Approche translationnelle du concept de cible en cancérologie (étude de l'effet combiné du Docetaxel et du Bevacizumab sur la boucle autocrine VEGF / VEGF-R2 dans des modèles cellulaires de cancer du sein et de la prostate)

Les thérapies ciblées font partie de l arsenal thérapeutique quotidien en cancérologie. Dans le cadre de la prise en charge des patients, l oncologue doit désormais connaître et maîtriser les différentes cibles thérapeutiques, et comprendre la synergie entre les thérapies ciblées et les chimiothérapies. La néoangiogenèse tumorale est un phe nomène majeur dans la carcinogenèse. La principale thérapie ciblée antiangiogénique est le Bévacizumab. Il s agit d un anticorps monoclonal inhibant la liaison du VEGF, le Vascular Endothelial Growth Factor , principal facteur angiogénique, à son récepteur. Le Docetaxel est une des chimiothérapies les plus utilisées. Il inhibe la dépolymérisation des microtubules. Dans les cancers du sein et de la prostate, la combinaison Bevacizumab et Docetaxel augmente la réponse thérapeutique comparé au Docetaxel seul. Nous avons donc cherché à démontrer l effet de la combinaison de ces deux traitements sur la boucle autocrine VEGF / VEGF-R2, dans des cellules de cancer du sein et de la prostate. Nous avons montré qu en condition normale, la cellule n a pas besoin de la voie VEGF / VEGF-R2 pour assurer sa survie. Par contre, lors d un traitement par le Docetaxel, les principales voies de croissance sont partiellement inhibées : cette boucle autocrine devient donc nécessaire pour la survie cellulaire. L ajout du Bevacizumab au Docetaxel inactive la boucle autocrine en diminuant le VEGF extracellulaire et en diminuant le VEGF-R2 membranaire, ce qui conduit à un arrêt de la prolifération cellulaire. Ce travail propose donc une nouvelle explication de la synergie entre les Taxanes et le Bevacizumab, qui ciblent directement la boucle autocrine VEGF / VEGF-R2 sur les cellules tumorales. Une autre approche de la compréhension des thérapies ciblées est l identification de cibles pronostiques et thérapeutiques. Dans la seconde partie de ce travail, nous avons étudié l expression des microARNs, dans 27 cancers du poumon stade 1. Nous avons montré, en riblant la microARNome sur puce, qu il existe une signature microARN prédisant la récidive de ces cancers : il s agit de la sous-expression de mir 99a de mir30a, et de la sur-expression de mir297 et de mir21. Cette signature est en cours de validation sur une série plus large. Ces deux parties de ce travail abordent donc d une façon différente le concept de cible en cancérologie, en identifiant des mécanismes de synergie entre une thérapie ciblée et une chimiothérapie, et en recherchant de nouvelles cibles potentielles que sont les microARN.Targeted therapies are and important part of cancer treatment. Oncologist may have an overview of potential targets, and may understand the synergic effect of chemotherapies and targeted therapies. Tumor neoangiogenesis represent a critical step in tumor development. Main anti angiogenesis targeted therapy is Bevacizumab, which is a monoclonal antibodies inhibiting the binding VEGF (vascular endothelial growth factor) to its receptor. Docetaxel is one of the most important chemotherapy in cancer treatment. It inhibits microtubule depolymerisation. In breast and prostate cancer, Docetaxel delivered in association with Bevacizumab increases tumor response compared with Docetaxel alone. In this work, we investigated the combined effect of both treatments on the VEGF / VEGF-R2 autocrine loop, in breast and prostate cancer cells. We have demonstated that, in standard condition, the VEGF / VEGF-R2 loop is redundant in terms of cell survival. However, when cells are treated with Docetaxel, main growth pathways are inhibited: then, the VEGF / VEGF-R2 autocrin,e loop is useful for cell survival. The addition of Bevacizumab to Docetaxel inhibits the autocrine loop by decreasing extracellular VEGF and membrane expression of VEGF-R2, leading to cell proliferation arrest. Then, inthis work, we propose a new explanation for the synergiec effect of Taxane and Bevacizumab on tumor cells. Another approach in the understanding of targeted therapy action is the identification of prognostic and therapeutic targets. In the second part of this work, we have investigated the microRNA expression pattern of 27 stage I lung adenocarcinomas. By screening microRNA expression on microchip, we have highlighted the presence of a prognostic signature, predicting cancer outcome : under expression of mir99a and mir30a, over expression of mir 297 and mir 21. The signature is under validation on a large series of patient. As a conclusion, both parts of this work investigate two aspects of the target concept in oncology, by studying mechanism of synergy between a targeted therapy and chemotherapy, and by searching new targets such as microRNA.NICE-BU Sciences (060882101) / SudocSudocFranceF

Modélisation de la récupération salivaire par un modèle linéaire mixte à partir de la dose reçue par les parotides après irradiation pour un cancer de l'oropharynx ou du cavum

NICE-BU Médecine Odontologie (060882102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Impact of correlation between CT numbers and tissue parameters on Monte Carlo simulations: dosimetric aspects

International audienceMonte Carlo (MC) simulation in radiotherapy is well known to be the reference forpatient deposit dose estimation. Correlation between CT images and MC tissue parameters isa major step before the estimation of the deposit dose. It requires transforming the CT dicomimages in the geometry input of MC code, and depends on the chosen samplings, whichmodify the CT number. However the CT number determine the density and the chemicalcomposition of each voxel. The purpose of this study is to highlight the dosimetric impact ofthe density and the chemical composition variation

Bevacizumab/docetaxel association is more efficient than docetaxel alone in reducing breast and prostate cancer cell growth: a new paradigm for understanding the therapeutic effect of combined treatment.

Bevacizumab (Bvz), a Vascular Endothelial Growth Factor (VEGF)-targeted humanised monoclonal antibody, provides clinical benefit in combination with docetaxel (DXL), a microtubule-stabilising agent, in the treatment of metastatic breast and prostate cancers. Since VEGF and their receptors are expressed by tumour cells, we hypothesised that Bvz, in addition to its impact on neo-vascularisation, could have an impact on tumour cells and enhance the DXL activity. Hence, we studied the effect of DXL and Bvz on metastatic breast (MDA MB-231) and prostate (PC3) cancer cells lines. Bvz alone did not decrease cell proliferation but in combination with DXL, Bvz enhanced the anti-proliferative activity of DXL. Other anti-angiogenic factors Sunitinib, Sorafenib and Gefitinib enhanced the anti-proliferative effect of DXL. qPCR experiments showed that DXL significantly increased the VEGF and VEGF receptor 2 (VEGF-R2) mRNA levels. Activation of VEGF and VEGF-R2 promoters demonstrated that enhanced mRNA levels are partly due to transcriptional activation. ELISA assays showed that DXL induced accumulation of cytoplasmic VEGF but decreased extracellular levels by 39% (MDA) and 48% (PC3). Cell surface localisation of VEGF-R2 was increased by DXL alone, but decreased after combined treatment of DXL plus Bvz. Abnormal expression of VEGF-R2 was also shown on breast and prostate tumour samples reinforcing the results obtained on cellular models. In conclusion, DXL and Bvz in combination decreased extracellular VEGF and VEGF-R2 levels at the plasma membrane thereby blocking an important growth/survival loop. Thus, the combined therapeutic impact of Bvz and DXL observed in clinical trials is associated with enhanced anti-proliferative activity and inhibition of the vascular network

Adapted EXTREME regimen in the first-line treatment of fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (ELAN-FIT): a multicentre, single-arm, phase 2 trial

International audienceBackgroundA standard treatment for fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) is yet to be established. In the previous EXTREME trial, few older patients were included. We aimed to evaluate the efficacy and tolerance of an adapted EXTREME regimen in fit, older patients with recurrent or metastatic HNSCC.MethodsThis single-arm, phase 2 study was done at 22 centres in France. Eligible patients were aged 70 years or older and assessed as not frail (fit) using the ELAN Geriatric Evaluation (EGE) and had recurrent or metastatic HNSCC in the first-line setting that was not eligible for local therapy (surgery or radiotherapy), and an Eastern Cooperative Oncology Group performance status of 0–1. The adapted EXTREME regimen consisted of six cycles of fluorouracil 4000 mg/m2 on days 1–4, carboplatin with an area under the curve of 5 on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 on cycle 1–day 1, and 250 mg/m2 subsequently), all intravenously, with cycles starting every 21 days. In patients with disease control after two to six cycles, cetuximab 500 mg/m2 was continued once every 2 weeks as maintenance therapy until disease progression or unacceptable toxicity. Granulocyte colony-stimulating factor was systematically administered and erythropoietin was recommended during chemotherapy. The study was based on the two-stage Bryant and Day design, combining efficacy and toxicity endpoints. The primary efficacy endpoint was objective response rate at week 12 after the start of treatment, assessed by central review (with an unacceptable rate of ≤15%). The primary toxicity endpoint was morbidity, defined as grade 4–5 adverse events, or cutaneous rash (grade ≥3) that required cetuximab to be discontinued, during the chemotherapy phase, or a decrease in functional autonomy (Activities of Daily Living score decrease ≥2 points from baseline) at 1 month after the end of chemotherapy (with an unacceptable morbidity rate of >40%). Analysis of the coprimary endpoints, and of safety in the chemotherapy phase, was based on the per-protocol population, defined as eligible patients who received at least one cycle of the adapted EXTREME regimen. Safety in the maintenance phase was assessed in all patients who received at least one dose of cetuximab as maintenance therapy. The study is registered with ClinicalTrials.gov, NCT01864772, and is completed.FindingsBetween Sept 27, 2013, and June 20, 2018, 85 patients were enrolled, of whom 78 were in the per-protocol population. 66 (85%) patients were male and 12 (15%) were female, and the median age was 75 years (IQR 72–79). The median number of chemotherapy cycles received was five (IQR 3–6). Objective response at week 12 was observed in 31 patients (40% [95% CI 30–51]) and morbidity events were observed in 24 patients (31% [22–42]). No fatal adverse events occurred. Four patients presented with a decrease in functional autonomy 1 month after the end of chemotherapy versus baseline. During chemotherapy, the most common grade 3–4 adverse events were haematological events (leukopenia [22 patients; 28%], neutropenia [20; 26%], thrombocytopenia [15; 19%], and anaemia [12; 15%]), oral mucositis (14; 18%), fatigue (11; 14%), rash acneiform (ten; 13%), and hypomagnesaemia (nine; 12%). Among 44 patients who received cetuximab during the maintenance phase, the most common grade 3–4 adverse events were hypomagnesaemia (six patients; 14%) and acneiform rash (six; 14%).InterpretationThe study met its primary objectives on objective response and morbidity, and showed overall survival to be as good as in younger patients treated with standard regimens, indicating that the adapted EXTREME regimen could be used in older patients with recurrent or metastatic HNSCC who are deemed fit with use of a geriatric evaluation tool adapted to patients with head and neck cancer, such as the EGE