a number of studies on the molecular and genetic aspects of cell and tissue responses to ionising radiation were launched. Experimental radiotherapy studies using mouse xenograft models and involving radiation and imaging techniques are also being developed. The SiRIC-Curie radiobiology program is a continuation of this work.
Optimising the response to radiation therapy and reducing side effects
1) Predictive genetic factors of efficiency and tolerance to radiotherapy
Project coordinated by Dr Alain Fourquet (IC) and Dr Romuald Le Scodan (IC)
This project is based on two main axes:
- Identification of biomarkers of tolerance and hypersensitivity to radiation in the case of patients with breast cancer
- Study of genomic profiles associated with a high risk of triggering an ipsilateral breast cancer after conservative treatments
2) Study of radiation-induced carcinogenesis
Project coordinated by Dr Bernard Malfoy (IC) and Dr Yulia Kirova (IC)
This project aims to study radiation-induced carcinogenesis using clinical and genomic data obtained in different contexts:
- Radiation-induced sarcoma (angiosarcoma)
- Radiation-induced tumours in children
- Effect of radiation-induced cancers after proton therapy
- Lymphangiosarcomes and atypical vascular lesions
- Radiation-induced breast cancer after treatment of Hodgkin lymphoma
3) Modulators of the susceptibility to radiation and innovative treatments
Project coordinated by Dr Marie Dutreix (CNRS / IC), Dr Vincent Favaudon (Inserm / IC) and Dr Didier Decaudin (IC)
Protection of normal tissues against the complications of radiotherapy
Pulse irradiation at ultra-high dose rate
Modern radiotherapy techniques use rapid alternation of radiation beams and / or a pulse irradiation of tissue over a variable period of time, from the second minute (Ponette V, et al. Int J Radiat Biol. 2000).
In order to assess whether changes in the dose could have an impact on tumour control as well as early and late responses, we developed a "FLASH" radiation methodology for which the doses are administered as short pulses (<500 ms) with an ultra-high dose rate (≥ 60 Gy / s). The classical pulmonary fibrosis model was used to test the therapeutic potential of the method (J. Sharplin, Radiation research. 1989).
Improving radiotherapy via DNA repair inhibitors
PARP inhibitors (PARPi)
The triple negative breast tumors (TNBC) are associated with a high risk of remote recurrence and reduced survival. As for other types of breast cancer the proposed locoregional treatment is either surgery or radiotherapy. This project proposes developing PARP inhibitors (PARPi, molecule inhibitors of poly (ADP-ribose) polymerases) to sensitise tumour cells, alone or in combination with chemo / radiotherapy.
The DNA repair is vital to recovery after radiation exposure (Helleday et al., Nat Rev Cancer 2008). We developed a new approach designed to block the pathways involved in detection, signalling and DNA damage repair. This approach uses small modified DNA molecules so as to mimic the double strand breaks (baits molecules called DBaits) and which bind to and activate PARP (poly-ADP-ribose polymerase) and DNA kinase. By inducing "false" signals damage in the cell the DBaits molecules prevent the recruitment of damage repair proteins induced by irradiation or chemotherapy (Quanz et al Clin Cancer Res 2009).
DT01, the clinical form of Dbait, is nontoxic and does not sensitise normal tissues to the radio or chemotherapy. Proof of concept was performed on nude mice bearing xenografts for which DT01 was administered locally or systemically before irradiation (Coquery et al, PLoS ONE 2012; Biau et al, Neoplasia, 2014).
Demonstration that FLASH irradiation protects lung fibrosis and causes a significant decrease in the incidence of apoptosis in normal lungs. FLASH Irradiation can save normal stem cells and improves the differential response between tumor and normal tissues, suggesting that the method may be advantageous in reducing the complications of radiotherapy, without loss of antitumor efficacy (Favaudon V, et al. Science Translational Medicine. 2014).
DRIIM clinical trial: "first in man" proof of concept of the therapeutic value of DT01 (clinical form of the Dbait molecule). DRIIM is a multicenter phase I trial with a pharmacokinetic study (PK) in patients with in transit and unresectable metastatic melanoma and for which radiotherapy is proposed. All patients were included and the test is now closed. The first results have been presented at the ASCO meeting.
The synopsis of a new clinical trial involving DT01 and radiotherapy in cases of advanced breast cancer is being prepared
Setting up an Experimental Radiotherapy platform : RadExp.