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1er centre de lutte contre le cancer en Europe, 3 000 professionnels mobilisés

Villejuif, 5th May 2015

Childhood cancer and targeted therapy: Publication in Nature Medicine

Panobinostat, identification of a new drug for the treatment of invasive brain-stem glioma (dipg)

DIPG (Diffuse Intrinsic Pontine Glioma) is a very serious childhood tumour, for which there has been no curative treatment up till the present. Those therapies that have been available (chemotherapy and targeted therapies) have only been transiently effective.
Dr. Jacques Grill, paediatric neuro-oncologist in the Gustave Roussy Department of Paediatric Oncology, is one of the principal authors of a recently-published study in Nature Medicine which identifies one agent, panobinostat, as a potential candidate for the treatment of invasive brain stem glioma (DIPG). This drug targets the epigenetic mechanisms operating in this tumour, whose oncogenesis depends on a specific mutation of a histone (histones are proteins which organise the disposition of DNA and its translation).
The findings of this study represent valuable preclinical data to enable testing of this agent in a clinical trial.

// An international collaboration

This work results from a transatlantic collaboration carried through by the DIPG Preclinical Consortium. It is the first time that an international group of clinicians and researchers have joined forces to find a targeted therapy for the condition. Dr Grill tells us that «This is a consortium of a number of North-American and European institutions, which have shared their laboratory resources, mainly tumour cell-lines, to perform large-scale pharmacological screening in order to identify potentially effective drugs».

// Identification of effective agents and potential targets

The study was jointly led by Dr Jacques Grill and Dr Michelle Monje, Stanford University, in close collaboration with the neurosurgical team from the Necker-Sick Children Hospital. It used 17 cell lines obtained from tumour biopsies in patients with DIPG. The researchers performed pharmacological screening on these lines and also sequenced the tumour exome and RNA. They then used an algorithm to integrate the data. Dr Grill explains that « By bringing together the information obtained on the tumour cell genomes with that for the most effective drugs, we have established a chart of target inhibition, which enables us to define effective combinations. »  
Chemical screening showed that tumour cells were sensitive to inhibitors of histone deacetylases and of cyclin-dependent kinases (CDK). Panobinostat is an inhibitor of histone deacetylases, which has marketing authorisation for treatment of multiple myeloma in the adult. Of the agents which were most effective when employed as monotherapy, panobinostat was chosen for in vivo testing in two different mouse models. An anti-tumour effect was also observed in these.      
In addition, pharmacological screening confirmed what had been observed clinically: relative resistance of tumour cells to standard chemotherapeutic agents such as temozolomide, carboplatin and vincristine.
Up to now, the search for a drug to treat DIPG was hampered by a lack of experimental models and a dearth of tumour tissue. Clinical trials were conducted without having preclinical data. The establishment of the DIPG Consortium and the resulting collaborative research will help in the design of clinical trials.   

This study published in Nature Medicine received support from the following charities: L’Etoile de Martin, la Famille et les amis de Noé Lemos and le Défi de Fortunée.

Information about the Gustave Roussy Department of Childhood and Adolescent Oncology

  • 40 beds and places
  • 880 patients admitted
  • 4,574 hospital stays
  • 457 new patients seen in Paediatric Outpatients
  • 49 active clinical trials (10 phase-1 trials)

Press Contact:

GUSTAVE ROUSSY : Communication Directorate – Christine Lascombe – +33 (0)1 42 11 41 75 –
AGENCE MEDIAL – Claire Parisel - +33 (0)1 53 83 81 52 –

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