Abstract
Pancreatic carcinoma is a leading cause of cancer deaths, and recent clinical trials of a number of oncology therapeutics have not substantially improved clinical outcomes. We have evaluated the therapeutic potential of AMG 479, a fully human monoclonal antibody against insulin-like growth factor (IGF) type I receptor (IGF-IR), in two IGF-IR-expressing pancreatic carcinoma cell lines, BxPC-3 and MiaPaCa2, which also differentially express insulin receptor (INSR). AMG 479 bound to IGF-IR (K(D) 0.33 nmol/L) and blocked IGF-I and IGF-II binding (IC(50) < 0.6 nmol/L) without cross-reacting to INSR. AMG 479 completely inhibited ligand-induced (IGF-I, IGF-II, and insulin) activation of IGF-IR homodimers and IGF-IR/INSR hybrids (but not INSR homodimers) leading to reduced cellular viability in serum-deprived cultures. AMG 479 inhibited >80% of basal IGF-IR activity in BxPC-3 and MiaPaCa2 xenografts and prevented IGF-IR and IGF-IR/INSR hybrid activation following challenge with supraphysiologic concentrations of IGF-I. As a single agent, AMG 479 inhibited (∼ 80%) the growth of pancreatic carcinoma xenografts, and long-term treatment was associated with reduced IGF-IR signaling activity and expression. Efficacy seemed to be the result of two distinct biological effects: proapoptotic in BxPC-3 and antimitogenic in MiaPaCa2. The combination of AMG 479 with gemcitabine resulted in additive inhibitory activity both in vitro and in vivo. These results indicate that AMG 479 is a clinical candidate, both as a single agent and in combination with gemcitabine, for the treatment of patients with pancreatic carcinoma
Highlights
Pancreatic carcinoma is one of the most deadly forms of cancer
AMG 479 bound to insulin-like growth factor (IGF)-IR(ECD)-mFc with an apparent KD of 0.33 ± 0.14 nmol/L without cross-reacting with the insulin receptor (INSR) (Fig. 1A and B)
We used purified IGF-IR extracellular domains to show that AMG 479 inhibits the high-affinity binding of IGF-I and IGF-II to IGF-IR
Summary
Pancreatic carcinoma is one of the most deadly forms of cancer. Less than 4% of the 200,000 patients annually diagnosed with pancreatic carcinoma live more than 5 years, due largely to extensive, unresectable, metastatic disease present at the time of diagnosis [1]. Gemcitabine, which was approved in 1996 based on a 1-month increase in median survival time, is the standard of care for patients with this disease [2]. Recent clinical trials of a number of approved oncology therapeutics combined with gemcitabine have not shown improved clinical benefit against pancreatic carcinoma, underscoring the need for new therapeutic targets to treat patients with this disease [3]. One potential therapeutic target in pancreatic carcinoma is the insulin-like growth factor (IGF) type I receptor (IGFIR), which regulates cell survival and cell cycle progression via the PI3K/Akt and extracellular signal–regulated kinase pathways through insulin receptor substrate (IRS) and Src homology and collagen adapter proteins [4]. Tumor expression of IGF-I has been observed [7], and high levels of IGF-I in plasma have been correlated with an increased cancer risk. The majority of circulating IGF-I and IGF-II is produced by hepatocytes, and the local abundance of these growth factors may explain why the liver is a preferred site for pancreatic cancer metastasis [9, 10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
