Akt/mTOR Pathway Induces Resistance to Cixutumumab
Shin et al. Page 2437
Insulin-like growth factor receptor (IGF-1R)-targeted monoclonal antibodies (mAb) have shown limited anticancer therapeutic efficacy. In this study, Shin and colleagues investigated the mechanisms of resistance to a fully humanized anti-IGF-1R mAb cixutumumab in head and neck squamous cell carcinoma (HNSCC). They found that resistance to IGF-1R inhibition by cixutumumab was associated with Akt/mammalian target of rapamycin (mTOR)-mediated de novo protein synthesis of EGFR, Akt1, and survivin and activation of the EGFR pathway, and cotargeting IGF-1R/mTOR had synergistic antitumor effects in vitro and in vivo. These results show potential clinical use of cotargeting IGF-1R and Akt/mTOR in patients with HNSCC.
Promise of Dual Energy Metabolic Pathway Targeted Therapy
Cheong et al. Page 2350
Cellular bioenergetics is an emerging therapeutic target in cancer. Despite the Warburg effect playing a critical role in providing bioenergetics to tumor cells, inhibition of glycolysis alone showed limited efficacy in clinical trials. Cheong and colleagues show that activation of AMPK as a consequence of decreased glycolysis increases transcription of genes in cellular respiration, thereby bypassing the effect of decreased glycolysis. Dual inhibition of both glycolysis with glycolysis inhibitor 2-deoxyglucose and oxidative phosphorylation with metformin leads to marked decrease in ATP and cell death, which is sufficient to suppress tumor growth in vivo. This combination could be readily and rapidly translated to the clinic.
AZD1480 Inhibits Growth and Prolongs Survival in Glioblastoma
McFarland et al. Page 2384
The JAK/STAT pathway has been linked to multiple cancers including glioblastoma (GBM). McFarland and colleagues tested the therapeutic potential of AZD1480, a newly developed JAK1/2 inhibitor in GBM. Patient-derived human GBM xenografts serially maintained in the flanks of nude mice were profiled and chosen for the study based on high JAK/STAT-3 activation. AZD1480 treatment inhibited the growth of the xenograft flank tumors and prolonged survival in an orthotopic model, which was attributed to decreased STAT-3 signaling. AZD1480 may potentially be an effective antitumor agent when combined with current therapies available for GBM.
Dual Targeting of PI3K and mTOR in Cancer
Wallin et al. Page 2426
The phosphoinositide-3 kinase (PI3K)/Akt signaling pathway is fundamental to numerous cellular processes. Abnormal activation of the pathway has been implicated in many cancers and therefore represents an attractive target for therapeutic intervention. GDC-0980 is a potent and selective inhibitor of Class I PI3K and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. Wallin and colleagues report that GDC-0980 potently inhibits xenograft growth of various malignancies and the effects on tumor growth correlate with changes in pharmacodynamic biomarkers. Thus, GDC-0980 is a promising therapeutic candidate for clinical cancer development.
- ©2011 American Association for Cancer Research.
Volume 10, Issue 12
