Cellular phosphorylation data (data not shown). This activity is potentially related to increases in resting

Cellular phosphorylation data (data not shown). This activity is potentially related to increases in resting glucose AZD4547 biological activity levels in animal models and patients that is seen after dosing of an IGF1R therapeutic [35]. Despite these complications, the promising efficacy thus far of these treatments in the clinic and the importance of the IGF pathway to human cancer biology warrant additional therapies to go forward into cancer patients where aberrant IGF signaling may be implicated. In this study we have shown the in vitro and in vivo antiproliferative effects of a novel pyrazolo [3,4-d]pyrimidine IGF1R small molecule inhibitor. We have characterized A928605 in an in vitro kinase panel and an oncogenedependent model cell line that enables rapid analysis ofFigure xenograft vitro and modifications the CD8-IGF1R proteins5inabrogatesis in vivo A-928605 flank model efficacious inof IGF pathway PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26266977 signaling 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). 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 A928605 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