abstract

The two faces of TRAIL-based therapies in pediatric bone tumors: how to
counteract the activation of pro-proliferative pathways?
Abstract ID : 1232
Submitted by : Françoise Redini the 2016-02-12 16:09:20
Category : Targeted Therapy
Typology : Communication orale / Oral communication
Status : Validated
Authorisation to disclose : Yes/Oui
------------------------------------Introduction: Osteosarcoma (OS) and Ewing sarcoma (EWS) are the two most common pediatric bone tumors arising
mostly in young people. No major therapeutic advances have been reported for the last three decades with a 5 yearsurvival rate of 70% for localized tumors and only around 20 % for metastatic forms or patients resistant to
chemotherapy. The pro-apoptotic cytokine TNF-Related Apoptosis Inducing Ligand (TRAIL) that selectively kills tumor
cells represents a promising therapeutic approach for patients at high risk. However, multiple resistance phenomena
were observed when studying TRAIL sensitivity in several OS and EWS cell lines. Among these resistance mechanisms,
the activation of TRAIL-induced surviving, migration and invasion pathways, (NF-kB, MAPK, PI3K/Akt…) involving the
same death receptors (DR4 and DR5) as those implicated in apoptosis, is our major concern.
Materials and methods: We used two different TRAIL death receptor agonists to induce TRAIL apoptotic and nonapoptotic pathways in in vitro and in vivo models of OS or EWS: a conventional antibody agonist to DR5 (AMG655 Amgen) and a TRAIL-receptor multiple agonist able to bind six receptors per molecule (APG880 - AbbVie).
Results: We show that AMG655 treatment allows the slowing down of tumor growth in an in vivo model of EWS, induced
in Nude mice by xenograft of human EWS cells initially sensitive to TRAIL. However, the same treatment accelerates
tumor growth in an OS in vivo model, induced by xenograft of cells initially resistant to TRAIL. We demonstrate by
shRNA technique that the key scaffolding protein RIPK1 is required for the induction of the non-apoptotic pathway
leading to increased tumor proliferation. Indeed, the downregulation of RIPK1 in OS in vivo model not only block the
induction of pro-proliferative pathways after AMG655 treatment, but also sensitizes the OS cells to the induction of the
pro-apoptotic pathway. Then, we hypothesize that increasing the clustering of TRAIL receptors could promote proapoptotic pathway instead of pro-proliferative pathway. The TRAIL receptor multiple agonist APG880 allows us to
confirm this hypothesis as APG880 treatment slows, or even stops, tumor development of an OS in vivo model initially
resistant to TRAIL.
Conclusion: In this study, we investigate the two paradoxical pro and anti-tumoral effects of TRAIL in pediatric bone
tumors to better understand the activation modalities of different signaling pathways. Our results suggest two
sensitization tracks: 1-Targeting the scaffold protein RIPK1 required for activation of pro-proliferative pathways; 2-The
use of compounds allowing TRAIL-receptor high-clustering to promote apoptosis instead of pro-tumoral effects.
------------------------------------Keywords : ewing sarcoma, osteosarcoma, TRAIL, resistance
Authors :
References : , , ,
Authors
Françoise REDINI 1, Romain GUIHO 1, Kevin BITEAU 1, Régis BRION 1, Julien TAURELLE 1, Malika GANTIER 1,
Simone FULDA 3, Dominique HEYMANN 1,
1. faculté de médecine, INSERM UMR957, Nantes, FRANCE
2. Faculté de médecine, INSERM UMR957, Nantes, FRANCE
3. Goethe University Hospital, Institute for Experimental Cancer Research in Pediatrics, Franckfurt, GERMANY
Authors (raw format)
REDINI Françoise - email : [email protected] Institution : INSERM UMR957 Department : faculté de
médecine City : Nantes Country : FRANCE Speaker : Yes
GUIHO Romain - email : [email protected] Institution : INSERM UMR957 Department : Faculté de médecine
City : Nantes Country : FRANCE Speaker : No
BITEAU Kevin - email : [email protected] Institution : INSERM UMR957 Department : faculté de médecine
City : Nantes Country : FRANCE Speaker : No
BRION Régis - email : [email protected] Institution : INSERM UMR957 Department : faculté de médecine City :
Nantes Country : FRANCE Speaker : No
TAURELLE Julien - email : [email protected] Institution : INSERM UMR957 Department : faculté de médecine
City : Nantes Country : FRANCE Speaker : No
GANTIER Malika - email : [email protected] Institution : INSERM UMR957 Department : faculté de
médecine City : Nantes Country : FRANCE Speaker : No
FULDA Simone - email : [email protected] Institution : Institute for Experimental Cancer Research in Pediatrics
Department : Goethe University Hospital City : Franckfurt Country : GERMANY Speaker : No
HEYMANN Dominique - email : [email protected] Institution : INSERM UMR957 Department : faculté
de médecine City : Nantes Country : FRANCE Speaker : No