Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of the Efficacy and Safety of Apricoxib in Combination With Either Docetaxel or Pemetrexed in Patients With Biomarker-Selected Non–Small-Cell Lung Cancer

Edelman, Martin J.; Tan, Ming; Fidler, Mary J.; Sanborn, Rachel E.; Otterson, G. A.; Sequist, Lecia V.; Evans, Tracey L.; Schneider, Bryan J.; Keresztes, Roger; Rogers, John; Mayolo, Jorge Antunez de; Feliciano, Josephine; Yang, Yang; Medeiros, Michelle; Zaknoen, Sara

doi:10.1200/jco.2014.55.5789

Cited by 28 publications

(36 citation statements)

References 12 publications

(8 reference statements)

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“…A criticism regarding the study is that a 50% decline in urinary PGEM levels was a low threshold with which to identify patients with tumors that could benefit from COX‐2 inhibitors. Similar results were observed by Edelman et al when apricoxib was combined with chemotherapy in patients with recurrent NSCLC who experienced a decline in urinary PGEM levels after a run‐in period . Edelman et al recently reported the results of a randomized phase 3 study evaluating the addition of celecoxib to frontline platinum‐based chemotherapy in patients with tumors that had elevated COX‐2 expression .…”

supporting

confidence: 71%

“…Similar results were observed by Edelman et al when apricoxib was combined with chemotherapy in patients with recurrent NSCLC who experienced a decline in urinary PGEM levels after a run-in period. 28 Edelman et al recently reported the results of a randomized phase 3 study evaluating the addition of celecoxib to frontline platinum-based chemotherapy in patients with tumors that had elevated COX-2 expression. 29 This study was based on a randomized phase 2 study conducted by the same investigators that demonstrated an improvement in survival with the addition of celecoxib in patients with tumors that had elevated COX-2 expression.…”

mentioning

confidence: 99%

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Cyclooxygenase 2 inhibition in patients with non–small cell lung cancer: Is this still a valid target for therapy?

Gadgeel

2015

Cancer

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The link between chronic inflammation and cancer is well recognized and was first proposed by Virchow in 1863. 1 He observed leukocytes at tumor sites and suggested that this "lymphoreticular" infiltrate at sites of chronic inflammation was connected to the development of cancers. The link between inflammatory bowel disease and colon cancer and chronic hepatitis and hepatocellular carcinoma as well as chronic gastritis induced by Helicobacter pylori infection and gastric cancer are well recognized observations that support this proposal. 1 It has also been proposed that lung cancer in smokers is linked to the chronic inflammation induced by reactive oxygen species in the cigarette smoke. 2 Chronic inflammatory states are characterized by repeated tissue injury followed by attempts at tissue repair. This cycle of repeated injury and repair can promote features of carcinogenesis such as DNA damage, cellular proliferation, and cell survival.The role of inflammation in the development of cancer was further supported by epidemiologic studies that suggested a reduced incidence of several cancers in individuals taking aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs) regularly. 3 NSAIDs exert their antiinflammatory effects primarily by inhibiting the cyclooxygenase enzyme (COX). COX exists in 2 isoforms: COX-1 and COX-2. 4 COX-1 has constitutive activity in nearly all cells and is involved in several homeostatic functions such as maintaining gastric mucosal integrity and resisting the activity of gastric acid, normal renal tubular function, and platelet function. COX-2 is the inducible form of the enzyme, and is not expressed in the majority of normal tissues but is upregulated in inflammatory tissues and many cancers in response to cytokines, growth factors, and hormones. COX-2-derived prostaglandin E2 (PGE2) is the primary mediator of inflammation and appears to have tumor-promoting properties, including tumor invasion, resistance to apoptosis, angiogenesis, and suppression of host immunity. [5][6][7] Preclinical studies have suggested that inhibition of COX-2 can result in a reduction in tumor growth in several cancers, including non-small cell lung cancer (NSCLC). [8][9][10] With the introduction of selective COX-2 inhibitors, there was an expectation that the inducible isoform of the COX enzyme can be targeted for both antiinflammatory and potentially anticancer properties while sparing the protective effects of the COX-1 isoform. COX-2 inhibitors were therefore evaluated for both cancer prevention and anticancer therapy. Celecoxib, a COX-2 inhibitor, was evaluated in patients with familial adenomatous polyposis, a genetic condition resulting from mutations in the adenomatous polyposis coli (APC) gene that leads to multiple adenomatous polyps with a nearly 100% risk of colon cancer. Preclinical studies have suggested that despite the presence of a mutation in the APC gene, blocking the activity of COX-2 and the production of PGE2 can prevent development of the adenomatous polyps. These preclinical resu...

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supporting

confidence: 71%

mentioning

confidence: 99%

Cyclooxygenase 2 inhibition in patients with non–small cell lung cancer: Is this still a valid target for therapy?

Gadgeel

2015

Cancer

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“…Another phase II study in previously untreated COX-2-positive advanced NSCLC patients showed therapeutic benefit to COX-2 inhibition in combination with platinum-based chemotherapy (Wang et al, 2008). A larger study however employing various biomarkers of COX activity and target engagement have reported no meaningful clinical benefit, highlighting the need for more specific strategies for targeting prostaglandin accumulation (Edelman et al, 2015). For example, the development of agents that lower the cellular levels of 15-d-PGJ2 or specifically inhibit 15-d-PGJ2 may constitute a useful approach for the chemosensitization of KRAS tumors.…”

Section: Discussionmentioning

confidence: 99%

Mutant KRAS Enhances Tumor Cell Fitness by Upregulating Stress Granules

Grabocka

Bar–Sagi

2016

Cell

149

160

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There is growing evidence that stress-coping mechanisms represent tumor cell vulnerabilities that may function as therapeutically beneficial targets. Recent work has delineated an integrated stress adaptation mechanism that is characterized by the formation of cytoplasmic mRNA/protein foci termed stress granules (SGs). Here, we demonstrate that SGs are markedly elevated in mutant KRAS cells following exposure to stress-inducing stimuli. The upregulation of SGs by mutant KRAS is dependent on the production of the signaling lipid molecule 15-deoxy-delta 12,14 prostaglandin J2 (15-d-PGJ2) and confers cytoprotection against stress stimuli and chemotherapeutic agents. The secretion of 15-d-PGJ2 by mutant KRAS cells is sufficient to enhance SG formation and stress resistance in cancer cells that are wild-type for KRAS. Our findings identify a mutant KRAS-dependent cell non-autonomous mechanism that may afford the establishment of a stress-resistant niche that encompasses different tumor sub-clones. These results should inform the design of strategies to eradicate tumor cell communities.

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“…Similarly, in our study, COX-2 inhibitors showed a synergistic effect with docetaxel on NSCLC cell line. However, in a recent phase II clinical trial the combination of docetaxel and apricoxib (COX-2 inhibitor) as second-line therapy on advanced NSCLC patients, showed negative results, implying that taxanes-driven augmentation of COX-2 expression might diminish the effect of COX-2 inhibitors [61].…”

Section: Discussionmentioning

confidence: 99%

COX-2 Inhibitors, a Potential Synergistic Effect with Antineoplastic Drugs in Lung Cancer

Hohenforst-Schmidt¹,

Petanidis²,

Zogas³

et al. 2017

Oncomedicine

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Background: Lung cancer represents the leading cause of cancer-related deaths worldwide and novel therapeutic approaches targeting crucial pathways are urgently needed to improve its treatment. Inflammation plays a critical role in multistage tumor development and increased evidence has supported the involvement of cyclooxygenase-2 expression in carcinogenesis. We investigated the potential use of COX-2 inhibitors in cancer proliferation and apoptosis. Methods: Celecoxib, rofecoxib, etoricoxib, meloxicam, ibufrofen and indomethacin are the COX-2 inhibitors included in this study. Docetaxel and Cisplatin are the chemotherapeutic agents that we combined with COX-2 inhibitors. Lung cancer cell lines (NCI-H1048-Small cell lung cancer, A549-Non-small cell lung cancer) were purchased from ATCC LGC Standards. At indicated time-point, following 24h and 48h incubation, cell viability and apoptosis were measured with Annexin V staining by flow cytometry. Statistical analysis was performed by GraphPad Prism. Results: In Small cell lung cancer cells, following 24h incubation, combinations of docetaxel and meloxicam, docetaxel and ibuprofen, docetaxel and indomethacin, showed increased apoptosis when compared to docetaxel alone (p<0.0001). In Non-small cell lung cancer cells, the 24h incubation was not enough to induce satisfactory apoptosis, but following 48h incubation, docetaxel plus indomethacin showed more cytotoxicity when compared to docetaxel alone (p<0.0001). In addition, the combination of cisplatin plus indomethacin was the only combination to be found with higher cytotoxicity when compared to cisplatin alone after 48h treatment (p<0.0001). Conclusion: Depending on the drug, the synergistic effect of COX-2 inhibitors plus chemotherapeutic agents has been demonstrated in lung cancer. Our suggestion is that COX-2 inhibitors could be used as additive and maintenance treatment in combination to antineoplastic agents in lung cancer patients.

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Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of the Efficacy and Safety of Apricoxib in Combination With Either Docetaxel or Pemetrexed in Patients With Biomarker-Selected Non–Small-Cell Lung Cancer

Cited by 28 publications

References 12 publications

Cyclooxygenase 2 inhibition in patients with non–small cell lung cancer: Is this still a valid target for therapy?

Cyclooxygenase 2 inhibition in patients with non–small cell lung cancer: Is this still a valid target for therapy?

Mutant KRAS Enhances Tumor Cell Fitness by Upregulating Stress Granules

COX-2 Inhibitors, a Potential Synergistic Effect with Antineoplastic Drugs in Lung Cancer

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