asparagine starvation inhibits rhabdomyosarcoma growth connective tissue oncology society 2014...
TRANSCRIPT
Asparagine starvation inhibits rhabdomyosarcoma
growth
Connective Tissue Oncology Society 2014 Annual Meeting in Berlin
Simone Hettmer, Anna C Schinzel, Daria Tchessalova,Nigel GJ Richards, William C Hahn, Amy J Wagers
Ras pathway activationin fusion-negative rhabdomyosarcoma
Skeletal muscle
Ras pathway activation
Sarcoma induction in skeletal muscle
Transcriptional profiling identified 141 discrete genesthat are upregulated
in Kras; p16p19null mouse sarcomas and in human rhabdomyosarcomascompared to skeletal muscle.
Negative controlshRNA
shRNASarcoma
genes
Positive controlshKras
shASNS
Functional screening ofsarcoma-relevant candidate genes
q<0.001
Customized shRNA proliferation screen (in vitro)
Asparagine Synthetase (ASNS)
The growth-inhibitory effects of ASNS silencing are due to Asparagine starvation
Kras;p16p19null mouse RMS cell line
Kras;p16p19null mouse RMS cell line
Asparagine starvation reduces the synthesis of nascent polypeptide chains in rhabdoyosarcoma cells
Asparagine starvation reduces human rhabdomyosarcoma growth and peptide synthesis
Human RMS cell line RH30 (PAX3:FOXO1a +)
Asparagine starvation reduces mouse rhabdomyosarcoma growth in vivo
shASNS
shLuc
100 cells per injection
Asparagine starvation reduces mouse rhabdomyosarcoma growth in vivo
shASNS
shLuc
Aspara-ginase
Aspara-ginase
100 cells per injection
Asparagine homeostasis is anactionable cellular process
Amino Sulfoximines
Asparaginase and Amino Sulfoximine 5 inhibit rhabdomyosarcoma growth
Amino Sulfoximine 5Asparaginase
Kras;p16p19null mouse RMS cell line
Asparaginase effects onrhabdomyosarcoma growth in vivo
Aspara-ginase
Mouse RMS Rh30 (Hu RMS) Rh41 (Hu RMS)
Aspara-ginase
Control Aspara-ginase
Control Aspara-ginase
Control
p=0.02 p=0.09 p=0.0004
Asparagine homeostasis is an actionable metabolic vulnerability in sarcoma
Sarcoma induction by Ras pathway activation in skeletal muscle identified a cluster of sarcoma-relevant genes.
Functional screening identified Asparagine homeostasis as a metabolic vulnerability in sarcoma.
Asparagine starvation inhibits growth and nascent peptide synthesis in mouse and human sarcomas.
Chemical targeting of Asparagine homeostasis reduces mouse and human rhabdomyosarcoma growth.
Acknowledgements
Amy Wagers
Wagers lab:Daria TchessalovaTata Nageswara Rao
DFCI shRNA screening core:Anna SchinzelWilliam Hahn
David Langenau
Nigel Richards
Peter HoughtonRichard Lock
Joslin Flow Cytometry Core
Funding:PALS/St Baldrick’s FoundationAlex’s Lemonade StandBear NecessitiesSARC