Altération de la réparation de l’ADN et cancer

International audienceMaintaining the genetic integrity is a key process in cell viability and is enabled by a wide network of repair pathways. When this system is defective, it generates genomic instability and results in an accumulation of chromosomal aberrations and mutations that may be responsible for various clinical phenotypes, including susceptibility to develop cancer. Indeed, these defects can promote not only the initiation of cancer, but also allow the tumor cells to rapidly acquire mutations during their evolution. Several genes are involved in these damage repair systems and particular polymorphisms are predictive of the onset of cancer, the best described of them being BRCA. In addition to its impact on carcinogenesis, the DNA damage repair system is now considered as a therapeutic target of choice for cancer treatment, as monotherapy or in combination with other cytotoxic therapies, such as chemotherapies or radiotherapy. PARP inhibitors are nowadays the best known, but other agents are emerging in the field of clinical research. The enthusiasm in this area is coupled with promising results and a successful collaboration between clinicians and biologists would allow to optimize treatment plans in order to take full advantage of the DNA repair system modulation.Le maintien de l’intégrité génétique est un processus central de la viabilité cellulaire qui est permis par un large réseau de voies de réparation. Lorsque ce système de réparation est défectueux, il génère une instabilité génomique et entraîne une accumulation d’aberrations chromosomiques et de mutations qui peuvent alors être responsables de divers phénotypes cliniques dont la susceptibilité à développer un cancer. En effet, ces défauts peuvent favoriser non seulement l’initiation du cancer, mais aussi permettre aux cellules tumorales d’acquérir rapidement des mutations pendant leur évolution. Plusieurs gènes sont impliqués dans ces systèmes de réparations et des polymorphismes particuliers sont prédictifs d’apparition d’un cancer, le mieux décrit d’entre eux étant BRCA. En plus de son impact sur la carcinogenèse, le système de réparation des lésions de l’ADN est aujourd’hui considéré comme une cible thérapeutique de choix pour lutter contre le cancer, en monothérapie ou en association avec d’autres thérapies cytotoxiques comme certaines chimiothérapies ou la radiothérapie. Les inhibiteurs de PARP sont aujourd’hui les plus connus, mais d’autres agents voient le jour dans le domaine de la recherche clinique. L’engouement dans ce nouveau pan de traitements anticancéreux est associé à des résultats prometteurs, et un mariage réussi entre cliniciens et biologistes permettrait d’optimiser au mieux les plans de traitement afin de tirer pleinement profit de la modulation du système de réparation de l’ADN

Radiothérapie et biomarqueurs de la réparation de l’ADN

International audienceThe identification of DNA repair biomarkers is of paramount importance. Indeed, it is the first step in the process of modulating radiosensitivity and radioresistance. Unlike tools of detection and measurement of DNA damage, DNA repair biomarkers highlight the variations of DNA damage responses, depending on the dose and the dose rate. The aim of the present review is to describe the main biomarkers of radiation-induced DNA repair. We will focus on double strand breaks (DSB), because of their major role in radiation-induced cell death. The most important DNA repair biomarkers are DNA damage signaling proteins, with ATM, DNA-PKcs, 53BP1 and γ-H2AX. They can be analyzed either using immunostaining, or using lived cell imaging. However, to date, these techniques are still time and money consuming. The development of “omics” technologies should lead the way to new (and usable in daily routine) DNA repair biomarkers.L’identification de biomarqueurs de la réparation de l’ADN est enjeu fondamental. En effet, cette connaissance est la première étape du processus visant à moduler les mécanismes de radiosensibilité et radiorésistance. Au contraire des outils de mesure des lésions de l’ADN, l’étude des biomarqueurs de la réparation de l’ADN permet d’appréhender la variation de la réponse de l’organisme, notamment en fonction de la dose et du débit de dose. Le but de cet article est d’effectuer une synthèse de la littérature, afin de présenter les principaux biomarqueurs des lésions d’ADN radio-induites. Nous centrerons essentiellement notre propos sur les cassures double brin (CDB), du fait de leur rôle prépondérant dans la mort cellulaire radio-induite. Les principaux biomarqueurs de la réparation des cassures double brin d’ADN sont les molécules de signalisation les plus spécifiques de ces cassures, à savoir ATM, DNA-PKcs, 53BP1 et γ-H2AX. Ces biomarqueurs peuvent : soit être analysés par immunomarquage sur des cellules fixées, soit par immunofluorescence sur des cellules vivantes. Cependant à ce jour, toutes ces techniques sont chronophages, coûteuses et ne peuvent être utilisées en routine. Le développement des technologies « omiques » devrait permettre l’identification de biomarqueurs plus accessibles, spécifiques de la réparation de l’ADN

Etat des lieux des essais cliniques en cancérologie : Inégalités entre France hexagonale et départements ultramarins

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Nanoparticles in radiation oncology: From bench-side to bedside

International audienceNanoparticles (NP) are “in vogue” in medical research. Pre-clinical studies accumulate evidence of NP enhancing radiation therapy. On one hand, NP, selected for their intrinsic physicochemical characteristics, are radio-sensitizers. Thus, when NP accumulate in cancer cells, they increase the radiation absorption coefficient specifically in tumour tissue, sparing healthy surrounding tissue from toxicity. On the other hand, NP, by being drug vectors, can carry radio-sensitizer therapeutics to cancer cells. Finally, NP present theranostic effects. Indeed they are used in imaging as contrast agents. NP therefore can be multi-tasking and have promising prospect in radiotherapy field.In spite of the numerous encouraging preclinical evidence, the very small number of clinical trials investigating NP possible involvement in the radiotherapy clinical practice suggests a physicians' unwillingness. Many prerequisites seem necessary including define biological mechanisms of NP radiosensitization pathways and of NP clearance. NP biocompatibility and toxicities should be better investigated to select, among the extensive range of possible systems, the harmless and most efficient one, and to finally come to a safe and successful clinical use. The present review focuses on the various interests of NP in the radiotherapy area and proposes a discussion about their role in the future clinical practice

Brain metastases from non-small cell lung carcinoma: Changing concepts for improving patients’ outcome

International audienceThe management of Non Small Cell Lung Cancer (NSCLC) brain metastases is challenging, as this frequent complication negatively impacts patients’ quality of life, and can be a life-threatening event. Through a review of the literature, we discuss the main therapeutic options and the recent developments that improved (and complicated) the management of NSCLC brain metastases patients. Most current validated approaches are local with exclusive or combined surgery, whole brain radiotherapy (WBRT) and stereotactic radiotherapy (SRT). At the same time, there is a growing role for systemic treatments that might significantly postpone WBRT. Targeted therapies efficacy/toxicity profile remains to be defined but predictive and prognostic molecular factors integration could help to select treatments fully adapted to life expectancy and progression risk

In Vitro Cell Death Determination for Drug Discovery: A Landscape Review of Real Issues

International audienceCell death plays a crucial role for a myriad of physiological processes, and several human diseases such as cancer are characterized by its deregulation. There are many methods available for both quantifying and qualifying the accurate process of cell death which occurs. Choosing the right assay tool is essential to generate meaningful data, provide sufficient information for clinical applications, and understand cell death processes. In vitro cell death assays are important steps in the search for new therapies against cancer as the ultimate goal remains the elaboration of drugs that interfere with specific cell death mechanisms. However, choosing a cell viability or cytotoxicity assay among the many available options is a daunting task. Indeed, cell death can be approached by several viewpoints and require a more holistic approach. This review provides an overview of cell death assays usually used in vitro for assessing cell death so as to elaborate new potential chemotherapeutics and discusses considerations for using each assay

Biological aspects of chondrosarcoma: Leaps and hurdles

International audienceChondrosarcomas are characterized by their chemo- and radioresistance leading to a therapeutic surgical approach which remains the only available treatment with a 10-year survival between 30% and 80% depending on the grade. Non-surgical treatments are under investigation and rely on an accurate biological understanding of drug resistance mechanisms. Novel targeted therapy which represents a new relevant therapeutic approach will open new treatment options by targeting several pathways responsible for processes of proliferation and invasion. Survival pathways such as PI3K, AKT, mTOR and VEGF have been shown to be involved in proliferation of chondrosarcoma cells and antiapoptotic proteins may also play a relevant role. Other proteins such as p53 or COX2 have been identified as potential new targets. This review provides an insight into the biological substantial treatment challenges of CHS and focuses on improving our understanding of CH biology through an overview of major signaling pathways that could represent targets for new therapeutic approaches

Radiotherapy in triple-negative breast cancer: Current situation and upcoming strategies

International audienceTriple-negative breast cancer (TNBC) (estrogen receptor-negative, progesterone receptor-negative, and HER2-negative) is viewed as an aggressive subgroup of breast cancer. Treating patients with TNBC remains clinically challenging. It's now well established than radiation therapy is able to improve locoregional control in breast cancer patients both after breast conserving surgery or mastectomy, with positive impact in high-risk patients for long-term survival. Biologic characterization of breast tumor different subtypes, in particular the heterogeneous subtype of TNBC could permit to adapt the treatment plan. In the present review, summarizing the molecular types, we describe clinical features and postoperative radiotherapy current situation for TNBC, and we provide new strategies and directions through an adapted radiation therapy