Data from Chemoprevention of Head and Neck Cancer with Celecoxib and Erlotinib: Results of a Phase Ib and Pharmacokinetic Study
Nabil F. SabaSelwyn J. HurwitzScott A. KonoChung S. YangYang ZhaoZhengjia ChenGabe SicaSusan J. MullerRachel Moreno-WilliamsMelinda LewisWilliam GristAmy Y. ChenCharles E. MooreTaofeek K. OwonikokoSuresh S. RamalingamJonathan J. BeitlerSreenivas NannapaneniHyung Ju C. ShinJennifer R. GrandisFadlo R. KhuriZhuo Georgia ChenDong M. Shin
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<div>Abstract<p>Epidermal growth factor receptor (EGFR) and COX-2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions. Thirty-six subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma <i>in situ</i> were screened for study participation; 12 consented and received therapy for a median of 5.38 months. Erlotinib was escalated following a standard 3+3 design at 50, 75, and 100 mg orally daily and celecoxib was fixed at 400 mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6, and 12 months. Erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400 mg BID was 50 mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response, 43%; partial response, 14%; stable disease, 29%; and disease progression, 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (approximately 308 L) and CL/F (8.3 L/h) compared with previous studies may be related to relatively large average bodyweights. Average erlotinib t<sub>1/2</sub> was 25.6 hours. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated. <i>Cancer Prev Res; 7(3); 283–91. ©2013 AACR</i>.</p></div>Keywords:
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2147 Erlotinib (Tarceva) inhibits the epidermal growth factor receptor (EGFR) tyrosine kinase by competing with ATP to inhibit phosphorylation of the kinase. Erlotinib was recently approved for use in combination with gemcitabine for advanced pancreatic cancer. However, in vitro evidence to support the use of erlotinib with gemcitabine as anticancer therapy is lacking. To address this gap, we created 2 erlotinib-resistant pools of A-431 cells, an EGFR-overexpressing, erlotinib-sensitive epidermoid cancer cell line, and assessed them for dose-response and cell cycling in response to erlotinib and gemcitabine. The resistant pools were developed by continuously exposing A-431 cells to erlotinib (pool 1, 3 μM for 1 mo, 5 μM for 1 mo, and 10 μM for 4 mo; pool 2, 3 μM for 1 mo and 5 μM for 5 mo). Basal expression of EGFR was no different among the 3 cell types, and erlotinib blocked EGF signaling in both resistant pools (as evidenced by EGFR phosphorylation after EGF stimulation). Intracellular concentrations of erlotinib (measured by LC/MS/MS) after a 24-h exposure were 0.98 ± 0.04 ng/ml for parental cells, 3.03 ± 0.97 ng/ml for pool 1, and 1.88 ± 0.47 ng/ml for pool 2, confirming that erlotinib penetrated the cell membrane in both pools. Next, parental cells (IC50 1.67 μM) and erlotinib-resistant cells (IC50 17.6 or 13.2 μM) were treated with 2-fold serial dilutions of erlotinib (0.125-16 μM), gemcitabine (0.000436-0.056 μM), or both. Combination indices (CI) for the 2 drugs were derived by using Calcusyn (Biosoft, Cambridge, UK). Drug synergy is indicated by a CI 1.0. In the parental cells, synergy between erlotinib and gemcitabine was noted (CI = 0.68 at IC50); strong synergy was also maintained in the erlotinib-resistant pools (CI = 0.69 for pool 1 and 0.56 for pool 2 at their respective IC50s) despite their being resistant to erlotinib. This synergism was confirmed by trypan blue exclusion. Flow cytometric cell-cycle analysis showed substantial increases in proportions of subdiploid (apoptotic) cells. These results suggest that synergistic effects between erlotinib and gemcitabine in cancer cells may not require sensitivity to erlotinib as a single agent at the concentration used as long as EGFR phosphorylation is blocked by erlotinib. Further studies are warranted to explore the use of erlotinib as a gemcitabine chemosensitizer in cancer cells that overexpress EGFR.
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A placebo-controlled phase 3 trial demonstrated that the epidermal growth factor receptor (EGFR) inhibitor erlotinib in combination with gemcitabine was especially efficient in a pancreatic ductal adenocarcinoma (PDAC) subgroup of patients developing skin toxicity. However, EGFR expression was not predictive for response, and markers to characterize an erlotinib-responding PDAC group are currently missing. In this work, we observed high erlotinib IC50 values in a panel of human and murine PDAC cell lines. Using EGFR small interfering RNA, we detected that the erlotinib response was marginally influenced by EGFR. To find novel EGFR targets, we used an unbiased chemical proteomics approach for target identification and quality-controlled target affinity determination combined with quantitative mass spectrometry based on stable isotope labeling by amino acids in cell culture. In contrast to gefitinib, we observed a broad target profile of erlotinib in PDAC cells by quantitative proteomics. Six protein kinases bind to erlotinib with similar or higher affinity (Kd = 0.09-0.358 μM) than the EGFR (Kd 0.434 μM). We provide evidence that one of the novel erlotinib targets, ARG, contributes in part to the erlotinib response in a PDAC cell line. Our data show that erlotinib is a multikinase inhibitor, which can act independent of EGFR in PDAC. These findings may help to monitor future erlotinib trials in the clinic.
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症例は49歳，女性．全身性エリテマトーデスにて通院中であったが，著明な肝機能異常（AST 1935 IU/l, ALT 1329 IU/l, ALP 553 IU/l）のため入院となった．入院の17日前より関節痛に対しCelecoxib 100 mg/日を内服していた．Celecoxibを中止し経過観察したところ，入院時に認めた高度の肝機能異常は速やかに改善し，その後再燃することなく安定している．第14病日に行った肝生検所見およびDDW-J 2004ワークショップ薬物性肝障害診断基準に基づき，Celecoxibによる薬物性肝障害と診断した．Celecoxibによる薬物性肝障害は稀であるが，他のNSAIDs同様に肝障害のリスクに注意を払う必要がある．
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Do proton‐pump inhibitors confer additional gastrointestinal protection in patients given celecoxib?
Abstract Objective Celecoxib has a superior upper‐gastrointestinal (GI) safety profile compared with nonselective nonsteroidal antiinflammatory drugs (NS‐NSAIDs). It is unclear whether the utilization of a proton‐pump inhibitor (PPI) with celecoxib confers additional protection in elderly patients. We assessed the association between GI hospitalizations and use of celecoxib with a PPI versus celecoxib alone, and NS‐NSAIDs with a PPI or NS‐NSAIDs alone in elderly patients. Methods We conducted a population‐based retrospective cohort study using the government of Quebec health services administrative databases. Elderly patients were included at their first dispensing date for celecoxib or an NS‐NSAID between April 1999 and December 2002. Prescriptions were separated into 4 groups: celecoxib, celecoxib plus PPI, NS‐NSAIDs, and NS‐NSAIDs plus PPI. Cox regression models with time‐dependent exposure were used to compare the hazard rates of GI hospitalization between the 4 groups adjusting for patient characteristics at baseline. Results There were 1,161,508 prescriptions for celecoxib, 360,799 for celecoxib plus PPI, 715,176 for NS‐NSAIDs, and 148,470 for NS‐NSAIDs plus PPI. The adjusted hazard ratios (HRs; 95% confidence intervals [95% CIs]) were 0.69 (0.52–0.93) for celecoxib plus PPI versus celecoxib, 0.98 (0.67–1.45) for NS‐NSAIDs plus PPI versus celecoxib, and 2.18 (1.82–2.61) for NS‐NSAIDs versus celecoxib. Subgroup analyses showed that use of a PPI with celecoxib may be beneficial in patients ages ≥75 years but was not better than celecoxib alone among those ages 66–74 years (HR 0.98, 95% CI 0.63–1.52). Conclusion Addition of a PPI to celecoxib conferred extra protection for patients ages ≥75 years. PPI did not seem necessary with celecoxib for patients ages 66–74 years.
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Objective To explore the effects of erlotinib combined with celecoxib on the tumor growth and angiogenesis of lung cancer xenografts in nude mice.Methods Human lung cancer cell A549 was subcutaneously injected to establish the nude mice xenograft model.The nude mice with tumor were randomly divided into four groups:the control group,the celecoxib group,the erlotinib group and the combined group.All the mice were given the gavage administration.The status of the mice were observed everyday,and the volume of the tumor was measured twice a week to obtain the tumor growth curve.The mice were put to death to collect the tumor tissues after 40 days.The microvessel density(MVD) was detected by the immunohistochemistry analyses and the expressions of Bcl-2 and Bax were detected by Western Blotting.Blood samples were collected to detect the sVEGF level by ELISA.Results The tumor volumes of the combined group were significantly smaller compared with the control group,the celecoxib group and the erlotinib group(P0.05).The microvessel density and the sVEGF level of the combined group were decreased compared with the control group,the celecoxib group and the erlotinib group(P0.05).The Bcl-2 level of the erlotinib group was lower compared with the control group.There was no significant difference of the Bcl-2 level between the celecoxib group and the control group(P0.05).The Bcl-2 level of the combined group is lower compared with the control group,the celecoxib group and the erlotinib group(P0.05).There was no significant difference of the Bax level among the control group,the celecoxib group and the combined group(P0.05).The value of Bcl-2/Bax of the combined group was lower compared with the celecoxib group and the erlotinib group(P0.05).Conclusion Erlotinib combined with celecoxib have more effective growth inhibition on the human lung cancer xenograft model than erlotinib or celecoxib separately.The possible mechanism may be related to the decrease of microvessels and the increase of tumor apoptosis.
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