5-LOX, 5-Lipoxygenase; CDK, cyclin-dependent kinase; DFMO, difluoromethylornithine; EGFR, epidermal growth factor receptor; ER, estrogen receptor; FGFR, fibroblast growth factor receptor; HIF-1α, hypoxia-inducible factor-1 alpha; IGF-1R, insulin-like growth factor-1 receptor; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; MMP, matrix metalloproteinases; mTOR, mammalian target of rapamycin; PDGFR, platelet-derived growth factor receptor; PPAR-γ, peroxisome proliferator-activated receptor gamma; SAHA, suberoylanilide hydroxamic acid; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.
∗ Target and agent involved in U.S. Food and Drug Administration–approved cancer risk reduction or IEN treatment.
∗∗ Target and agent involved in established cancer-risk reduction/chemoprevention.
† Therapy targets and agents with potential for chemoprevention.
Targeting the insulin-like growth factor (IGF) axis continues to be an important area of research for both prevention and therapy, as illustrated by recent data in the aerodigestive tract. Elevated levels of IGF-1 and reduced levels of IGF binding protein 3 (IGFBP-3) are associated with increased risk and poor prognosis in lung and other cancers 60
; IGF-1 is a mitogen for a number of neoplastic cells types. The IGF-1 receptor (IGF-1R) is activated during lung carcinogenesis in vitro and in vivo in animals. Targeting IGFR and its downstream pathways (e.g., by the use of IGFBP-3) inhibits survival of premalignant and malignant bronchial epithelial cells and vascular endothelial cells, decreases tumor growth and angiogenesis, and for this reason may be effective for cancer chemoprevention. 61
However, several recent Phase III chemotherapy trials using IGF-1R-targeting antibodies to target late-stage solid tumors have failed to demonstrate signs of clinical efficacy, 62
suggesting that the need to identify potential biomarkers that could help parse out patients who would benefit most is critical. Despite the poor therapeutic outcome with the anti-IGF1R trials, encouraging results from studies targeting the IGF axis in a combinatorial fashion (e.g., STAT3 or IL-6) may be an alternative strategy for chemoprevention. 63
Targeting the PI3K/Akt/mTOR signaling pathway is another promising approach, especially in the lung. Tobacco carcinogens induce Akt activation and lung carcinogenesis. The Akt pathway is activated in bronchial premalignancy (both proximal airway and alveolar epithelium) in smokers and patients with lung IEN or cancer. Preclinical in vivo studies show that deguelin and myo-inositol have preventive activity in lung tumorigenesis, in part via suppressing the PI3K/Akt pathway, disrupting Hsp90 function, and inhibiting HIF-1α expression. 64–66
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