RGD Reference Report - Reversal of oncogene transformation and suppression of tumor growth by the novel IGF1R kinase inhibitor A-928605. - Rat Genome Database

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Reversal of oncogene transformation and suppression of tumor growth by the novel IGF1R kinase inhibitor A-928605.

Authors: Pappano, WN  Jung, PM  Meulbroek, JA  Wang, YC  Hubbard, RD  Zhang, Q  Grudzien, MM  Soni, NB  Johnson, EF  Sheppard, GS  Donawho, C  Buchanan, FG  Davidsen, SK  Bell, RL  Wang, J 
Citation: Pappano WN, etal., BMC Cancer. 2009 Sep 4;9:314.
RGD ID: 2317642
Pubmed: PMID:19732452   (View Abstract at PubMed)
PMCID: PMC2749869   (View Article at PubMed Central)
DOI: DOI:10.1186/1471-2407-9-314   (Journal Full-text)

BACKGROUND: The insulin-like growth factor (IGF) axis is an important signaling pathway in the growth and survival of many cell and tissue types. This pathway has also been implicated in many aspects of cancer progression from tumorigenesis to metastasis. The multiple roles of IGF signaling in cancer suggest that inhibition of the pathway might yield clinically effective therapeutics. METHODS: We describe A-928605, a novel pyrazolo [3,4-d]pyrimidine small molecule inhibitor of the receptor tyrosine kinases (IGF1R and IR) responsible for IGF signal transduction. This compound was first tested for its activity and selectivity via conventional in vitro kinome profiling and cellular IGF1R autophosphorylation. Additionally, cellular selectivity and efficacy of A-928605 were analyzed in an IGF1R oncogene-addicted cell line by proliferation, signaling and microarray studies. Finally, in vivo efficacy of A-928605 was assessed in the oncogene-addicted cell line and in a neuroblastoma model as a single agent as well as in combination with clinically approved therapeutics targeting EGFR in models of pancreatic and non-small cell lung cancers. RESULTS: A-928605 is a selective IGF1R inhibitor that is able to abrogate activation of the pathway both in vitro and in vivo. This novel compound dosed as a single agent is able to produce significant growth inhibition of neuroblastoma xenografts in vivo. A-928605 is also able to provide additive effects when used in combination with clinically approved agents directed against EGFR in non-small cell lung and human pancreatic tumor models. CONCLUSION: These results suggest that a selective IGF1R inhibitor such as A-928605 may provide a useful clinical therapeutic for IGF pathway affected tumors and warrants further investigation.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
pancreatic cancer  IMP 2317642 RGD 
pancreatic cancer  ISOIGF1R (Homo sapiens)2317642; 2317642 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Igf1r  (insulin-like growth factor 1 receptor)

Genes (Mus musculus)
Igf1r  (insulin-like growth factor I receptor)

Genes (Homo sapiens)
IGF1R  (insulin like growth factor 1 receptor)


Additional Information