The visit took place in Caen on November 3, 2010 in the comprehensive cancer center building, Centre François Baclesse. The site vist began at 8:30 am with a meeting of the committee with the AERES representative.

At 9 am, the group leader first briefly introduced the general strategy of the lab. This was followed by 4 short presentations by several scientists from the team until 11 am. The committee then split into 3 subgroups in order to meet separately the PhD students, the technicians, and the scientists. The committee then met University, INSERM and other local representatives during 30 minutes.

At 1 :30 pm, the committee met for debriefing and drafting the report. The visit ended at 3 :45 pm.

 History and geographical localization of the research unit, and brief presentation of its field and scientific activities

The BioTICLA project is based on the previous EA1772 (GRECAN: Groupe Régional d'Etudes sur le Cancer) in Caen. The lab is located on the premises of the Centre François BACLESSE with which it has strong relationships, CHU of Caen. The project of unit involves the fusion of the former BiocTICLA team with the HIQ (Histo-imagerie Quantitative) team. This latter team will give rise to an internal Technological team named MICA. Overall, the lab will use 700 square meters of lab space.

 Management team

The unit will be directed by the former responsible of the BoTICLA team. The director appears clearly as the leader of the unit. 2  Overall appreciation on the research unit

 Summary

The BioTICLA and HIQ (Histo-imagerie quantitative) teams are joining their efforts to develop a project on ovarian cancer, a locally aggressive cancer which is characterized by a high rate of recurrence after first line chemotherapy, associated with chemoresistance acquisition. Condidering the high mortality rate of ovarian cancer due to the absence of curative treatment, new therapeutic strategies are urgently needed. One of the major goals of the study is to block the antiapoptotic effects of Bcl-xL and McL1 which are overexpressed in this tumor. The therapeutic strategy presented is based on the use of: i) siRNA technology (coupled to various synthetic vectors and transporters); ii) BH3-mimetic molecules, both being applied on ovarian cancer cell lines and animal models. The pharmacological approach is developped with an industrial group by testing the ABT-737 compound. Another major aspect of the project is to find a signature of chemoresistance of ovarian cancer using proteomics and miRNA expression studies. In addition, an in vivo approach investigated the use of PET (positron emission tomography) imaging in the evaluation of the response to treament in mice. The HIQ team evaluated more specifically the stroma reaction of ovarian cancer on histological sections.

 Strenghts and opportunities

The unit is highly integrated in a medical and scientific environment that would allow transfer from bench to the bedside. The unit is closely related (geographically, medically, scientifically anf functionnally) to the comprehensive cancer center (Centre F. Baclesse) and the University Hospital. The research is oriented "on" and "against" ovarian cancer with many opportunities such as: tumor bank, ascitis bank, good recruitment of ovarian cancer patients, several dynamic young MD/PhD researchers, financial support (especially from Low Normandy Region), and finally all the forces are concentrated on a single, severe and locally aggressive disease. The research team is closely associated with the management of clinical trials

 Weaknesses and threats

The MICA projects displays a low lisibility and integration within the other major scientific priorities of the unit. Moreover, there is a low number of full time permanent researchers involved in the miRNA project, which is however a highly competitive project. In general, the review committee found that the large number of projects contrasted with a rather low number of full time permanent researchers. No high-ranking publications were published or are currently in revision/press.

 Recommendations

The unit might focus its research on the miRNA and BH3 projects and must more clearly integrate the imaging process to the biological research program of the unit. The miRNA project would benefit from the recruitment of a full time researcher. -"BH3 mimetic project": the use of BH3-mimetics to reverse the resistance of ovarian cancer cells to chemotherapy-induced apoptosis is an up-to-date and relevant project for the pathology. Moreover, it is reinforced by good partnerships (especially industry) and a clinical approach. This is a really integrated program with new and promising results.

-Therapeutic siRNA project: It is a long lasting project with a few publications and results for the in vitro approaches, but no consistent results with the in vivo applications. A good point is that the team joined a network for this project, however there is apparently no specific researcher to conduct this project.

-miRNA project It is a very integrated and interesting project in the field of ovary cancer (linked to biological resources and clinical activity of the cancer center with a large patient recruitment). However, today this project is entering in a highly competitive area.

-Imaging and innovative treatments:

-The « PET project" is a useful and interesting aspect of this program with several publications and great potential.

-The MICA project involves many people, with a strong histological and clinical background, but there are very few publications and there is no clear proposal.

During the 4 past years, the different teams that plan to set up the BioTICLA unit produced 31 original papers (16 with IF <3 or not indexed, 11 with IF between 3 and 5 and 1 with IF betwen 5 and 10) and two patents. 28 out of these publications involve lab members as first and/or senior author. The best publications were in good but not top specialty journals (Int J Cancer, Carcinogenesis, Proteomics). 14 PhD have been graduated.

There is a good and stable partnership with industry, local institutions and clinical centers and laboratories.

 Appreciation on the impact, the attractiveness of the research unit and of the quality of its links with international, national and local partners

The director of the unit gave 31 communications but few invited conferences (mainly national); there is no award.

There is a good potential for attractiveness and efforts. However, no foreign students and post docs were welcomed; this should be improved. There have been no visiting scientists but it is difficult to consider this item because this is a new project and a new unit.

There is a good funding (near 1 million euros over 4 years) from region Low Normandy, Ligue against Cancer, OSEO, Canceropole, ARC, General Council of Calvados, Caisse d'épargne ; good industrial links and financial partnership with industry. In the future, fundings for post-doc should be considered.

The unit has a good networking activity and participates to the Ligue consortium (CIT program), and has been involved in European FP7 and siRNA consortium.



Appreciation on the management and the scientific strategy

The management of the team is good in terms of obtaining funding, collaborations and teaching. Each PhD student obtained a mean of 2 to 3 publications. Some of them acquired a position (MCU). There are good initiatives for scientific animation as well as to develop cutting edge and pre-clinical projects. Several actors participate to a good and effective relationship with the local scientific and clinical (CLCCC and CHU) institutions: host organization, platform, clinical study, structuration of local research and network for research against cancer,  Appreciation on the scientific strategy and the project:

Taking into account the past difficulties on the in vivo approach, as well as the international competition, the committee recommends to slow down or reconsider the siRNA project.

Regarding the competition and the hot aspect of the miRNA program in ovarian cancer, the committee encourages the unit to put their forces in this project (especially in terms of researchers). It is very important to obtain a stable position for the scientist mainly in charge of this project.

`The MICA project: The weak background in image processing should be improved in order to stay within the international competition and it is thus recommended to link/share this project to an image processing team. The MICA projects should be more integrated within the scientific project on ovarian cancer.

The BH3 project represents a cutting edge and original project but it is recommended to develop a more fundamental and mechanistic research. A return to the bench would be interesting in this program especially if clinical results prove not to the expectancy. The BioTICLA team would like to thank the review committee for the quality of the preparation of the visit as well as for its helpful comments and recommendations. We agree with the overall conclusions of the committee, as well for the strengths as for the weaknesses pointed out by the committee. However, we would like either to give some complementary information or to clarify some items, particularly concerning the committee's recommendations.

Additional information concerning siRNA project

In agreement with the recommendation of the committee, we chose to reconsider the siRNA project.

Indeed, we decided to work exclusively with industrial partners ready-to-go through clinical trials, if applicable with our Bcl-xL/Mcl-1 multi-targeted strategy. We will thus work this year in the context of an international collaboration with a US partner already involved in preclinical and clinical validation of siRNA strategies (MTA in preparation). This partnership is established with the support of the "Ligue Nationale Contre le Cancer", within the national Consortium "validation préclinique de siRNA d'intérêt pour le traitement des cancers", itself part of the CIT ® program. We planned in vivo experiments aiming to confirm the interest of the proposed vectorization system to silence expression of the targeted gene, followed by the validation of anti-tumor effect of this multitargeted strategy. Metabolic imaging (FDG and/or FLT µPET) will be particularly useful to demonstrate such effects. Moreover, iodinated-siRNA imaging will also be performed in collaboration within the consortium to precise siRNA bio-distribution. These works will be placed, as previously, under the direct responsibility of the director of the Unit (this point is specified as the committee wrote "there is apparently no specific researcher to conduct this project"). A PhD student is currently working on this project and part of the technical staff also participates to this program. Moreover, a dedicated technician will be recruited in a few weeks for one year to allow a fast move on this project (financial support requested from LNCC). In case of successful experiments within the 18 next months, a collaborative early phase clinical trial will be proposed to this pharmaceutical partner. In case of unsuccessful experiments, the team will close this program, and will put its forces in the other projects of the Unit. However, we think that the "know-how" acquired during the last years in the field of preclinical evaluation of siRNA-based strategies as well as in the field of metabolic imaging would be highly valorised through this short-term project (at least for the first phase of its potential development), and that the taken risk is modest as compared to the possible increase of international visibility in case of success.

Reinforcement of the miRNA project

The committee recommends stabilising the position of "the scientist mainly in charge of this project". This is indeed the priority of the Unit in term of recruitment. We thus presented a high profile post-doc at Inserm (CSS7) and CNRS (30 th section) competitive recruitment procedures to obtain a stable full-time research position. After two successive selections and auditions, he was successively classified by Inserm in 10 th and 12 th position without final selection. He will postulate once more this year, in the new context of the structuration of the Unit and of cancer research in Caen.

It should be specified that CNRS detached a CR1 researcher to our Unit from two years, and that the activity of this researcher has been progressively dedicated to the miRNA project. A first article concerning his "miRNA activity" has been recently published (Breast Cancer and Research Treatment, 2011) and a second one has been submitted, as presented below. Moreover, we asked the University to support our Unit through the creation of an Assistant Professor (MCU) position dedicated to the project "predictive and therapeutic interfering RNA". We also hope to reinforce soon the staff working on this project, through the recruitment of a PhD student and/or post-doc (French or foreign) and of a dedicated technician thanks to the support of Low Normandy Region.

We also would like to inform the Committee that a publication concerning this project has just been submitted

to

Clarification about the activity of MICA project and its integration within the priorities of the Unit

First of all, it should be mentioned that the integration of MICA activities in the scientific project of the Unit constitutes the objective of the next quadrennial plan; we agree that we would have to further clarify the proposal in this field, and to present more clearly the expected benefit of the fusion of the former BioTICLA and HIQ teams of GRECAN. Thus, we would like to re-express these points here.

ERT MICA declines its activity around two main activity domains, that concern (i): the design of algorithms adapted to the optimal treatment of virtual slides in oncology; (ii): the development of a quality control approach for image processing. The tools and developments proposed by ERT MICA can be used to allow convenient histological interpretations, thus being particularly interesting in the context of pre-clinical and clinical assessment of the response to treatment and/or for the design of predictive tools. They will be progressively applied to the specific themes of the Unit. First, this will soon be the case in the context of clinical trials currently under preparation (NaviCarbo study, PHRC 2010; AMICAT study…), as well as in the context of preclinical studies in progress (ABT/CARBO ex vivo study, siRNA in vivo etc.). Such common works have been previously realised between HIQ and BioTICLA internal teams of GRECAN, as attested by common publications (de Bouard et al. 2007, Aide et al. 2008and 2009, Labiche et al. 2009).

Moreover, these tools could allow removing technological difficulties such as the ones that are met for automatic quantification of apoptotic cell death in situ or for apprehension of tissue heterogeneity for instance. These points will lead our team to specific common developments.

The other own projects of ERT MICA, some of them progressively converging towards ovarian pathology, will contribute to reinforce its experience in the field of algorithm design and quality control.

All the possible points of convergence between ERT MICA and BioTICLA scientific priorities are now clearly identified. Our emerging Unit also identified the absolute necessity to merge imaging activities with its other scientific project and will work in this way to lead quickly to an integrated research.

Concerning the few number of publications of ERT MICA and corresponding Impact Factor: It should be specified that this point has been clearly identified as critical by our Unit, and the progression of the number of publication per researcher and per year is a priority. Thus, 5 papers are expected during the next year (2 of them are in press, the submission of 3 more papers is expected in 2011). Moreover, concerning the low impact factors, it should be specified that the best IF in the field of image analysis and processing is not over 3.

It could be also noticed that the University recently decided to reinforce the Imaging Core Facility of IFR146 ICORE which is placed under the responsibility and closely related to ERT MICA by the recruitment in 2011 of a

Research Engineer. This will of course favourably impact on ERT MICA activity.

The Committee also recommends to ERT MICA to "develop its interaction with image processing teams".

The ERT MICA presents multidisciplinary features, merging biologists, pathologists and image processing researchers. This multidisciplinary allowed the setting up of original solutions attested for instance by corresponding international patents. Moreover, agreeing with the necessity to reinforce and complements its own competences in image processing, ERT MICA developed several collaborations with national and international teams clearly identified as specialist in the field of image processing : (i) Lantuéjoul). The two first collaborations are contractually formalized. These collaborations will be reinforced in the next quadrennial plan.

BH3-mimetic project

The committee wrote "The BH3 project represents a cutting edge and original project but it is This approach includes the study, in collaboration with the chemists of the "Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN)", of the interest of a new family of molecules as Mcl-1 inhibitors, some of them presenting exciting properties as showed by our preliminary results. Associated molecular modelling approach as well as protein-protein interaction studies are currently under development in our partner's laboratories. This multidisciplinary project is under expertise to obtain a three years financial support from Low Normandy Region (Emergence Project).

Overall in the progression in the publication rank

We would like to highlight the fact that a clear progression of the level of impact factors has been achieved by BioTICLA internal team of GRECAN from 2006 to 2010. Indeed, the mean impact factor was 3.656 in 2006 for 5 papers versus 4.957 in 2010 with 8 papers. We will strive to continue this progression during the next quadrennial plan.

Attractiveness

The committee mentioned: "There is a good potential for attractiveness and efforts. However, no foreign students and post docs were welcomed".

A Chinese surgeon has been welcome for 4 years for a PhD thesis before going back to China for a permanent position. During the past 4 years, the Unit welcomed 3 undergraduate foreign students (Spain, Denmark and Lithuania) for short training periods (3-6 months). Moreover, we are currently studying the possibility to obtain post-doctoral fellowship from Low Normandy Region to attract foreign researchers (miRNA project).

In summary, the construction of BioTICLA Unit in the next five years will integrate all the suggestions of the AERES committee members. Efforts will be concentrated on miRNA and BH3-mimetic projects, associated to a short term "valorise or close" approach concerning the siRNA project. Metabolic and histological imaging competences and activities will be integrated and focused on the scientific priorities of the Unit in the field of ovarian cancers therapeutic care, at the preclinical as well as clinical translational levels.

A reinforcement of the Unit is expected from the institutions, mainly for the interfering RNA projects.

Transient recruitments (post-docs and technicians) will also be essential in the next years, as well as the planned reinforcement of the number of accredited research supervisor (HDR) and associated PhD students.

The Unit will also reinforce its position in the context of national networks for research against ovarian cancers Laurent POULAIN



  Date and execution of the visit:



  Staff members (on the basis of the application file submitted to the AERES) of Ph.D. students (Form 2.7 of the application file) 4 N7: Number of staff members with a HDR or a similar grade 7 6



  Production results A1: Number of permanent researchers with teaching duties (recorded in N1) who are active in research 7 A2: Number of permanent researchers without teaching duties (recorded in N2) who are active in research 10 A3: Ratio of members who are active in research among staff members [(A1 + A2)/(N1 + N2)] 87.5% A4: Number of HDR granted during the past 4 years 2 A5: Number of PhD granted during the past 4 years 10 3  Specific comments  Appreciation on the results

  Oncogene (Targeting of Bcl-x L by miR-491-5p or Mcl-1 by miR-193b induce apoptosis in a Bim-dependent manner in chemoresistant ovarian carcinoma cells. C. Denoyelle, B. Lambert, et al.).

  recommended to development a more fundamental and mechanistic research. A return to the bench would be interesting in this program especially if clinical results prove not to the expectancy." These aspects have been briefly presented in the Unit project but are currently in development as active parts of the BH3-mimetic project. These fundamental works, presented below, could allow the design of new Mcl-1 inhibiting strategies, that constitutes a major challenge for the success of clinical applications of the multitargeted strategies developed by the Unit. • Molecular mechanisms involved in the modulation of Mcl-1 expression in response to BH3-mimetics The possible involvement of endoplasmic reticulum, calcium flux and subsequent activation/inactivation of signalling pathways in transcriptional and/or post-transcriptional control of Mcl-1 is under investigation. Moreover, the impact of such events on the expression of BH3-only proteins able to modulate the activity of Mcl-1 (Noxa, Puma, Bim…) is carefully investigated, as well as the modulation of partnerships of Bcl-x L and Mcl-1 with other Blc-2 family members after exposure to BH3-mimetic molecules. • Molecular mechanisms of Bcl-x L /Mcl-1 cooperation The mechanisms through which these two proteins specifically cooperate (other anti-apoptotic Bcl-2 family members being not involved) to protect ovarian cancer cells remain to be elucidated. Bax/Bak inactivation does not seem to impede cell death in response to Bcl-x L /Mcl-1 multitargeted strategies (work in progress). We thus wonder about the possible involvement of concomitant sequestration of Bok by Mcl-1 and of BNIP3 by Bcl-x L , these two proteins cooperating themselves to induce cell death. The results of this work could also impact on the development of such multitargeted strategies. • Identification of pharmacological tools for Mcl-1 inhibition Platinum derivatives that we currently use to directly (transcriptional regulation) or indirectly (BH3-only protein activation…) inhibit Mcl-1 show a lower efficiency than siRNA. Since siRNA are not (yet) applicable for clinical use, the design of other Mcl-1-targeting agents appears as a major challenge. In order to prepare future clinical trials with BH3-mimetics (post NaviCarbo trial), we will study the interest of various pharmacological agents, either currently in clinical use or specifically designed to inhibit Mcl-1 activity (innovative drugs), to improve the efficiency of Mcl-1 inhibition to be associated to BH3-mimetics-based Bcl-x L inhibiting strategies in a more potent, more specific and less toxic manner. A PhD student will be recruited in 2011 (half financial support obtained from ABBOTT, complementary support requested from Low Normandy Region).

(

  FEDEGYN, GINECO, GINOVA, and hopefully INCa-piloted workgroup). Associated to the very recent recognition by INCa of the early phase clinical trial activity of the Clinical Research Unit of the CLCC F. Baclesse, these elements should be favourable to the development by BioTICLA Unit of effective translational research, from bench to bedside…to bench.

les résultats SVE2 ne sont pas définitifs au 06/05/2011. Intitulés des domaines scientifiques Sciences du Vivant et Environnement • SVE1 Biologie, santé SVE1_LS1 Biologie moléculaire, Biologie structurale, Biochimie SVE1_LS2 Génétique, Génomique, Bioinformatique, Biologie des systèmes SVE1_LS3 Biologie cellulaire, Biologie du développement animal SVE1_LS4 Physiologie, Physiopathologie, Endocrinologie SVE1_LS5 Neurosciences SVE1_LS6 Immunologie, Infectiologie SVE1_LS7 Recherche clinique, Santé publique • SVE2 Ecologie, environnement SVE2_LS8 Evolution, Ecologie, Biologie de l'environnement SVE2_LS9 Sciences et technologies du vivant, Biotechnologie SVE2_LS3 Biologie cellulaire, Biologie du développement végétal

  Responsable de l'Unité : « Biologie et Thérapies Innovantes des Cancers Localement Agressifs » (BioTICLA) du Groupe Régional d'Etudes sur le Cancers (EA 1772 et IFR 146 ICORE de l'Université de Caen Basse-Normandie) Centre de Lutte Contre le Cancer François Baclesse, 3, Avenue du Général Harris, 14076 CAEN Cedex 05. Answer from BioTICLA Unit to the AERES Review Committee members (Date of the visit: 3 November 2010)

	Note globale A+ A B C Non noté Total A+ A B C Non noté Total e-mail : l.poulain@baclesse.fr SVE1_LS1_LS2 7 27 6 1 1 42 16,7% 64,3% 14,3% 2,4% 2,4% 100,0% Tél. (33) 2.31.45.52.05 * Dr Laurent Poulain Fax. (33) 2.31.45.51.72	SVE1_LS3 3 1 1 5 60,0% 20,0% 20,0% 100,0%	SVE1_LS4 1 13 6 20 5,0% 65,0% 30,0% 100,0%	SVE1_LS5 4 20 2 26 15,4% 76,9% 7,7% 100,0% Caen, 24 March 2011 SVE1_LS6 7 21 8 36 19,4% 58,3% 22,2% 100,0%	SVE1_LS7 6 26 23 4 59 10,2% 44,1% 39,0% 6,8% 100,0%	SVE2 _LS3 * 2 3 5 40,0% 60,0% 100,0%	SVE2_LS8 * 2 12 3 17 11,8% 70,6% 17,6% 100,0%	SVE2_LS9 * 23 6 29 79,3% 20,7% 100,0%	Total 30 145 58 5 1 239 12,6% 60,7% 24,3% 2,1% 0,4% 100,0%
	Intitulé UR / équipe	C1	C2	C3	C4	Note globale
	BIOLOGIE ET THÉRAPIES INNOVANTES DES
	CANCERS LOCALEMENT AGRESSIFS	B	B	A	B	B
	(BIOTICLA)
	C1 Qualité scientifique et production
	C2 Rayonnement et attractivité, intégration dans
	l'environnement
	C3 Gouvernance et vie du laboratoire
	C4 Stratégie et projet scientifique

Statistiques de notes globales par domaines scientifiques

(État au 06/05/2011)

Sciences du Vivant et Environnement

  The Clinical Image Analysis Laboratory, Department of Biomedical Informatics of Ohio State University, USA (Dr Metin Gurcan); (ii) the Stereology and Electron Microscopy Research Laboratory, Department of Computer Science of Aarhus University, Denmark (Dr R. Nyengaard and Dr E. Jensen) and (iii) the "Ecole des Mines de Paris, Centre de Morphologie Mathématique de Fontainebleau et Centre de géostatistique" (Dr F. Meyer, Dr D. Jeulin and Dr C.


M Florent

D E Vathaire

Ms Hélène Sancho-Garnier

Jean Rosenbaum

Marie-Josèphe Mrs

Leroy-Zamia

Josette Mrs

Travers

Pierre Mr

Vice-President, Denise

Jean-Louis Mr

Gerard

Formstecher

Alain Mr

Directeur Lamy

Adjoint

Emmanuel Mr

Doizy

Directeur Khaled Meflah

Crlcc F Baclesse Mr

Xavier Drouet

Report 1  Introduction

The evaluation visit had been very well prepared by the Unit. The visit took place on November 2nd 2010. All presentations were in French, with the slides in English. Both written documents and oral presentations were of high quality, complete and giving a detailed description of the scientific activities. A hand-out of the slides was given to the Committee. The committee was able to ask questions to technicians, assistants, students, post-doctorates and researchers in separate meetings, the interaction with the team being immediate and straightforward. The Committee also met various authorities responsible for local cancer prevention and control, research, and the university. The evaluation began at 9h00 and finished at 16h15. The research Unit is located in Caen, and its members come from two cancer epidemiology research groups, as well as from the biostatistics department of the Regional Cancer Center (CRLCC François Baclesse) and of the University Hospital of Caen (CHU of Caen). The research unit includes also the research activity of 3 cancer registries: the general cancer registry of the Calvados department, the specialised cancer registry of digestive tumors of Calvados and the multicentric mesothelioma registry.

At the time of the visit the Unit was located in 2 places, in the CHU and the CRLCC.

The Unit works on various aspects of cancer epidemiology : cancer risk factors, cancer screening, quality of life, and social inequalities in cancer.

The head of the Unit is Mr Guy Launoy. He is assisted by a co-director. The unit has a strong track record and occupies a solid position in the field of epidemiology of cancer in France. Its activities are divided into 4 main topics.

Topic 1: Occupational and environment cancer risk factors. The activity is mainly focused on the management of a large scale cohort of farmers (AGRICAN), which includes about 180,000 French farmers and aims to study the effects of agricultural occupational exposures on the risk of cancers. A biological resource center on about 1,000 individuals is associated with this cohort, and it is planned to extend this group to about 6000 individuals in view to study some biomarkers of genotoxicity. Up to now, and due to the cohort experimental design, the scientific production in this research area is still quite limited. Another research area of the team is asbestos related cancers, in which the unit has historically a specific epidemiological experience and develops also some biological investigations, in relation with pathological modifications linked with abestosis and possibility of screening for lung cancer in the exposed population.

Topic 2: Cancer screening The unit investigates various aspects of lung, colon and prostate cancer screening. This research is mainly guided by local or national screening committee considerations; the approach is global and multidisciplinary and concerns both choice of screening techniques, and organizational and economical aspects. In particular, the team has conducted several prospective studies, including tens of thousands of individuals, and demonstrated that immunological fecal occult blood tests are superior to gaiac haemocult tests for colon cancer screening, by having a higher sensitivity without decreasing significantly the specificity. Lung cancer screening projects are related to automated cytological screening of asbestos-exposed workers. Prostate cancer screening investigations are used to study population behavioural aspects concerning participation to screening.

Topic 3: Living with cancer: quality of life. The projects of the Unit are mostly focused on prostate cancer and benefit from the experience of the clinicians in the Unit, who are involved in all of the projects. The projects are original in concept, of very high level, and will provide new information on this topic, in order to offer a better quality of life to the cancer survivors.

Topic 4: Studying social and geographical inequalities in the management care of cancer patients The Unit investigates social inequalities in several aspects of the care and management of cancer patients, in order to understand the mechanisms responsible for these inequalities and the possible answers. The investigations are supported by their interconnections with cancer registries, and aim to identify the mechanisms responsible for the emergence of social and territorial inequalities, as well as to elaborate a geographical index of social deprivation. A specific projet is to evaluate the relevance in France of "screening guide," similar to the "patient navigator" in United States, in order to reduce the social inequalities in access to cancer screening .

 Strenghts and opportunities

The Unit has a portfolio of high level applied and interventional research in public health, and is one of the few in France having this profile. The good representation of biologists and clinicians in an epidemiological unit is one of the most important strengths, and the deep and effective involvement with the National Cancer Plan is another. The committee has noted the current dynamic in the increase in human resources, particularly in the number of PhD students, and of HDR. The capacity of the Unit to adapt to local opportunities as well as national priorities is also a manifest strength. Amongst the projects, the AGRICAN cohort is clearly of major international importance, and therefore of exceptional interest. Additionally, the excellent integration of the Unit with the local deliverers of health care, public health and biomedical research, as well as its strong support by the local partners, are considered as of value. Lastly, the strong involvement of the Unit head with the North-West Canceropole, as co-cordinator of the Axis "Cancers, Individuals and Society" is a very positive feature.

 Weaknesses and threats

The project presents two limitations.

1) There are no full time researchers from national research structures, and probably as a consequency, no post doctoral research staff. This is one of the major weaknesses of the present projects, and means to resolve this should be investigated as a priority.

2) The international visibility of the unit exists, but is still limited, and greater participation in international scientific meetings, notably for doctoral students, should be developed

 Recommendations

The Committee considers that AGRICAN is a major feature of the French epidemiological landscape, and strongly recommends the creation of an international scientific committee, in order to support the investigators in charge of the cohort. The Committee strongly recommends that support in the the long term is needed, so that the full benefits of this large scale project can be realised. The committee also recommends the establishement of a biological databank including all or most of the AGRICAN participants. A more specific suggestion from the committee is to investigate also biological risk factors for cancer, rather than only the chemical ones.

One of the most urgent point to correct is the lack of full time researchers and post-doctoral fellows. The Committee supports the creation of a Master of Epidemiology and Public Health, which is planned, as being one of the way to resolve this limitation.

The committee recommends that the research unit investigates different ways to increase its international visibility, which it considers to be insufficient

The consolidation in one unique geographical location of the Unit, which is now located in two different places, is planned. The Committee strongly endorses the importance of this issue, which needs to be addressed with minimal delay. This consolidation should help the integration in the Unit, comprising as it does researchers with different backgrounds and experience. The scientific productivity of the researchers who participate in the proposed Unit is of excellent quality. A total of 205 articles have been published for the last 5 years, for a full time equivalent of 7.5 researchers, corresponding to an annual average of 5.4 articles per full time position, and an average of 3.4 articles per year and per researcher. 74 out of the 205 involved a lab member in first and/or senior position. More than 22% of the articles were in the top 10 according to the JCR classification. This includes articles in Gut, Int J Cancer, Br J Cancer. Of the researchers, 2 have an average Index Factor, corrected by the position, superior to 10 during a 5 years period, with, respectively 2 and 3 articles each year, really rather exceptional in epidemiology.

A total of 7 theses are on going, for 7 researchers holding an HDR, what can be considered acceptable, given the lack of full time researchers.

 Appreciation on the impact, the attractiveness of the research unit and of the quality of its links with international, national and local partners

The scientific activity of the Unit puts it at the top level, with an excellent scientific quality of research, an high applicability to the national and local framework, and with a potential for a strong impact on public health policy in France, and in particular on the National Cancer Plan. The international visibility is nevertheless insufficient at present, in part because of its focus on national public health issues. This will probably change in the coming years, when the follow-up of the AGRICAN cohort will be sufficient. Another reason to be optimistic is the fact that the Unit is well implicated in European and international research networks.

The capacity of the Unit to obtain funds is excellent,as it obtained several large grants from the National Cancer Institute (INCa). Funding is however mostly limited to the national level.

The findings of the Unit with respect to technological aspects of colon cancer screening directly inspired measure 16.3 of the Cancer National Plan, which aims to gradually extend the use of the immunological test for colorectal cancer screening to the entire country, replacing the gaiac hemocult test. The results of this research are of major importance and this unit is considered as one of the two best research teams working on colon screening in France. The fact that the international visibilty of the Unit in this area is not very developed is considered by the Committee to be a consequence of focusing its activity on national public health issues.

 Appreciation on the management and life of the research unit

In general the management of the Unit by the director and co-director was considered to be of very good quality in all aspects of organisation and leadership. The Unit is well embedded in the medical faculty and in the universitary environment, and tightly supported by the university and the actors of the regional research.

Most of the PhD students have a background in science (a positive point), and some have co-directors of their theses. It has been noted by the Committee that the PhD students frequently share their questions and experience with others, rather than being isolated. However, none of the students has made a presentation at an international meeting, which is a clear weakness in their training, although they do participate in international consortia. PhD students are well integrated within the Unit, and they are aware of the major issues, including the origin of fundings.

Most of the researchers come from France, of whom about half from the area of Caen, from the medical and pharmacy faculties, were they have also teaching duties. Researchers participate in the definition of scientific policies of the Unit and in funding issues.

 Appreciation on the scientific strategy and the project Topic 1. The AGRICAN cohort is of exceptional interest, as being one of the most important cohorts in France, and will be one of the most important resources worldwide for evaluating the risk associated with chemical and biological risk factors specific to agricultural activity. To evaluate the consequences of agricultural practices is of specific relevance to France, which is one of the most extensive users of pesticides internationally. The interest of this cohort goes well beyond oncology and concerns many other areas of medical and biomedical research. Additionally, this cohort is included in an international consortium; the Committee considered that this was an indicator of past, and a guarantee of future quality and efficacy. However, the Committee expressed regret that there is no international scientific committee in AGRICAN, and that the planned size of the subcohort for the biological bank seems to be only of about 6000 individuals. Concerning the second area of research within this theme, the Committee considers that, although the study on pleural plaques is quite innovative, the overall activity is still determined by local and historical constraints, and lacks international visibility. Topic 2. Overall the investigations of the Unit on this theme were considered by the committee as translational research of a high level of quality, very relevant to, and integrated with present local French considerations, and the medical context, which interacts with them. The major public health problem represented by the wide spread of individual prostate cancer screening creating deleterious effects without clear benefit on mortality is also one of the important topic studied by this unit. The Unit has to be careful not to extend too much the number of different on going projects, in order to maintain a high capacity of innovation Topic 3. The projected work in the area is of high quality. The major source of strength derives from the tight interaction between epidemiologists, clinicians and psychologists with good experience and a real knowledge of the problems faced by cancer survivors. Again, here the application to prostate cancer may be useful to decide above a public health decision on this problem. Despite the very high level and diversity of experience within the Unit, which guarantees quality of investigations and results, the Committee was concerned about a possible lack of coherence within the whole topic. Topic 4. The projects are well structured and conducted. The committee had some concerns that the focus of the studies on geographical inequalities might not be sufficient to answer questions concerning the underlying mechanisms of inequality, and that more thought should be given to collection of data on more proximal variables,for more detailed studies.

A1:

  Number of permanent researchers with teaching duties (recorded in N1) who are active in research 10 A2: Number of permanent researchers without teaching duties (recorded in N2) who are active in research 3 A3: Ratio of members who are active in research among staff members [(A1 + A2)/(N1 + N2)] 83% A4: Number of HDR granted during the past 4 years 1 A5: Number of PhD granted during the past 4 years 2 3  Specific comments  Appreciation on the results



  Staff members are the following (on the basis of the application file submitted to the AERES) :

	2
		Past	Future
	N1: Number of researchers with teaching duties (Form 2.1 of the application file)	7	12
	N2: Number of full time researchers from research organizations (Form 2.3 of the application file)	0	0
	N3: Number of other researchers including postdoctoral fellows (Form 2.2 and 2.4 of the application file)	4	4
	N4: Number of engineers, technicians and administrative staff with a tenured position (Form 2.5 of the application file)	4	5
	N5: Number engineers, technicians and administrative staff without a tenured position (Form 2.6 of the application file)	15
	N6: Number of Ph.D. students (Form 2.7 of the application file)	4
	N7: Number of staff members with a HDR or a similar grade	5	8

 Overall appreciation on the research unit  Summary

Statistiques de notes globales par domaines scientifiques

  (État au 06/05/2011)

	Intitulé UR / équipe	C1	C2	C3	C4	Note globale
	CANCERS & PRÉVENTIONS	A+	A	A+	A+	A+
	C1 Qualité scientifique et production
	C2 Rayonnement et attractivité, intégration dans l'environnement
	C3 Gouvernance et vie du laboratoire
	C4 Stratégie et projet scientifique

Sciences du Vivant et Environnement

	Note globale	SVE1_LS1_LS2	SVE1_LS3	SVE1_LS4	SVE1_LS5	SVE1_LS6	SVE1_LS7	SVE2 _LS3 *	SVE2_LS8 *	SVE2_LS9 *	Total
	A+	7	3	1	4	7	6		2		30
	A	27	1	13	20	21	26	2	12	23	145
	B	6	1	6	2	8	23	3	3	6	58
	C	1					4				5
	Non noté	1									1
	Total	42	5	20	26	36	59	5	17	29	239
	A+	16,7%	60,0%	5,0%	15,4%	19,4%	10,2%		11,8%		12,6%
	A	64,3%	20,0%	65,0%	76,9%	58,3%	44,1%	40,0%	70,6%	79,3%	60,7%
	B	14,3%	20,0%	30,0%	7,7%	22,2%	39,0%	60,0%	17,6%	20,7%	24,3%
	C	2,4%					6,8%				2,1%
	Non noté	2,4%									0,4%
	Total	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%
	*

les résultats SVE2 ne sont pas définitifs au 06/05/2011. Intitulés des domaines scientifiques Sciences du Vivant et Environnement • SVE1 Biologie, santé SVE1_LS1 Biologie moléculaire, Biologie structurale, Biochimie SVE1_LS2 Génétique, Génomique, Bioinformatique, Biologie des systèmes SVE1_LS3 Biologie cellulaire, Biologie du développement animal SVE1_LS4 Physiologie, Physiopathologie, Endocrinologie SVE1_LS5 Neurosciences SVE1_LS6 Immunologie, Infectiologie SVE1_LS7 Recherche clinique, Santé publique • SVE2 Ecologie, environnement SVE2_LS8 Evolution, Ecologie, Biologie de l'environnement SVE2_LS9 Sciences et technologies du vivant, Biotechnologie SVE2_LS3 Biologie cellulaire, Biologie du développement végétal


president Michel Cosnard

Alan Harvey

Evaluation report

This report is the sole result of evaluation by the expert committee, the composition of which is specified below.

The assessments contained herein are the expression of an independent and collegial reviewing by the committee.

Management team

CERMN is led by its present director, Mr Patrick DALLEMAGNE, along with the deputy director, Mr Ronan BUREAU.

HCERES nomenclature

ST4

SVE1

Scientific domains

The scientific activities of CERMN are mainly dedicated to the design of compounds of biological interest as potential leads to new drugs, chemoinformatics (computer-aided drug design), organic and medicinal chemistry, and evaluation of the drug-like properties of new compounds. Oncology and neurosciences are the main therapeutic areas being developed in the unit. 2  Overall assessment of the interdisciplinary unit Introduction CERMN is essentially a strong and well-organized medicinal chemistry research unit which, in recent years, has begun to develop a screening and druggability platform. A new building with labs, offices and meeting rooms has been constructed on the campus close to the faculties of medicine and pharmacy, and this building is now fully occupied by CERMN.

Unit workforce

There are 15 permanent academic staff plus nine permanent technical/engineering staff. Additionally, there are technical staff/engineers on contracts supported by industry. Currently, there are four post-doctoral researchers and nine PhD students.

CERMN has developed a library of ~15,000 organic compounds as a resource for drug discovery screening, and is the main contributor to the national library of compounds. CERMN is organised with four distinct technological platforms (the chemical collection, synthetic and medicinal chemistry, chemoinformatics, and screening and druggability), and expertise from these is combined to conduct two main thematic projects, one in cancer and the other one related to possible treatment of Alzheimer disease. A third theme relating to ecotoxicology is being wound down following a change in staff.

Global assessment of the unit

The PI is the former dean of the pharmacy faculty; he is also the previous head of the research unit since 2012. His ambition is to develop the unit from medicinal chemistry to have drugs on the market. The unit life is well organized, and the involvement and commitment of the engineers and technicians is notable. The environment is good, both within CERMN and locally, and the unit is present in several networks (GDR and European Interreg networks). The unit is very well integrated in the pharmacy and chemistry networks locally. CERMN has a substantial budget: €3.4 M in 2014, including funds from European contracts (€108K) and industry (€350K). In the review period, output is very good: ~100 publications, with many in top journals for the discipline (4 papers in J Med Chem which is no.1 in medicinal chemistry; 3 papers in Bioorg Med Chem which is no. 2; 13 papers in Eur J Med Chem which is no. 4), plus two papers in the highly ranked PNAS. They have also 10 patent applications since 2010. There are plans to create a company, Whizzomics around CERMN's chemoinformatics platform.

Strengths and opportunities in the context

CERMN is very strong in synthetic and medicinal chemistry, as well as in chemoinformatics and computer-aided drug design. The druggability assessment area is a developing strength, and the collection of screening compounds is a unique asset. The team of technicians and engineers is highly qualified and provides a very strong technical base for the work of the unit. The network of scientific collaborators is also a strength.

Two potential lead compounds have been identified in the main thematic areas (donecopride for Alzheimer's disease; pyridoclax for cancer), bringing opportunities to translate the basic research into clinical development programmes. External collaborators who have screened the CERMN compound collection have also identified hits that might form the basis for drug development projects as antibiotics and anti-parasitics.

Weaknesses and threats in the context

The amount of de novo drug discovery and drug design apparently being undertaken by CERMN is low. Given the attrition rate in drug development (as many as nine out of ten compounds drop out between preclinical development and marketing approval), there is a real threat that CERMN's ambition of having one of its compounds reach the market will not be achievable, based on only two promising preclinical compounds.

The current screening platform appears to be underpowered to support a substantial increase in drug discovery activity: the range of assays is narrow and critical elements (radioligand binding and cell-based studies) have to be provided by external collaborators. There appears to be little biological or disease-related expertise within CERMN, meaning that the unit depends on the quality of input from collaborators for its mission-critical translational research.

Although CERMN has a large and diverse collection of apparently drug-like chemicals available for testing for bioactivity, the unit does not appear to have the intention to use the compounds for novel in-house drug discovery. This weakness would appear to stem from the technical limitations of the screening platform and from the absence of biomedical expertise.

For a unit with 14 qualified research supervisors (HDRs), CERMN has few PhD students (9 at present), meaning that the quantity of research and the ability to expand the range of research will be limited.

CERMN is well-connected in regional networks but its international presence should be developed (through Horizon 2020 awards; Marie Skłodowska-Curie studentships or fellowships; by industrial collaborations outside of France; by academic collaborations outside of France). Given the growth of academic drug discovery groups in USA and in UK and other parts of Europe, CERMN may lose opportunities to participate in EU funding and may simply be invisible to non-French companies that are out-sourcing drug discovery and design projects.

Recommendations

The committee would like to encourage the unit to pursue ambitious scientific activities at the international level in the field of medicinal chemistry. To achieve this objective, the committee recommends that the unit reinforces its collaborations with local teams pursuing similar objectives and brings new researchers to the unit.

The committee recommends that the management unit re-evaluates the current plans for the next five years, taking into account the comments contained in the review and with the aim of agreeing explicit targets and goals, plus plans to reach those goals.

  Mr François DAUPHIN, Doctoral school n°497, BISE Mr Jacques ROUDEN, Doctoral school n°508, NC 1  Introduction History and geographical location of the unit CERMN is part of the University of Caen. Initially founded by Mr Max ROBBA in 1974, this laboratory has, during four decades and under the guidance of three successive directors, regularly pursued its development and it has made important scientific contributions to Caen's faculty of pharmacy.

Unit workforce Number on 30/06/2015 Number on 01/01/2017 N1: Permanent professors and similar positions 17 17 N2: Permanent researchers

	N7: PhD students	9
	TOTAL N1 to N7	44 (42.8)

from Institutions and similar positions N3: Other permanent staff (technicians and administrative personnel) 9 (7.8) 9 (7.8) N4: Other professors (Emeritus Professor, on-contract Professor, etc.) 2 N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.) 4 N6: Other contractual staff (technicians and administrative personnel) 3

Qualified research supervisors (HDR) or similar positions Unit record From 01/01/2010 to 30/06/2015

	PhD theses defended	17
	Postdoctoral scientists having spent at least 12 months in the unit	17
	Number of Research Supervisor Qualifications (HDR) obtained during the period	6


president Michel Cosnard

Herman Waldmann

Evaluation report

This report is the sole result of evaluation by the expert committee, the composition of which is specified below.

The assessments contained herein are the expression of an independent and collegial reviewing by the committee.

Unit name:

Centre CRTI is located in a unique site at Nantes University Hospital of Hôtel-Dieu (CHU de Nantes), and is part of the Institute of Transplantation Urology and Nephrology (ITUN), bringing together clinical and research departments.

Management team

The CRTI is managed by a director, Mr Ignacio ANEGON, and a deputy-director, Mr Régis JOSIEN. For the new fiveyear contract, Mr Régis JOSIEN will be the director, assisted by Ms Sophie BROUARD as deputy director, and a board of team leaders for the strategic decision (steering committee).

HCERES nomenclature

SVE1_LS3

SVE1_LS6

Scientific domains

The major scientific domains covered by the CRTI are the mechanisms of allograft tolerance and dysfunction, the new therapeutic strategies in transplantation and the evolution of graft function and survival. 2  Overall assessment of the unit Global assessment of the unit CRTI is an effective and well-integrated unit, with a broad range of research activities in the areas of transplantation immunology and cutting edge fundamental immunology. It has successfully taken a number of projects through to varying degrees of commercialisation and early clinical trials. On this basis it has acquired a world-leading reputation in a number of areas, namely: the discovery of biomarkers which promise better management of transplant recipients, the development of novel genetic technologies to study elements of the immune system, and the development of therapeutic antibodies which block immune activation and graft rejection. CRTI research aims to understand, predict and prevent allograft rejection, with a view to minimizing drug immunosuppression. Currently used immunosuppressive drugs have numerous side effects and fail to prevent chronic rejection, with consequent human suffering and elevated health-care costs. CRTI research is therefore of great medical importance. An attractive route to minimizing immunosuppression is to be able to harness the body's natural mechanisms of immunological tolerance by using short-term treatments to reprogram the immune system. CRTI research has identified a number of such tolerance mechanisms that might be harnessed in patients, either through blocking diverse signalling pathways with drugs and antibodies, or by using cell therapy to amplify tolerogenic events.

Unit workforce

Unit

Inevitably such research aimed at controlling inflammation may itself have broad applicability in control of autoimmune diseases and other forms of immunopathology. CRTI is therefore extending its research efforts to apply such general principles to diverse immune diseases. Exploitation of tolerance processes carries with it the possibility of smuggling into the host potential immunogenic therapeutic agents and cell replacements. This area is also being developed at CRTI, particularly in the areas of gene therapy, and hepatic cell replacement. The unit has gathered an excellent national and international visibility. The quality of science is very good to excellent, with a considerable number of publications during the evaluation period. The CRTI research programme is competitive on the international stage with a healthy balance of straightforward and also somewhat more risky research projects. As such it provides excellent training for scientists working in transplantation and related fields.

Strengths and opportunities in the context

CRTI has made significant advances in monitoring and control of transplant rejection. It has developed outstanding platforms and state-of-the-art technologies to enable cutting edge basic and clinical research. It has established many collaborations with high level national and international centres for immunology. Consequently the unit provides an excellent training centre for young researchers, and a focus for the evolution of local industrial activity in immunology and genetics.

Weaknesses and threats in the context

Given the scope of research topics, there is always the risk that the breadth of research activities may diminish the depth that can be achieved. Despite its successes the unit would do well to attract more international postdoctoral scientists and graduate students.

Recommendations

The unit needs to define a strategy to improve the impact factors of its generally high level publications.

Given the scope of its research, there is wisdom in ensuring continuous assessment of the competitiveness of research projects it undertakes.

With substantive new infrastructure developments emerging with the new biomedical campus being created in Nantes, it will be vital to maintain the very strong links between the clinic and the basic science laboratories.

As one of the largest center in France in the area of transplantation and immunology, further bridges and outreach should be constructed to other key European centers in this area. Also, as mentioned in the SWOT analyses provided by the center leadership, further attention could be drawn to the recruitment of international students and post-docs.

  de Recherche en Transplantation et Immunologie

	1  Introduction
		Mr Sébastien YOUINOU, Université de Nantes
	History and geographical location of the unit
	Head of Doctoral School: The Center for Research in Transplantation and Immunology (CRTI) was created in 2012 as a joint INSERM and
	Ms Corinne MIRAL, Doctoral School n° 52, BS "Biologie-Santé" Nantes University research unit (UMR 1064), as a logical continuation to the previous UMR 643 INSERM unit. CRTI
	teams are part of the Labex IGO and the Labex Transplantex.
	Unit acronym:	CRTI
	Label requested:	UMR Inserm -U Nantes
	Current number:	CR 1064 / UMR_S 1064
	Name of Director	Mr Ignacio ANEGON
	(2015-2016):
	Name of Project Leader	Mr Régis JOSIEN
	(2017-2021):
	Expert committee members

Chair:

Mr Herman WALDMANN, Sir William School of Pathology, UK Experts: Mr Michel BRAUN, Université Libre de Bruxelles, Belgium Ms Sophie CAILLAT-ZUCMAN, Hôpital Saint-Louis, Paris (representative of INSERM) Ms Guislaine CARCELAIN, Université de Paris 6 (representative of CNU) Mr Jan D LÜNEMAN, University of Zurich, Switzerland Mr Axel SCHAMBACH, Hannover Medical School, Germany Mr Joost VAN MEERWIJK, Université de Toulouse 3 Scientific delegate representing the HCERES: Ms Sophie EZINE Representatives of supervising institutions and bodies: Mr Frédéric BENHAMOU, Université de Nantes Ms Marianne DESMEDT, Inserm Mr Martin HOLSTEIN, Région Pays de la Loire Ms Stéphanie POMMIER, Inserm Ms Anne ROYER-MOES, Faculté de Médecine de Nantes