kinases such as IGF-1R.60 In-vivo data from breast and prostate cancer cell lines indicate that acquired resistance to ge.tinib is associated with in-creased signaling via the IGF-1R pathway,61 suggesting that sup-pression of IGF-1R signaling may prevent or delay sumatriptan development of resistance to ge.tinib. In addition, in NSCLC cell lines, IGF-1R activation interferes with the antitumor activity of erlotinib by causing an increase in the levels of cell membrane-localized EGFR/IGF-1R heterodimers, resulting in enhanced synthesis of anti-apoptotic survivin proteins. In this system, inhibition of IGF-1R activation abolished resistance to erlotinib and induced apopto-sis.62 Treatment of NSCLC cell lines with ge.tinib induced EGFR/ IGF-1R heterodimerization and activation of IGF-1R and its down-stream signaling mediators, resulting in increased expression of survivin.

In NSCLC tumor samples, high co-expression of IGFR-I and EGFR was associated with Biochanin A shorter disease-free survival.64 Ta-ken together, these and other data present the rationale to inte-grate IGF-1R-targeted agents with EGFR-TKIs for the treatment of patients with NSCLC. Clinical experience with IGF-1R inhibitors in development Compounds in development to inhibit IGF-1R signaling com-prise highly speci.c mAbs and small-molecule agents. Most of the mAbs bind to the receptor’s extracellular domain to block li-gand binding and prevent activation. Subtypes of mAbs have different af.nities and may be aweeks for up to 6 cycles. Patients treated with chemo-therapy plus .gitumumab who responded or had stable disease were eligible to continue .gitumumab as a single agent, and pa-tients receiving chemotherapy alone who had disease progres-sion could also receive .gitumumab either as a single agent or in combination with chemotherapy within a continuation study.69 After completion of the randomized portion of the study, further patients with non-adenocarcinoma NSCLC were enrolled into a single-arm supplier VX-950 extension cohort In the randomized portion of the study, objective responses were observed in 54% of patients receiving chemotherapy plus .gitumumab, compared with 42% of patients receiving chemo-therapy alone. Promising activity was seen in tumors of squa-mous cell histology. As shown in Fig, the response rate of patients with squamous cell tumors receiving chemotherapy plus .gitumumab was numerically the highest.

Among the patients with squamous cell tumors, 9/14 patients with bulky tumors underwent more reduction, and resolution of a superior vena cava syndrome was observed in a price brompheniramine patient after one dose. In addition, two patients achieved PRs while receiving single-agent .gitumumab. Patients with one or two prior chemother-apy regimens received dalotuzumab as either intravenous weekly doses in combination with erlotinib 150 mg/ Taken together these data suggest that IGF-1R when combined with associated signaling molecules such as IGF-1 2 and IRS-1 -2 may be a relatively strong negative predictive factor, but that IGF-1R alone is a weak positive predictive factor. Thus, it seems likely that further biomarker-directed studies will be of value. and despite re-cent stock prices progress in the treatment of NSCLC with molecularly-targeted agents – such as bevacizumab in combination with platinum-based chemotherapy.