Notch receptors are key regulators of development by controlling cell-fate determination in many multicellular organisms.

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Notch3 is a member of an evolutionarily conserved family of cell surface receptors important in cell-fate determination in both vertebrates and invertebrates. Significant data support the role of Notch pathway in cancer development, although the conflicting role of Notch signaling pathways in tumorigenesis suggests that its action is highly context-dependent. Furthermore, although Notch receptors signal primarily through the regulation of hairy enhancer of split (HES) and HES-related (HRT) genes, they are known to crosstalk with other signaling pathways, including the epidermal growth factor (EGF) and the mitogen-activated protein kinase pathways. Whereas much is known about the role of Notch1 in human cancer, the role of Notch3 in epithelial tumors, such as lung carcinomas, has not been well established. In this study, we show that Notch3 is expressed in 80 of 207 (39%) resected human lung tumors and that its expression is positively correlated with EGF receptor expression. Inhibition of the Notch3 pathway using a dominant-negative receptor dramatically reduces growth in soft agar and increases growth factor dependence. We also find that Notch inhibition increases sensitivity to EGF receptor tyrosine kinase inhibition and decrease in phosphorylation of the mitogen-activated protein kinase. These observations support a role for Notch3 signaling in lung cancer, and one potential mechanism of maintaining the neoplastic phenotype is through the modulation of the EGF pathway. (Cancer Res 2005; 65(9): 3555-61)

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Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in prostaglandin (PG) synthesis and is overexpressed in 70% to 90% of non^small cell lung cancers (NSCLC). Preclinical studies suggest inhibition of COX-2 can enhance the cytotoxic effect of docetaxel. To test this concept clinically, we administered celecoxib (400 mg p.o. twice daily) plus docetaxel (75 mg/m 2 every 3 weeks) to a cohort of patients with recurrent, previously treated NSCLC. Patients first received single agent celecoxib for 5 to 10 days to ascertain the effectiveness of COX-2 inhibition, which was determined by measuring pre-and post-celecoxib levels of urinary 11a-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of prostaglandin E 2 (PGE 2 ). We enrolled 56 patients (35 men, 21women; median age, 61years). All patients had received at least one prior chemotherapy regimen. The overall response rate was 11% and median survival was 6 months, similar to that observed with docetaxel alone. Pre-celecoxib urinary PGE-M decreased from a mean level of 27.2 to 12.2 ng/mg Cr after 5 to 10 days of celecoxib (P = 0.001).When grouped by quartile, patients with the greatest proportional decline in urinary PGE-M levels experienced a longer survival compared to those with no change or an increase in PGE-M (14.8 versus 6.3 versus 5.0 months). Our data suggest that combining celecoxib with docetaxel using the doses and schedule employed does not improve survival in unselected patients with recurrent, previously treated NSCLC. However, in light of the apparent survival prolongation in the subset with a marked decline in urinary PGE-M levels, further investigation of strategies designed to decrease PGE 2 synthesis in NSCLC seems warranted.Cyclooxygenase-2 (COX-2), a cyclic endoperoxidase that catalyzes the rate-limiting step in prostaglandin (PG) synthesis, is frequently overexpressed in human premalignant pulmonary lesions such as atypical adenomatous hyperplasia and carcinoma in situ, as well as in invasive carcinomas (1 -4). Preclinical and clinical data indicate that tumors with up-regulation of COX-2 synthesize high levels of prostaglandin E 2 (PGE 2 ; refs. 5 -11). In turn, high PGE 2 levels are associated with increased production of proangiogenic factors, altered immune responses, and enhanced metastatic potential (12 -16). These findings suggest that increased COX-2 expression may play a significant role in the development and growth of malignancies, such as nonsmall cell lung cancers (NSCLC), and possibly in the acquisition of an invasive and metastatic phenotype (17, 18). Thus, selective inhibition of COX-2 could prove useful both in understanding the role of eicosanoids in lung cancer pathogenesis as well as in the management of established malignancies (19,20).Docetaxel is modestly beneficial in the treatment of recurrent NSCLC (21). Notably, recent preclinical data indicate that the cytotoxic effect of docetaxel is enhanced in the presence of a selective COX-2 inhibitor (22). Based on these find...