Changes in PI3K Pathway Mutations and PTEN Levels
Gonzalez-Angulo et al., Page 1093
As new targeted therapies enter clinical trials in the metastatic setting, using primary tumor signatures for patient selection may have profound outcome implications if biomarkers are discordant between the primary and metastatic site. A discordance between the level of potential biomarkers in primary tumor and metastasis could occur due to alterations in gene expression, different microenvironmental stimuli, stochastic events during metastasis, clonal selection during metastasis, or clonal evolution either at the primary site or in the metastasis. PIK3CA mutation and loss of PTEN expression are being pursued as potential predictors of response to novel PI3K pathway inhibitors. A high level of discordance in PTEN level, PIK3CA mutations, and receptor status between primary tumors and metastases may influence patient selection and response to PI3K-targeted therapies.
IGFBP-2 and IGFBP-3 in Trastuzumab Resistance
Dokmanovic et al., Page 917
The activation of insulin-like growth factor-I receptor (IGF-IR) contributes to trastuzumab resistance. To understand the roles of insulin-like growth factor binding proteins (IGFBP) in trastuzumab resistance, Dokmanovic and colleagues characterize IGFBP-2 and IGFBP-3 in trastuzumab-sensitive and trastuzumab-resistant breast cancer cells. The authors show that the high levels of secreted IGFBP-3 are associated with trastuzumabsensitive breast cancer cells, whereas the secretion of IGFBP-2 is upregulated in trastuzumab-resistant breast cancer cells. Changes in secretion profiles of IGFBP-2 and IGFBP-3 warrant further clinical investigations as potential biomarkers for trastuzumab resistance.
Targeted Nanogels for Drug Delivery
Murphy et al., Page 972
Targeted nanoparticles represent an approach to minimize dose-limiting toxicities associated with chemotherapeutics. A study by Murphy and colleagues describes the design and characterization of a versatile nanoparticle platform, described as nanogels, that combines a lipid bilayer with a cross-linked gel core. The nanogels load a wide array of chemotypes and imaging agents for use as both drug delivery systems and diagnostic tools. The nanogels improve efficacy beyond Abraxane, a clinically approved nanoparticle formulation, in murine orthotopic pancreas and breast cancer models, thereby demonstrating the benefits of targeted nanotherapies in treating malignant disease.
Apoptosis of Osteosarcoma Cells by SCH 727965
Fu et al., Page 1018
Osteosarcoma is an aggressive, often metastatic bone cancer. Toward the goal of developing new treatments for osteosarcoma, Fu and colleagues show apoptosis of osteosarcoma cells by SCH 727965 (SCH), a new cyclindependent kinase inhibitor. Osteosarcoma cell lines resistant to doxorubicin and dasatinib, osteosarcoma cell lines prepared by the authors from patients who had received adjuvant chemotherapy, and osteosarcoma explants derived from a human xenograft in mice were responsive to SCH 727965. Apoptosis occurred at SCH concentrations of 10–20 nM and was p53-independent. SCH did not induce the apoptosis of normal osteoblasts or fibroblasts. Thus, SCH is a promising anticancer agent for osteosarcoma.