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

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 - BMC Cancer (2009)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. bill.pappano@abbott.com

ABSTRACT

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.

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Efficacy of A-928605 in the SK-N-FI neuroblastoma xenograft as a renal subcapsule model. A, A-928605 inhibits proliferation of SK-N-FI cells in vitro. B-D, Beginning on day 14 post tumor cell injection, mice were dosed intraperitoneally with A-928605 at 37.5 mg/kg, b.i.d. for 14 days. B, Representative photograph taken of the tumor bearing and contralateral kidneys prior to the initiation of dosing on day 14 post tumor cell injection, indicating a tumor weight of 0.07 g. C, Representative photograph taken of the tumor bearing and contralateral kidneys at the end of the dosing schedule (day 28). D, At the end of the dosing schedule, the %T/C (A-928605 vs. vehicle) was 58 (P < 0.001).
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Figure 5: Efficacy of A-928605 in the SK-N-FI neuroblastoma xenograft as a renal subcapsule model. A, A-928605 inhibits proliferation of SK-N-FI cells in vitro. B-D, Beginning on day 14 post tumor cell injection, mice were dosed intraperitoneally with A-928605 at 37.5 mg/kg, b.i.d. for 14 days. B, Representative photograph taken of the tumor bearing and contralateral kidneys prior to the initiation of dosing on day 14 post tumor cell injection, indicating a tumor weight of 0.07 g. C, Representative photograph taken of the tumor bearing and contralateral kidneys at the end of the dosing schedule (day 28). D, At the end of the dosing schedule, the %T/C (A-928605 vs. vehicle) was 58 (P < 0.001).

Mentions: The constitutively activated IGF signaling in the CD8-IGF1R line results in phosphorylation of various signaling proteins, including AKT and ERK1/2, that lead to changes in proliferation via cell cycle control by up-regulation and stabilization of proteins like Cyclin D1 (Figure 5A). As expected, treatment of CD8-IGF1R cells with A-928605 leads to inhibition of the phosphorylation of the IGF1R cytotail and downstream effectors AKT and ERK1/2 shortly after treatment (Figure 5A). The microarray analyses shown in Figure 4 were performed on samples after 24 hours of A-928695 treatment to assess the transcriptional changes that occur as a direct result of this pathway inhibition seen in Figure 5A. The results of this analysis point towards gene changes that lead to the significant inhibition of proliferation in the CD8-IGF1R cells versus the vector control cells. One example is the 4.8-fold decrease in Ccn d1 transcripts that occurs after 24 hours of A-928605 treatment that is also visible at the translational level (Figure 5B). The data collected at both the transcriptional and translational levels in CD8-IGF1R transformed cells treated with A-928605 provide evidence that this small molecule is effective at inhibiting both the immediate modifications to the IGF signaling pathway as well as its functional read-out in a highly specific manner.


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

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 - BMC Cancer (2009)

Efficacy of A-928605 in the SK-N-FI neuroblastoma xenograft as a renal subcapsule model. A, A-928605 inhibits proliferation of SK-N-FI cells in vitro. B-D, Beginning on day 14 post tumor cell injection, mice were dosed intraperitoneally with A-928605 at 37.5 mg/kg, b.i.d. for 14 days. B, Representative photograph taken of the tumor bearing and contralateral kidneys prior to the initiation of dosing on day 14 post tumor cell injection, indicating a tumor weight of 0.07 g. C, Representative photograph taken of the tumor bearing and contralateral kidneys at the end of the dosing schedule (day 28). D, At the end of the dosing schedule, the %T/C (A-928605 vs. vehicle) was 58 (P < 0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2749869&req=5

Figure 5: Efficacy of A-928605 in the SK-N-FI neuroblastoma xenograft as a renal subcapsule model. A, A-928605 inhibits proliferation of SK-N-FI cells in vitro. B-D, Beginning on day 14 post tumor cell injection, mice were dosed intraperitoneally with A-928605 at 37.5 mg/kg, b.i.d. for 14 days. B, Representative photograph taken of the tumor bearing and contralateral kidneys prior to the initiation of dosing on day 14 post tumor cell injection, indicating a tumor weight of 0.07 g. C, Representative photograph taken of the tumor bearing and contralateral kidneys at the end of the dosing schedule (day 28). D, At the end of the dosing schedule, the %T/C (A-928605 vs. vehicle) was 58 (P < 0.001).
Mentions: The constitutively activated IGF signaling in the CD8-IGF1R line results in phosphorylation of various signaling proteins, including AKT and ERK1/2, that lead to changes in proliferation via cell cycle control by up-regulation and stabilization of proteins like Cyclin D1 (Figure 5A). As expected, treatment of CD8-IGF1R cells with A-928605 leads to inhibition of the phosphorylation of the IGF1R cytotail and downstream effectors AKT and ERK1/2 shortly after treatment (Figure 5A). The microarray analyses shown in Figure 4 were performed on samples after 24 hours of A-928695 treatment to assess the transcriptional changes that occur as a direct result of this pathway inhibition seen in Figure 5A. The results of this analysis point towards gene changes that lead to the significant inhibition of proliferation in the CD8-IGF1R cells versus the vector control cells. One example is the 4.8-fold decrease in Ccn d1 transcripts that occurs after 24 hours of A-928605 treatment that is also visible at the translational level (Figure 5B). The data collected at both the transcriptional and translational levels in CD8-IGF1R transformed cells treated with A-928605 provide evidence that this small molecule is effective at inhibiting both the immediate modifications to the IGF signaling pathway as well as its functional read-out in a highly specific manner.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. bill.pappano@abbott.com

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus