Istiratumab

This study tested the solubilization of phosphorus by five actinobacterial strains in liquid media containing Ca3PO4; AlPO4 or FePO4 as the sole phosphate source, and discusses the possible mechanisms involved in this process. P solubilization by different strains was accompanied by a significant drop in pH from 7.0 to 2.15–5.0 after 14 days. The efficiency of different strains depended on the P‐source. Streptomyces spp. MM140 and MM141 were the most efficient in solubilizing Ca3PO4, MM136, and MM141 were the most efficient in solubilizing AlPO4, while all strains were equally efficient in solubilizing FePO4. Gluconic, oxalic, citric, malic, succinic, formic, and acetic acid were detected in the medium with Ca3PO4, while all except acetic acid were detected in the media with FePO4 or AlPO4. Although we did not use an organic source of phosphorus in the media, all strains produced acid and alkaline phosphatase. It is concluded from this study that actinobacteria produced multiple organic acids followed by a decrease in the pH to solubilize phosphate salts. As well as producing phosphatase, these microorganisms were found to have different ways of making P available, suggesting an ecological advantage as they form part of soil microbiomes important for plants.

Purpose: Insulin-like growth factor receptor 1 (IGF-1R) is critically involved in pancreatic cancer pathophysiology, promoting cancer cell survival and therapeutic resistance. Assessment of IGF-1R inhibitors in combination with standard-of-care chemotherapy, however, failed to demonstrate significant clinical benefit. The aim of this work is to unravel mechanisms of resistance to IGF-1R inhibition in pancreatic cancer and develop novel strategies to improve the activity of standard-of-care therapies.Experimental Design: Growth factor screening in pancreatic cancer cell lines was performed to identify activators of prosurvival PI3K/AKT signaling. The prevalence of activating growth factors and their receptors was assessed in pancreatic cancer patient samples. Effects of a bispecific IGF-1R and ErbB3 targeting antibody on receptor expression, signaling, cancer cell viability and apoptosis, spheroid growth, and in vivo chemotherapy activity in pancreatic cancer xenograft models were determined.Results: Growth factor screening in pancreatic cancer cells revealed insulin-like growth factor 1 (IGF-1) and heregulin (HRG) as the most potent AKT activators. Both growth factors reduced pancreatic cancer cell sensitivity to gemcitabine or paclitaxel in spheroid growth assays. Istiratumab (MM-141), a novel bispecific antibody that blocks IGF-1R and ErbB3, restored the activity of paclitaxel and gemcitabine in the presence of IGF-1 and HRG in vitro. Dual IGF-1R/ErbB3 blocking enhanced chemosensitivity through inhibition of AKT phosphorylation and promotion of IGF-1R and ErbB3 degradation. Addition of istiratumab to gemcitabine and nab-paclitaxel improved chemotherapy activity in vivo.Conclusions: Our findings suggest a critical role for the HRG/ErbB3 axis and support the clinical exploration of dual IGF-1R/ErbB3 blocking in pancreatic cancer. Clin Cancer Res; 24(12); 2873–85. ©2018 AACR.