Reverse Molecular Pharmacology in pediatric oncology (REMAP-4Kids)

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Using existing drugs to reveal the vulnerabilities of pediatric cancers and improve patient care.

 
 
REMAP-4Kids is a multi-disciplinary team led by cancer biologist Dr Eddy Pasquier and pediatric oncologist Prof Nicolas André, and composed of scientists, pharmacists and clinicians. Our research program builds on an integrative approach that we have recently developed and termed reverse molecular pharmacology, which combines high-throughput screening and pharmaco-proteomics. Our approach is applied to childhood cancers, which have singular features that are not found in adult cancers, requiring dedicated research programs.

Using existing drugs as molecular tools, our work leads to a better understanding of the biology of pediatric cancers and to the discovery of new therapeutic targets. Indeed, our original and integrative workflow aims at identifying potent drug combinations and deciphering their mechanism(s) of action in tumor cells.

To do that, we perform upfront combination drug screens using custom-made drug libraries to first reveal potentially synergistic drug associations, which are then validated in clinically-relevant models of pediatric cancers (3D tumor spheroids, patient-derived tumoroids, ex vivo organotypic co-cultures and in vivo models). Once validated, the interactome of each drug individually and in combination is characterized by a pharmaco-proteomics method called thermal proteome profiling.

This unsupervised approach can reveal the full extent of the poly-pharmacology of a drug of interest (i.e. the capacity of a given drug to interact with multiple molecular targets in a specific cellular context), thus potentially unveiling novel actionable vulnerabilities in pediatric cancers. The biological role of these targets is then studied using functional genomics combined with a large panel of cell biology assays, to define their role in the clonogenicity, stemness and resistance to treatment of pediatric tumors.

The overall objective of the REMAP-4Kids team is to both improve our knowledge in pediatric cancer biology and identify innovative therapeutic strategies.

Keywords

  • Drug poly-pharmacology (i.e. the capacity of a given drug to interact with multiple molecular targets in a specific cellular context)
  • Pharmaco-proteomics (i.e. to uncover the cellular interactome of drugs using mass spectrometry)
  • Pediatric oncology 
  • Translational research

the Team publications
Feb 2022 Nucleic acids research

Eukaryotic stress-induced mutagenesis is limited by a local control of translesion synthesis.

Masłowska KH, Villafañez F, Laureti L, Iwai S, Pagès V

Jun 2022 PLoS genetics

Single strand gap repair: The presynaptic phase plays a pivotal role in modulating lesion tolerance pathways.

Laureti L, Lee L, Philippin G, Kahi M, Pagès V

Aug 2019 Nucleic acids research

iDamage: a method to integrate modified DNA into the yeast genome.

Masłowska KH, Laureti L, Pagès V

Mar 2022 Journal of medicinal chemistry

CRCM5484: A BET-BDII Selective Compound with Differential Anti-leukemic Drug Modulation.

Carrasco K, Montersino C, Derviaux C, Saez-Ayala M, Hoffer L, Restouin A, Castellano R, Casassa J, Roche P, Pasquier E, Combes S, Morelli X, Collette Y, Betzi S

Oct 2020 Molecular oncology

In silico molecular target prediction unveils mebendazole as a potent MAPK14 inhibitor.

Ariey-Bonnet J, Carrasco K, Le Grand M, Hoffer L, Betzi S, Feracci M, Tsvetkov P, Devred F, Collette Y, Morelli X, Ballester P, Pasquier E

Jan 2020 Theranostics

Interplay between MycN and c-Myc regulates radioresistance and cancer stem cell phenotype in neuroblastoma upon glutamine deprivation.

Le Grand M, Mukha A, Püschel J, Valli E, Kamili A, Vittorio O, Dubrovska A, Kavallaris M

Jan 2019 Organic & biomolecular chemistry

Tuning the properties of a cyclic RGD-containing tetrapeptide through backbone fluorination.

Au C, Gonzalez C, Leung YC, Mansour F, Trinh J, Wang Z, Hu XG, Griffith R, Pasquier E, Hunter L

Mar 2018 European respiratory review : an official journal of the European Respiratory Society

Drug repurposing in malignant pleural mesothelioma: a breath of fresh air?

Boyer A, Pasquier E, Tomasini P, Ciccolini J, Greillier L, Andre N, Barlesi F, Mascaux C

Jan 2018 International journal of nanomedicine

From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer.

Rodallec A, Sicard G, Giacometti S, Carré M, Pourroy B, Bouquet F, Savina A, Lacarelle B, Ciccolini J, Fanciullino R

Jan 2018 Frontiers in pharmacology

Metronomics: Intrinsic Anakoinosis Modulator?

Nicolas A, Carré M, Pasquier E

Jan 2018 Frontiers in pharmacology

Metronomic Four-Drug Regimen Has Anti-tumor Activity in Pediatric Low-Grade Glioma; The Results of a Phase II Clinical Trial.

Verschuur A, Heng-Maillard MA, Dory-Lautrec P, Truillet R, Jouve E, Chastagner P, Leblond P, Aerts I, Honoré S, Entz-Werle N, Sirvent N, Gentet JC, Corradini N, André N

Sep 2017 Cancer research

Pharmacokinetics and Pharmacodynamics-Based Mathematical Modeling Identifies an Optimal Protocol for Metronomic Chemotherapy.

Ciccolini J, Barbolosi D, Meille C, Lombard A, Serdjebi C, Giacometti S, Padovani L, Pasquier E, André N

Mar 2017 Scientific reports

Akt targeting as a strategy to boost chemotherapy efficacy in non-small cell lung cancer through metabolism suppression.

Le Grand M, Berges R, Pasquier E, Montero MP, Borge L, Carrier A, Vasseur S, Bourgarel V, Buric D, André N, Braguer D, Carré M