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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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Related in: MedlinePlus

A, Efficacy of A-928605 and cetuximab, alone and in combination, in the MiaPaCa-2 pancreatic xenograft flank model. Beginning on day 16 post tumor cell injection, mice were dosed intraperitoneally with A-928605 at 37.5 mg/kg, b.i.d. for 20 days. Cetuximab and human IgG Control were dosed intraperitoneally at 30 mg/kg, once daily, 3×/week for a total of 6 doses. At the end of the dosing schedule, the %T/Cs (combination vs. vehicle and vs. human IgG control) were approximately 60 (P < 0.00001) and (combination vs. A-928605 + human IgG Control and vs. cetuximab) were approximately 72 (P < 0.05). B, Efficacy of A-928605 and erlotinib in combination in the HCC-827 NCSLC xenograft flank model. Beginning on day 20 post tumor cell injection, mice were dosed intraperitoneally with A-928605 at 37.5 mg/kg, b.i.d. for 16 days. Erlotinib was dosed orally at 3.1 mg/kg, b.i.d. for 16 days. At the end of the dosing schedule, the %T/Cs (combination vs. vehicle) was 17 (P < 0.00001) and (combination vs. erlotinib) was 27 (P < 0.005). In a separate arm of the study, A-928605 as a monotherapy was not consistently statistically different from its vehicle control (data not shown).
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Figure 6: A, Efficacy of A-928605 and cetuximab, alone and in combination, in the MiaPaCa-2 pancreatic xenograft flank model. Beginning on day 16 post tumor cell injection, mice were dosed intraperitoneally with A-928605 at 37.5 mg/kg, b.i.d. for 20 days. Cetuximab and human IgG Control were dosed intraperitoneally at 30 mg/kg, once daily, 3×/week for a total of 6 doses. At the end of the dosing schedule, the %T/Cs (combination vs. vehicle and vs. human IgG control) were approximately 60 (P < 0.00001) and (combination vs. A-928605 + human IgG Control and vs. cetuximab) were approximately 72 (P < 0.05). B, Efficacy of A-928605 and erlotinib in combination in the HCC-827 NCSLC xenograft flank model. Beginning on day 20 post tumor cell injection, mice were dosed intraperitoneally with A-928605 at 37.5 mg/kg, b.i.d. for 16 days. Erlotinib was dosed orally at 3.1 mg/kg, b.i.d. for 16 days. At the end of the dosing schedule, the %T/Cs (combination vs. vehicle) was 17 (P < 0.00001) and (combination vs. erlotinib) was 27 (P < 0.005). In a separate arm of the study, A-928605 as a monotherapy was not consistently statistically different from its vehicle control (data not shown).

Mentions: The ability of A-928605 to significantly inhibit growth in the SK-N-FI model as a single agent led to the analysis of this agent in other human tumor models in combination with clinically approved therapeutics targeting EGFR. The in vivo activity of A-928605 was first assessed in combination with cetuximab, a clinically approved EGFR monoclonal antibody, in the human pancreatic line MiaPaCa-2. First, treatment mice bearing MiaPaCa-2 tumors with A-928605 and cetuximab, alone and in combination, resulted in significant monotherapy activity for each compound, with %T/Cs of approximately 80 (P < 0.05) compared to appropriate controls (Figure 6A). For combination therapy with A-928605 and cetuximab, an additive effect was seen, with the %T/Cs of approximately 72 (P < 0.05) when comparing the combination to each monotherapy and %T/Cs of approximately 60 (P < 0.00001) when comparing the combination to the appropriate negative controls (Figure 6A). The in vivo activity of A-928605 was also assessed in combination with erlotinib, a clinically approved small molecule tyrosine kinase inhibitor of EGFR, in the human NSCLC line HCC827. The HCC827 cell line has greatly increased copy number of the EGFR gene (> 20) and harbors an activating mutation caused by a deletion within exon 19 of the EGFR coding sequence [32]. Treatment of size-matched HCC827 xenografts with A-928605 (data not shown) or erlotinib results in partial responses within these study groups, but the combination of these two therapies leads to a synergistic response and regression of the tumors (Figure 6B). These in vivo results suggest that A-928605 can be an effective therapeutic as a single agent in IGF-dependent tumors, and it can also be quite effective in combination therapy in tumors known to be sensitive to other targeting agents.


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)

A, Efficacy of A-928605 and cetuximab, alone and in combination, in the MiaPaCa-2 pancreatic xenograft flank model. Beginning on day 16 post tumor cell injection, mice were dosed intraperitoneally with A-928605 at 37.5 mg/kg, b.i.d. for 20 days. Cetuximab and human IgG Control were dosed intraperitoneally at 30 mg/kg, once daily, 3×/week for a total of 6 doses. At the end of the dosing schedule, the %T/Cs (combination vs. vehicle and vs. human IgG control) were approximately 60 (P < 0.00001) and (combination vs. A-928605 + human IgG Control and vs. cetuximab) were approximately 72 (P < 0.05). B, Efficacy of A-928605 and erlotinib in combination in the HCC-827 NCSLC xenograft flank model. Beginning on day 20 post tumor cell injection, mice were dosed intraperitoneally with A-928605 at 37.5 mg/kg, b.i.d. for 16 days. Erlotinib was dosed orally at 3.1 mg/kg, b.i.d. for 16 days. At the end of the dosing schedule, the %T/Cs (combination vs. vehicle) was 17 (P < 0.00001) and (combination vs. erlotinib) was 27 (P < 0.005). In a separate arm of the study, A-928605 as a monotherapy was not consistently statistically different from its vehicle control (data not shown).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: A, Efficacy of A-928605 and cetuximab, alone and in combination, in the MiaPaCa-2 pancreatic xenograft flank model. Beginning on day 16 post tumor cell injection, mice were dosed intraperitoneally with A-928605 at 37.5 mg/kg, b.i.d. for 20 days. Cetuximab and human IgG Control were dosed intraperitoneally at 30 mg/kg, once daily, 3×/week for a total of 6 doses. At the end of the dosing schedule, the %T/Cs (combination vs. vehicle and vs. human IgG control) were approximately 60 (P < 0.00001) and (combination vs. A-928605 + human IgG Control and vs. cetuximab) were approximately 72 (P < 0.05). B, Efficacy of A-928605 and erlotinib in combination in the HCC-827 NCSLC xenograft flank model. Beginning on day 20 post tumor cell injection, mice were dosed intraperitoneally with A-928605 at 37.5 mg/kg, b.i.d. for 16 days. Erlotinib was dosed orally at 3.1 mg/kg, b.i.d. for 16 days. At the end of the dosing schedule, the %T/Cs (combination vs. vehicle) was 17 (P < 0.00001) and (combination vs. erlotinib) was 27 (P < 0.005). In a separate arm of the study, A-928605 as a monotherapy was not consistently statistically different from its vehicle control (data not shown).
Mentions: The ability of A-928605 to significantly inhibit growth in the SK-N-FI model as a single agent led to the analysis of this agent in other human tumor models in combination with clinically approved therapeutics targeting EGFR. The in vivo activity of A-928605 was first assessed in combination with cetuximab, a clinically approved EGFR monoclonal antibody, in the human pancreatic line MiaPaCa-2. First, treatment mice bearing MiaPaCa-2 tumors with A-928605 and cetuximab, alone and in combination, resulted in significant monotherapy activity for each compound, with %T/Cs of approximately 80 (P < 0.05) compared to appropriate controls (Figure 6A). For combination therapy with A-928605 and cetuximab, an additive effect was seen, with the %T/Cs of approximately 72 (P < 0.05) when comparing the combination to each monotherapy and %T/Cs of approximately 60 (P < 0.00001) when comparing the combination to the appropriate negative controls (Figure 6A). The in vivo activity of A-928605 was also assessed in combination with erlotinib, a clinically approved small molecule tyrosine kinase inhibitor of EGFR, in the human NSCLC line HCC827. The HCC827 cell line has greatly increased copy number of the EGFR gene (> 20) and harbors an activating mutation caused by a deletion within exon 19 of the EGFR coding sequence [32]. Treatment of size-matched HCC827 xenografts with A-928605 (data not shown) or erlotinib results in partial responses within these study groups, but the combination of these two therapies leads to a synergistic response and regression of the tumors (Figure 6B). These in vivo results suggest that A-928605 can be an effective therapeutic as a single agent in IGF-dependent tumors, and it can also be quite effective in combination therapy in tumors known to be sensitive to other targeting agents.

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