[Radiation dose intensification for glioblastoma]. / Majoration de dose d'irradiation pour les glioblastomes.

Glioblastoma is the most common brain tumor in adults; its treatment includes surgical excision or biopsy followed by radio-chemotherapy. Even if radiotherapy increases the survival of all patients regardless of their age or their general condition, there are always sources of radioresistance, where relapses occur and therefore treatment fails. Indeed, these foci result in a local relapse, which is observed in 95% of cases in the irradiation fields. We will describe here the current approaches to overcome this radioresistance by dose escalation, without or with guidance by metabolic and functional imaging (dose-painting). We will detail several prospective trials including the French phase III trial, SPECTRO-GLIO, randomizing the use of an integrated boost guided by spectrometric magnetic resonance imaging and similar trials developed across the Atlantic. We will also discuss approaches using different PET markers as well as diffusion or perfusion magnetic resonance imaging.

RadioTransNet: Preclinical research network coordinated at the SFRO and SFPM.

The RadioTransNet programme launched under the auspices of French societies for radiation oncology (SFRO) and medical physics (SFPM) was approved by the French national cancer institute (INCa) in December 2018 and is dedicated to proposing a relevant national and transversal structure for preclinical research including translational research in radiation oncology with well-defined priority areas of research. Its activities, coordinated by a scientific committee that includes radiation oncologists, medical physicists, academic biologists, are structured around several main areas, i.e.: target volume definition, interaction of radiation with normal tissues, combined treatments and modern dose calculation approaches. Four work packages have been created in these areas and are associated with other objectives pertaining to fundamental radiobiology, early implementation of new drugs in a preclinical setting, contribution of imaging in this task, research in medical physics including transversal components such as medical oncology, radiology, nuclear medicine and also cost/efficiency evaluation. All these tasks will be included in a national network that uses the complementary expertise provided by partners involved in the scheme. Calls for proposals will be selected by the scientific council to be submitted to INCa and the various academic associations to obtain funding for the human and technical resources required to conduct under optimal conditions projects in preclinical and translational research in radiation-oncology.

Radioresistant tumours: From identification to targeting.

From surviving fraction to tumour curability, definitions of tumour radioresistance may vary depending on the view angle. Yet, mechanisms of radioresistance have been identified and involve tumour-specific oncogenic signalling pathways, tumour metabolism and proliferation, tumour microenvironment/hypoxia, genomics. Correlations between tumour biology (histology) and imaging allow theragnostic approaches that use non-invasive biological imaging using tracer functionalization of tumour pathway biomarkers, imaging of hypoxia, etc. Modelling dose prescription function based on their tumour radio-resistant factor enhancement ratio, related to metabolism, proliferation, hypoxia is an area of investigation. Yet, the delivery of dose painting by numbers/voxel-based radiotherapy with low lineal energy transfer particles may be limited by the degree of modulation complexity needed to achieve the doses needed to counteract radioresistance. Higher lineal energy transfer particles or combinations of different particles, or combinations with drugs and devices such as done with radioenhancing nanoparticles may be promising.

[RadioTransNet, the French network for preclinical research in oncological radiotherapy]. / RadioTransNet, le réseau national de radiothérapie oncologique préclinique.

The ambition of the RADIOTRANSNET network, launched by the INCa at the end of 2018, is to create a French research consortium dedicated to preclinical radiotherapy to foster scientific and clinical interactions at the interface of radiotherapy and radiobiology, and to identify research priorities dedicated to innovation in radiotherapy. The activities of the network are organized around four major axes that are target definition, normal tissue, combined treatments and dose modelling. Under the supervision of the Scientific Council, headed by a coordinator designated by the SFRO and a co-coordinator designated by the SFPM, three leaders coordinate each axis: a radiation-oncologist, a medical physicist and a biologist, who are responsible for organizing a scientific meeting based on the consensus conference methodology to identify priority issues. The selected themes will be the basis for the establishment of a strategic research agenda and a roadmap to help coordinate national basic and translational research efforts in oncological radiotherapy. This work will be published and will be transmitted to the funding institutions and bodies with the aim of opening dedicated calls to finance the necessary human and technical resources. Structuration of a preclinical research network will allow coordinating the efforts of all the actors in the field and thus promoting innovation in radiotherapy.

Subventricular zone involvement at recurrence is a strong predictive factor of outcome following high grade glioma reirradiation.

We aimed to assess the efficacy of stereotactic irradiation for patients with recurrent high-grade glioma (HGG) and identify predictive factors of progression-free survival (PFS) and overall survival (OS) following reirradiation. We identified 32 patients with recurrent brain HGG who had been treated with either single-dose (stereotactic radiosurgery) or fractionated stereotactic radiotherapy between April 2008 and October 2015. Median follow up was 21.4 months (range 12.9-23.2) and median PFS was and 3.3 months (95% CI [2.3-4.7]), respectively. OS was 90.40% (95% CI [73.09-96.80]) at 6 months and 79.55% (95% CI [59.9-90.29]) at 12 months. Univariate analysis showed that biological effective dose at isocenter ≤ 76 Gy was a poor prognostic factor for both OS (83.33 vs. 100% at 6 months, p = 0.032) and median PFS (2.7 vs. 4.7 months, p = 0.025), as was gross tumor volume (GTV) above 1 cm3 for OS (86.15 vs. 94.12% at 6 months, p = 0.043). Contact with the subventricular zone (SVZ) was also a poor prognostic factor for median PFS (2.3 vs. 4.7 months, p = 0.002). Multivariate analysis showed that SVZ contact remained a poor prognostic factor for PFS (hazard ratio = 3.44, 95% CI [1.21-9.82], p = 0.021). Results suggest that reirradiation is a safe and effective treatment option for recurrent HGG in patients with a good Karnosfsky Performance Scale score, a long progression-free interval since first radiation and limited GTV, and that contact to SVZ is a strong prognostic factor for PFS.

Subventricular zones: new key targets for glioblastoma treatment.

BACKGROUND: We aimed to identify subventricular zone (SVZ)-related prognostic factors of survival and patterns of recurrence among patients with glioblastoma. METHODS: Forty-three patients with primary diagnosed glioblastoma treated in our Cancer Center between 2006 and 2010 were identified. All patients received surgical resection, followed by temozolomide-based chemoradiation. Ipsilateral (iSVZ), contralateral (cSVZ) and bilateral (bSVZ) SVZs were retrospectively segmented and radiation dose-volume histograms were generated. Multivariate analysis using the Cox proportional hazards model was assessed to examine the relationship between prognostic factors and time to progression (TTP) or overall survival (OS). RESULTS: Median age was 59 years (range: 25-85). Median follow-up, OS and TTP were 22.7 months (range 7.5-69.7 months), 22.7 months (95% CI 14.5-26.2 months) and 6.4 months (95% CI 4.4-9.3 months), respectively. On univariate analysis, initial contact to SVZ was a poor prognostic factor for OS (18.7 vs 41.7 months, p = 0.014) and TTP (4.6 vs 12.9 months, p = 0.002). Patients whose bSVZ volume receiving at least 20 Gy (V20Gy) was greater than 84% had a significantly improved TTP (17.7 months vs 5.2 months, p = 0.017). This radiation dose coverage was compatible with an hippocampal sparing. On multivariate analysis, initial contact to SVZ and V20 Gy to bSVZ lesser than 84% remained poor prognostic factors for TTP (HR = 3.07, p = 0.012 and HR = 2.67, p = 0.047, respectively). CONCLUSION: Our results suggest that contact to SVZ, as well as insufficient bSVZ radiation dose coverage (V20Gy <84%), might be independent poor prognostic factors for TTP. Therefore, targeting SVZ could be of crucial interest for optimizing glioblastoma treatment.

Progastrin a new pro-angiogenic factor in colorectal cancer.

Angiogenesis is essential in tumor progression and metastatic process, and increased angiogenesis has been associated with poor prognosis and relapse of colorectal cancer (CRC). VEGF has become the main target of anti-angiogenic therapy. However, most patients relapse after an initial response or present a resistance to the treatment. Identification of new pro-angiogenic factors may help to improve anti-angiogenic therapy. In this study, we demonstrated that the pro-hormone progastrin (PG), over-expressed in CRC, recognized as a growth factor, is a potent pro-angiogenic factor. In transgenic mice and human colorectal HPs producing high levels of PG, we correlated PG overexpression with an increased vascularization. In vitro, exogenous PG and conditioned media (CM) from CRC cells producing PG increased endothelial cell proliferation and migration. We also showed that treatment with exogenous PG can increase the ability of endothelial cells to form capillary-like structures. Moreover, we demonstrated that PG enhanced endothelial permeability. The finding that PG stimulated the phosphorylation of vascular endothelial (VE)-cadherin, p125-FAK, paxillin and induced actin remodelling was consistent with a role of these components in PG-stimulated endothelial cell migration and permeability. The pro-angiogenic effects observed with CM were significantly inhibited when CRC cells expressed a PG shRNA. In vivo, we found an important decrease in tumor growth and neovascularization when the CRC cells expressing the PG shRNA were xenografted in mice or in the chick chorioallantoic membrane model. We also observed an increase in the coverage of blood vessels by pericytes and a decrease in endothelial permeability when PG expression was blocked. Our results demonstrate that PG is a new pro-angiogenic factor in CRC and an attractive therapeutic target.

Ionizing radiations sustain glioblastoma cell dedifferentiation to a stem-like phenotype through survivin: possible involvement in radioresistance.

Glioblastomas (GBM) are some bad prognosis brain tumors despite a conventional treatment associating surgical resection and subsequent radio-chemotherapy. Among these heterogeneous tumors, a subpopulation of chemo- and radioresistant GBM stem-like cells appears to be involved in the systematic GBM recurrence. Moreover, recent studies showed that differentiated tumor cells may have the ability to dedifferentiate and acquire a stem-like phenotype, a phenomenon also called plasticity, in response to microenvironment stresses such as hypoxia. We hypothesized that GBM cells could be subjected to a similar dedifferentiation process after ionizing radiations (IRs), then supporting the GBM rapid recurrence after radiotherapy. In the present study we demonstrated that subtoxic IR exposure of differentiated GBM cells isolated from patient resections potentiated the long-term reacquisition of stem-associated properties such as the ability to generate primary and secondary neurospheres, the expression of stemness markers and an increased tumorigenicity. We also identified during this process an upregulation of the anti-apoptotic protein survivin and we showed that its specific downregulation led to the blockade of the IR-induced plasticity. Altogether, these results demonstrated that irradiation could regulate GBM cell dedifferentiation via a survivin-dependent pathway. Targeting the mechanisms associated with IR-induced plasticity will likely contribute to the development of some innovating pharmacological strategies for an improved radiosensitization of these aggressive brain cancers.

[From bench to bedside: experience of the glioblastoma model for the optimization of radiosensitization]. / Du laboratoire vers la clinique : expérience du glioblastome pour moduler la radiosensibilité tumorale.

Despite significant progress in the treatment of glioblastoma, the prognosis of these radioresistant, invasive and hypoxic tumours remain dark. The constant relapse after treatment of this tumour is in part due to its intra-cellular but also micro-environmental radioresistance, largely controlled by growth factors and their receptors. The complexity of the biology of these tumours and the presence of numerous cross-talks between the pathways of these different growth factors can be in part responsible for the negative results obtained in clinical trials associating radiotherapy and targeted drugs designed without previous in vitro and in vivo studies validating the proof of concept of a specific target as key factor of radioresistance. In the aim to optimize the treatment of glioblastoma and to reduce the risks of failure of new trials, several laboratories and clinical departments are developing translational research in radiotherapy and radiobiology, validating in vitro and then in orthotopic xenografts interesting targets, then studying the radiosensitizing effect of targeted drugs directed against these proteins, studying the mechanisms of action and resistance of these drugs, validating these proteins as predictive factors of response to radiotherapy in the patients, and then designing clinical trials, integrating metabolic or functional imaging and surrogate markers to better understand the mechanism of action of these associations. We describe in this article the main translational research axis developed for radiosensitizing glioblastoma, which our lab and department have pursued for several years.

[Angiogenic inhibitors and radiotherapy: from the concept to the clinical trial]. / Thérapies antiangiogéniques et radiothérapie: du concept à l'essai clinique.

Increasing studies show the central role of the tumor microenvironment, and more particularly the angiogenesis, in the response to anticancer treatment such as radiotherapy. Thus the association of angiogenesis inhibitors to radiotherapy is a strategy whose concept is based on several mechanisms of actions, such as the implication of the angiogenic factors in the control of tumor radiosensitivity, the regulation of the tumor radiosensitivity by that of the endothelial cells, the induction of hypoxia by the tumor angiogenesis, the induction of HIF-1alpha by irradiation and finally the importance of the angiogenic factors in the tumor stem cells survival, known to be radioresistant. These mechanisms will be detailed in this article as well as several clinical trials associating these inhibitors with radiotherapy.