The FHU Oncoage had the pleasure to welcome several world leading experts for the Mini Symposium “Update in Lung Cancer Biomarkers” providing novel insights on the development of biomarkers in Lung Cancer.
Dr. Catherine Alix-Panabières
Pr. Benjamin Besse, Head of the Thoracic Oncology Unit at Gustave Roussy Cancer in Paris and chair of the EORTC Lung Cancer Group provided a fascinating insight on the role of Radon in Lung Cancer development, followed by an intriguing presentation by Dr. Catherine Alix-Panabières, Director of the Laboratory Rare Circulating Human Cells at the CHU of Montpellier, about the importance of circulating tumor cells. The symposium was concluded by Prof. Angel Märten, Global Medical Advisor at Boehringer Ingelheim presenting great work about the importance of uncommon EGFR mutations in lung Cancer and Prof. Albrecht Stenzinger, Head of the IPH Center for Molecular Pathology who highlighted the importance of biomarker development for anti-cancer immunotherapy.
The symposium was concluded by the thesis defense of Simon Heeke, PhD candidate in the team of Pr. Paul Hofman, Director of the FHU Oncoage.
From left to right : Prof. Angel Märten, Prof. Albrecht Stenzinger, Dr. Nathalie Mazure, Pr. Paul Hofman, Dr. Catherine Alix-Panabières, Pr. Benjamin Besse
Friday, November 8, 2019 was held the 2nd OncoAge workshop on lung cancer “Lung Cancer Physiopathology”, with the participation of speakers from the Leon Berard Cancer Center (Lyon), the Mediterranean Center of Molecular Medicine (C3M, Nice) and the Institute for Research on Cancer and Aging, Nice (IRCAN, Nice).
A high-level working session, several collaborations between the different teams are in perspective, to be continued
Speakers and participants of OncoAge workshop at Saint Paul Hotel, in Nice
As a student in dual curriculum (medical and scientific studies) at the Faculty of Medicine of Nice and at the INSERM Liliane Bettencourt School, I had the opportunity to carry out two research internships. My first choice was Professor Hofman’s laboratory without hesitation. I was able to discover their projects during the courses of the Master Biopathology directed by Pr Ilié at the Faculty of Medicine, and I was immediately enthusiastic about the interest and quality of the research conducted in their laboratory. Professor Ilié became my mentor in the laboratory and introduced me to the world of research.
At the Laboratory of Clinical and Experimental Pathology (LPCE), I learned the essential skills that allow me to thrive in my new projects today. Indeed, thanks to Professor Hofman’s help and recommendations, I am currently doing my internship at the MD ANDERSON CANCER CENTER in Houston (USA). I am fortunate to be able to work with Professor Calin’s team on the role played by microRNAs and other non-coding RNAs in the development of cancers.
During my internship at the LPCE, having worked on a project to evaluate the response of lung cancer patients to immunotherapy, I quickly realized the importance of this area in the future management of patients. So I decided, as of the beginning of the next academic year, to integrate the Master 2 Immunology at the Pierre and Marie Curie University (Paris, France), as well as the Pasteur “Advanced Immunology” courses. My research internship will take place at Dana Farber Cancer Center in Boston, USA.
I thank Professor Hofman, Professor Ilié and all the members of the LPCE for sharing their passion for research with me and for allowing me to seize such great opportunities. My transition to the LPCE has made me mature from both a scientific and a human point of view.
Nice University Hospital is one of the 15 partners of the DiscovAIR project (“Discovering the cellular landscape of the airways and the lung”) which has just been accepted within the framework of the H2020 calls for projects. In collaboration with the both CNRS team of the IPMC of Sophia Antipolis (Pr Pascal Barbry) and FHU ONCOAGE members at Nice Hospital (Dr Sylvie Leroy and Pr Charles Hugo Marquette, Pneumology Department; Pr Paul Hofman, LPCE) we are the only french representatives of this European consortium (see list below).
The Lung Cell Atlas: a novel approach to face the huge burden of lung disease
Lung disease is a leading cause of death worldwide1, with incidence increasing at an alarming rate while curative interventions are lacking. Research into lung disease lags behind compared to cancer and cardiovascular disease, the other 2 major causes of death2. One reason for this may be the high complexity of the lung, with at least 40 different cell types organised in a complex, three-dimensional structure. Hence, there is an urgent need to grasp this complexity and propel basic, translational and clinical research in lung disease into a fast-track for the development of precision diagnostics and therapeutics. To achieve this, a detailed understanding is required of the cells that make up the lung, their fixed and variable features, their interactions and their organization into macroscopic tissue architecture in health and disease. DiscovAIR will establish the first draft of the Human Lung Cell Atlas, focusing on healthy lung, but including small disease cohorts, enabling accelerated translational and clinical research into lung disease. The discovAIR results will facilitate progress in regenerative and precision medicine and identify novel candidates for precision diagnostics and curative interventions in lung disease for the diagnostic and pharmacological industry, thereby contributing to healthy ageing and active living in Europe.
DiscovAIR: a foundation for integrated mapping of molecular state and spatial location of single cells
Recent progress in multimodal molecular profiling of single cells has allowed discovAIR partners to draft the first cellular census of healthy human lung3, and to describe the alterations in molecular states and relative frequencies of cells in the airway wall in asthma. In this work, we identified novel, disease-relevant cell states, such as mucous- producing ciliated cells, and confirmed novel cell types, such as the ionocyte – a newly discovered cell type highly expressing CFTR, the cystic fibrosis gene4. We also chart a radically changed intercellular communication network in disease, revealing a wealth of novel interactions specific to the asthmatic airway wall, that need to be tested for diagnostic and therapeutic applications. We now need to chart the cellular makeup of the lung at higher resolution, sampling more locations along the bronchial tree and in the parenchyma. In particular, we need to map lung cells onto the tissue architecture, chart the local cellular neighbourhoods and their alterations in a wider range of diseases, and identify their molecular fingerprints. This will guide the identification of the processes driving disease inception, progression and exacerbation as well as the development of novel diagnostic and therapeutic approaches.
DiscovAIR will move beyond the current state of the art by combining multimodal profiling of lung tissue cells with a detailed spatial mapping of the identified cell states, 3D reconstruction of lung tissue architecture from transcriptionally defined cell states, in-depth molecular phenotyping of local cellular neighbourhoods and development of novel computational approaches to integrate the multimodal data of the spatial and the cellular branches of discovAIR.
First draft of the Lung Cell Atlas: delivering a blueprint for the Human Cell Atlas
The lung is a complex and highly structured organ, containing an extensive variety of cell types. Molecular phenotypes of lung cells are determined by their role in maintaining physical and immunological barrier functions or facilitating gas exchange, as well as by their location within the tissue architecture. Importantly, healthy lung tissue is available to a large number of research groups through bronchoscopy programs involving healthy volunteers and patients with lung disease, and from lung transplantation and resection programs. This combination of a highly ordered tissue architecture – facilitating the implementation of a common coordinate framework – and good community-wide availability of tissue makes lung especially well-suited as a lead organ for the HCA to develop the infrastructure, workflows and platforms needed for a community-driven mapping effort as laid down in the vision of the Human Cell Atlas consortium5. Consequently, atlases of both the airways and parenchymal lung tissue have been selected by the HCA consortium as a priority effort, with the potential for the Lung Cell Atlas to grow into one of the HCA Flagship projects6. The infrastructure, workflows and platforms developed by discovAIR – rooted within the HCA Lung working group – will serve as blueprints within the HCA community. Best practices and lessons learned from the Human Lung Cell Atlas delivered by the discovAIR project will empower the HCA to achieve its ambition of charting every cell in the healthy human body.
Laura Moreno Leon, Marine Gautier, Richard Allan, Marius Ilié, Nicolas Nottet, Nicolas Pons, Agnes Paquet, Kévin Lebrigand, Marin Truchi, Julien Fassy, Virginie Magnone, Garrett Kinnebrew, Milan Radovich, Meyling Hua-Chen Cheok, Pascal Barbry, Georges Vassaux, Charles-Hugo Marquette, Gilles Ponzio, Mircea Ivan, Nicolas Pottier, Paul Hofman, Bernard Mari & Roger Rezzonico
Lung cancer is the leading cause of cancer death worldwide, with poor prognosis and a high rate of recurrence despite early surgical removal. Hypoxic regions within tumors represent sources of aggressiveness and resistance to therapy. Although long non-coding RNAs (lncRNAs) are increasingly recognized as major gene expression regulators, their regulation and function following hypoxic stress are still largely unexplored. Combining profiling studies on early-stage lung adenocarcinoma (LUAD) biopsies and on A549 LUAD cell lines cultured in normoxic or hypoxic conditions, we identified a subset of lncRNAs that are both correlated with the hypoxic status of tumors and regulated by hypoxia in vitro.
We focused on a new transcript, NLUCAT1, which is strongly upregulated by hypoxia in vitro and correlated with hypoxic markers and poor prognosis in LUADs. Full molecular characterization showed that NLUCAT1 is a large nuclear transcript composed of six exons and mainly regulated by NF-κB and NRF2 transcription factors. CRISPR-Cas9-mediated invalidation of NLUCAT1 revealed a decrease in proliferative and invasive properties, an increase in oxidative stress and a higher sensitivity to cisplatin-induced apoptosis. Transcriptome analysis of NLUCAT1-deficient cells showed repressed genes within the antioxidant and/or cisplatin-response networks. We demonstrated that the concomitant knockdown of four of these genes products, GPX2, GLRX, ALDH3A1, and PDK4, significantly increased ROS-dependent caspase activation, thus partially mimicking the consequences of NLUCAT1 inactivation in LUAD cells. Overall, we demonstrate that NLUCAT1 contributes to an aggressive phenotype in early-stage hypoxic tumors, suggesting it may represent a new potential therapeutic target in LUADs.
Tumor mutational burden (TMB) has emerged as an important potential biomarker for prediction of response to immune-checkpoint inhibitors (ICIs), notably in non-small cell lung cancer (NSCLC). However, its in-house assessment in routine clinical practice is currently challenging and validation is urgently needed. We have analyzed sixty NSCLC and thirty-six melanoma patients with ICI treatment, using the FoundationOne test (FO) in addition to in-house testing using the Oncomine TML (OTML) panel and evaluated the durable clinical benefit (DCB), defined by >6 months without progressive disease. Comparison of TMB values obtained by both tests demonstrated a high correlation in NSCLC (R2 = 0.73) and melanoma (R2 = 0.94). The association of TMB with DCB was comparable between OTML (area-under the curve (AUC) = 0.67) and FO (AUC = 0.71) in NSCLC.
Median TMB was higher in the DCB cohort and progression-free survival (PFS) was prolonged in patients with high TMB (OTML HR = 0.35; FO HR = 0.45). In contrast, we detected no dierences in PFS and median TMB in our melanoma cohort. Combining TMB with PD-L1 and CD8-expression by immunohistochemistry improved the predictive value. We conclude that in our cohort both approaches are equally able to assess TMB and to predict DCB in NSCLC.
Professor of Neurology and works at the University Hospital of Nice as Head of the Peripheral Nervous System and Muscle Department, Head of the Rare Neuromuscular Diseases Reference Centre and the Competence Centre for Neurogenetic Diseases. She is also a researcher at IRCAN (Institut of Research on Cancer and Aging of Nice, INSERM U1081 – CNRS UMR 7284) directed by Professor Eric GILSON. Very active in research, both in the clinical and fundamental aspects, she obtained a PhD in Science from UNSA in 2008 and an Habilitation to Lead Research in 2012. His main research interests are Facio-Scapulo-Humeral Muscular Dystrophy and degenerative muscle diseases, with a particular focus on the impact of ageing and genomic instability on the pathophysiology of these rare diseases, as well as on the possible impact on innovative therapies. She is also interested in the use of new technologies to improve the diagnosis and clinical evaluation of neuromuscular diseases.
Interview of Sabrina Sacconi:
What research, innovations or major advances in knowledge are you currently focusing on?
advances in new technologies, innovative immunological and gene therapies in
the field of neuromuscular and neurodegenerative diseases are making major
advances and are beginning to be tested and used on patients.
these new opportunities, many clinical and biological questions arise as to how
to develop new therapies that are more effective or less toxic, how to identify
and select patients who could benefit from them, how to quantify the biological
effects in the short and long term, and what strategy to adopt in more advanced
therapies could also be applicable to the aging of muscles and brains and
furthering knowledge about normal aging and pathological aging in these two
tissues could lead to the development of more therapies for neuromuscular and
neurodegenerative diseases and all diseases related to aging.
You are currently working on many research projects, can you tell us a few words about them? Do you have any other plans for the future?
The research projects I am working on answer the questions raised above. Currently I am working on the constitution of cohorts that integrate new digital technologies for data collection, sample storage in bio-banks to stimulate translational research and artificial intelligence for statistical analysis and the creation of mathematical models (RESOLVE International Project, French National Observatory DMFSH). Using new digital technologies, in vitro and in vivo models of normal and pathological aging, we are developing and testing new therapeutic strategies (such as immunotherapies for patients with neuromuscular genetic diseases), new indicators for measuring the progression of a disease or the effectiveness of a therapeutic approach (FACE NMD project, RESOLVE France, SMA2T) applicable at a distance (ALCOTRA PROSOL European Project, PROSOLCARE telemedicine platform) or biomarkers of severity or therapeutic monitoring in the field of neuromuscular diseases (FSHD CYTO) and ageing. For the future, I would like to continue and expand these projects and promote collaborations with the teams investing in fundamental and translational research within OncoAge and with the clinical teams within the OPTIMAGE Consortium.
Can the federation be
a support to help you progress through the network it leads?
Most of the projects I am working on are the result of
collaborations promoted within the ONCOAGE Federation with research teams from
IRCAN and CHUN, of which I am a member, but also from INRIA, IPMC and ICP. The
transversal and multidisciplinary approach and the sharing of human and
technological resources have made it possible to progress more quickly in the
construction of projects.
The support for dissemination and training through
logistical support for the organization of congresses made it possible to
organize within ONCOAGE the first European congress on e-health and innovation
in the field of neuromuscular diseases « eNMD 2019: e-health and
innovation to overcome barriers in NMD ».
Your willingness for
this working group as a Work Package Leader?
Within OncoAge, I intend to federate, the research and fundamental teams involved in the field of neuromuscular and neurodegenerative diseases around concrete objectives, decided in a collegial manner; while benefiting from and developing new technologies and innovative therapeutic approaches in the field of normal and pathological ageing of the brain and muscle.
Une étude présentée en amont du congrès de l’AACR met en évidence la concordance entre un test sur ADN circulant et la biopsie tissulaire pour l’identification des anomalies génétiques dans les cancers du poumon non à petites cellules (CPNPC). Il ne faudrait toutefois pas conclure hâtivement que la biopsie liquide pourrait se substituer totalement à la biopsie tissulaire.
Proposer des thérapies ciblées aux patients atteints de CPNPC suppose d’avoir identifié les potentielles altérations génétiques dans les cellules tumorales. Le Guardant360 de Guardant Health est un test pratiqué sur l’ADN circulant à la recherche de mutations sur les gènes EGFR, ALK, ROS1, BRAF, RET, MET, HER2, NTRK, et d’un biomarqueur pronostique, les mutations sur KRAS. Disponible depuis environ 2 ans, c’est un test très performant, très utilisé par certaines équipes en particulier aux États-Unis et en Grande-Bretagne dans les CPNPC en phase métastatique ou dans la détection précoce des cancers. Autres arguments en faveur de la biopsie liquide, son caractère non invasif et la rapidité d’obtention des résultats.
Une détection des anomalies génétiques en 9 jours
Présentée en amont du congrès de
l’AACR, l’étude prospective multicentrique NILE (Noninvasive versus Invasive
Lung Evaluation), menée chez 280 patients avec un CPNPC nouvellement
diagnostiqué, montre la concordance entre le Guardant360 et la biopsie
tissulaire pour la détection des anomalies géniques, avec des résultats obtenus
en 9 jours au lieu de 15. Cette étude pourrait amener à conclure qu’un
test sanguin bien validé, complet et sensible pourrait être une alternative aux
biopsies tissulaires pour identifier les biomarqueurs prédictifs de la réponse
thérapeutique aux thérapies ciblées. Une conclusion un peu rapide, puisque ces
recherches ne concernent que les adénocarcinomes et non les épidermoïdes, et
que, comme le reconnaît le Pr Vassiliki Papadimitrakopoulou, qui
présentait l’étude, le Guardant360 est comparé à des tests tissulaires
standards et non avec le NGS (Next-Generation Sequencing). « La comparaison porte sur deux approches qui ne sont pas
identiques. Avec le NGS au niveau tissulaire, le délai de réponse peut aussi
être de neuf jours », commente le
Pr Hofman. « On manque aussi d’informations sur les tests utilisés pour
les biopsies tissulaires, leur sensibilité et sur le type de biopsies
Biopsie liquide ou tissulaire ?
L’étude apporte des éléments nouveaux en montrant pour la première fois que pour les cibles thérapeutiques de l’EGFR, ALK, ROS1 et BRAF, ce test concorde avec la biopsie tissulaire avec une VPP de 100 % alors qu’on avait plutôt la notion de 65 % de VPP. Seules ces 4 altérations sont associées à un médicament ayant l’AMM, celles portant sur RET, MET et HER2 pourraient orienter vers un traitement qui n’a pas l’AMM actuellement dans les CPNPC. Par contre, la recherche de PDL1 et la charge tumorale mutationnelle qui doivent être recherchées dans les CPNBC ne peuvent l’être au mieux actuellement que sur les biopsies tissulaires, de même que l’amplification de MET ou les réarrangements de NTRK pour lesquels la biopsie tissulaire est bien plus sensible que l’ADN circulant. « C’est un travail très intéressant, mais qui porte sur une cohorte assez limitée, et il ne permet pas d’affirmer que la biopsie liquide va faire disparaître la biopsie tissulaire. Il faut attendre la présentation officielle de l’étude et les débats qu’elle ne manquera pas de susciter », tempère le pathologiste.
Actuellement, les tests sanguins sont
intéressants lorsque les résultats de la biopsie tissulaire ne sont pas
significatifs, que l’état général du patient ou la localisation de la tumeur la
rendent impossible et ils ont surtout une place dans la surveillance des
traitements afin de repérer l’apparition de mutations de résistance
thérapeutique ou vérifier l’évolution de la quantité d’ADN libre circulant.
D’après un entretien avec le Pr Paul Hofman, pathologiste, CHU de Nice Papadimitrakopoulou V.A. (MD Anderson Cancer Center, Houston), « Clinical utility of comprehensive cell-free DNA (cfDNA) analysis to identify genomic biomarkers in newly diagnosed metastatic non-small cell lung cancer », conférence de Presse de présentation de l’AACR.
Professor of Dermatology at the University Hospital of Nice. He also heads the laboratory INSERM U1065 team 12, C3M, dedicated to the study of molecular mechanisms involved in pigmentation and melanoma. He heads the University laser center in Nice. He is president of the Department of Clinical Research and Innovation of Nice University hospital and vice-president of Côte d’Azur University. He has seven international patents and more than 220 publications in scientific journals (h-index 41). He is co-founder of YUKIN therapeutics. His fields of research includes pigmentary disorders (including vitiligo and melasma), melanoma, hidradenitis suppurativa, alopecia areata and lasers.
Interview of Thierry Passeron:
What research, innovations or major advances in knowledge are you currently focusing on?
Skin cancers and melanoma in particular, have been the subject of major therapeutic advances in the past few years. Thus, targeted therapies and immunotherapy have for the first time significantly increased the overall survival of patients with metastatic melanoma. These treatments have recently been proposed as adjuvants, particularly after lymph node involvement.
proposed for melanoma, immunotherapy is now available for many cancers.
Unfortunately, full response rates are still insufficient. There is a lot of
work being done at the moment to try to find predictive response factors on the
one hand, but also to improve immunotherapy.
You are joining OncoAge to create a new Work Package, what do you expect from the federation?
We have always
had close links with Professor Hofman’s Clinical and Experimental Pathology
Laboratory (CEPL). The Dermatology department has the opportunity to work with
3 INSERM units dedicated to melanoma, one of which I co-lead. Thanks to the
CEPA Tumour Library, we have been conducting translational research on our
patients’ tissue and blood samples for several years. By joining the OncoAge
federation we will be able to pool our resources and samples with other
specialities such as pneumology for example. We will also be able to set up
more ambitious research projects and respond to international calls for
tenders. Finally, we have developed several agents in our research
laboratories. One of them is the first NIK allosteric inhibitor. This kinase
controls the non-canonical pathway of NFkB and plays a key role in most solid cancers
by controlling the oncogene EZH2. By inhibiting NIK, it “warms”
tumors and greatly enhances the response to immunotherapy (especially anti-PD1
Ac). We have very encouraging results in vitro but also on murine models in
melanoma and colon cancer. Since May 2018 we have created with the Advent
investment fund, the startup YUKUN therapeutics. Since April 2019, another
partner (Medixci) has been a shareholder in order to bring our compounds into
the clinical phase in humans. If we reach this stage, the clinical phase will
be coordinated by our centre and the product can be tested on several cancers
within the framework of the OncoAge federation.
Can links be made between oncology, aging and cancer in dermatology and other specialties through the exchanges that OncoAge allows with other research teams?
These links are
naturally strong. In our region we see a large proportion of elderly patients.
We check this every week in our multidisciplinary consultation meetings in
oncodermatology. As the population ages, the number of older people who will be
able to receive cancer treatment will increase and it is essential to conduct
specific studies on this age group. Our federation must be in the front line to
meet this challenge and propose institutional and industrial studies for this
group of patients.