Hiroto Kishi

Expression of constitutively activated EGFRvIII in non-small cell lung cancer.

The epidermal growth factor receptor (EGFR) variant type III (variously called EGFRvlll, de2–7 EGFR or ΔGFR) has an in‐frame deletion of the extracellular domain and is found in numerous types of human tumors. Since EGFRvlll has been reported to be tumorspecific and has oncogenic potential, it is being investigated as a potential therapeutic target. Because the cell‐specific expression of EGFRvlll in lung has not been well documented, we examined the expression of EGFRvlll in 76 non‐small cell lung cancers (NSCLCs) and 10 non‐neoplastic lung tissues by immunohistochemistry using a new monoclonal antibody specific for this variant receptor. We found a higher incidence (30 of 76, 39%) of enhanced EGFRvlll expression in NSCLC than previously described. Interestingly, the presence of EGFRvlll was also observed in several normal tissue components of lung (e.g., normal bronchial epithelium). Given the high prevalence of EGFRvlll in NSCLC, a newly developed phospho‐specific (activated) EGFR antibody was employed for immunohistochemical analysis that permitted visualization of activated EGFR and/or EGFRvlll in tumors. This study presents evidence, for the first time, that EGFRvlll expressed in human tumors is phosphorylated and hence activated. Our results suggest that the sustained activation of EGFRvlll is implicated in the pathogenesis of NSCLC and thus EGFRvlll is a potential therapeutic target in this challenging disease. (Cancer Sci 2003; 94: 50–56)

Osmotic Shock Induces G1 Arrest through p53 Phosphorylation at Ser33 by Activated p38MAPK without Phosphorylation at Ser15 and Ser20

Osmotic shock induced transient stabilization of p53, possibly due to increased degradation of Mdm2. Stabilized p53 was activated by p38MAPK, resulting in G1arrest through induction of p21WAF1. Among the postulated phosphorylation sites involved in p53 stabilization or activation (Ser15, Ser20, Ser33, and Ser46), only Ser33 was phosphorylated. Furthermore, interaction of p53 with the transcriptional coactivator p300 was induced, and Lys382 of p53 was acetylated. Although inhibition of p38MAPK did not prevent nuclear accumulation of p53, phosphorylation of Ser33 was markedly suppressed by SB203580, a specific inhibitor of p38MAPK. Under these conditions, acetylation of Lys382 and induction of p21WAF1 were also inhibited, and cells with elevated levels of p53 showed normal cell cycle progression. Activated p38MAPK phosphorylated endogenous p53 at Ser33in living cells. In stable transformants expressing dominant negative MKK6, an upstream protein kinase of p38MAPK, p53 stabilization was induced normally following osmotic shock, but phosphorylation of Ser33, acetylation of Lys382, and induction of p21WAF1 were almost completely inhibited. These results suggest that phosphorylation at Ser33 by p38MAPK is critical for activation of p53 following osmotic shock. Phosphorylation of neither Ser15 nor Ser20 was needed in this activation.

Pharmacokinetics of amrubicin and its active metabolite amrubicinol in lung cancer patients

Amrubicin, a synthetic 9-aminoanthracycline agent, was recently approved in Japan for treatment of small-cell lung cancer and non-small-cell lung cancer. Amrubicin is converted enzymatically to the C-13 hydroxy metabolite amrubicinol, which is active and possesses a cytotoxicity 10 to 100 times that of the parent drug. The purpose of this study was to characterize the pharmacokinetics of amrubicin and its active metabolite amrubicinol. Amrubicin was administered on days 1-3 in 16 patients with advanced lung cancer. The pharmacokinetics analysis of amrubicin and amrubicinol was performed by high-performance liquid chromatography. When 45 mg/m2 amrubicin was administered in a bolus injection once every 24 hours for 3 consecutive days, the areas under the curves (0 to 72 hours) for amrubicin and amrubicinol were 13,490 and 2585 ng · h/mL, respectively. The apparent total clearance (CLapp) of amrubicin was 15.4 L/h. The area-under-the-curve ratio of amrubicinol to amrubicin was 15.1 ± 4.6% (mean ± SD) at doses ranging from 30 to 45 mg/m2. Interindividual variability in the enzymatic conversion of amrubicin to amrubicinol was small. In contrast, a large interindividual variability in the CLapp of amrubicin was observed (CV = 49.8%). The areas under the curves of amrubicin and amrubicinol seemed to be associated with the severity of hematologic toxicities. There is a possibility that monitoring of the plasma concentrations of amrubicin and amrubicinol may provide an efficient tool for establishing the optimal dosage of amrubicin in each patient.

Association of ABCB1 polymorphisms with erlotinib pharmacokinetics and toxicity in Japanese patients with non-small-cell lung cancer

AIMS We analyzed the association of ABCB1 polymorphisms with erlotinib-induced toxicity and the pharmacokinetics in patients with non-small-cell lung cancer. MATERIALS & METHODS After erlotinib 150 mg was administered to 50 patients, ABCB1 polymorphisms were analyzed via either TaqMan(®) assays or direct nucleotide sequencing. Plasma concentrations were measured by HPLC. RESULTS The trough concentration at steady state in patients with the ABCB1 1236TT-2677TT-3435TT genotype was higher compared with others groups (p = 0.021) and patients carrying this genotype had a higher risk of developing higher grade 2 toxicity (p = 0.012). CONCLUSION The present study suggested that the ABCB1 1236TT-2677TT-3435TT genotype was associated with higher plasma concentration and the risk of developing higher toxicity in patients treated with erlotinib.

Phase II trial of weekly nab-paclitaxel for previously treated advanced non-small cell lung cancer: Kumamoto thoracic oncology study group (KTOSG) trial 1301.

OBJECTIVES We performed an open-label, multicenter, single-arm phase II study (UMIN ID 000010532) to prospectively evaluate the efficacy and safety of nab-paclitaxel for previously treated patients with advanced non-small cell lung cancer (NSCLC). METHODS Patients with advanced NSCLC who experienced failure of prior platinum-doublet chemotherapy received weekly nab-paclitaxel (100mg/m(2)) on days 1, 8, and 15 of a 21-day cycle until disease progression or the development of unacceptable toxicity. The primary end point of the study was objective response rate (ORR). RESULTS Forty-one patients were enrolled between September 2013 and April 2015. The ORR was 31.7% (90% confidence interval, 19.3%-44.1%), which met the primary objective of the study. Median progression-free survival was 4.9 months (95% confidence interval, 2.4-7.4 months) and median overall survival was 13.0 (95% confidence interval, 8.0-18.0 months) months. The median number of treatment cycles was four (range, 1-17) over the entire study period, and the median dose intensity was 89.1mg/m(2) per week. Hematologic toxicities of grade 3 or 4 included neutropenia (19.5%) and leukopenia (17.1%), with no cases of febrile neutropenia being observed. Individual nonhematologic toxicities of grade 3 or higher occurred with a frequency of <5%. CONCLUSION Weekly nab-paclitaxel was associated with acceptable toxicity and a favorable ORR in previously treated patients with advanced NSCLC. Our results justify the undertaking of a phase III trial comparing nab-paclitaxel with docetaxel in this patient population.

Dose escalation and pharmacokinetic study of carboplatin plus pemetrexed for elderly patients with advanced nonsquamous non-small-cell lung cancer: Kumamoto thoracic oncology study group trial 1002

Objectives: This study was designed to determine the recommended dose of carboplatin and pemetrexed for elderly (≥70-year-old) chemotherapy-naïve patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) and to investigate the pharmacokinetics of pemetrexed. Methods: The patients were treated with 4-6 cycles of carboplatin plus a fixed dose of pemetrexed (500 mg/m2) every 3 weeks; the dose of carboplatin was escalated [from area under the curve (AUC) 4 to AUC 6]. To examine the pharmacokinetics of pemetrexed, blood samples were collected before and after pemetrexed infusion, and the blood levels of pemetrexed were measured by liquid chromatography-mass spectrometry. Results: Grade 3 infection as a dose-limiting toxicity was observed at a carboplatin dose of AUC 6. We therefore determined a carboplatin dose of AUC 5 and a pemetrexed dose of 500 mg/m2 as the recommended doses from this study. The pharmacokinetic study showed a significant inverse correlation between the AUC of pemetrexed and the creatinine clearance. Conclusions: For elderly chemotherapy-naïve patients with advanced nonsquamous NSCLC, the combination of carboplatin AUC 5 plus pemetrexed 500 mg/m2 is recommended as a promising regimen; however, a reduction of the pemetrexed dose may be required for patients with renal dysfunction because of the high risk of hematotoxicities.

Multicenter phase II study of the combination of carboplatin and paclitaxel as first line treatment in elderly patients with advanced non small cell lung cancer (NSCLC)

7239 Purpose: Thirty percent of NSCLC arise in patients over 70 years. The purpose of this phase II trial is to evaluate the efficacy and the safety of the combination of carboplatin and paclitaxel for advanced NSCLC in elderly patients aged 70 years or older. PATIENTS AND METHOD Eligibility criteria included: chemotherapy-naive advanced NSCLC, age>=70; measurable lesion; ECOG PS 0-1; adequate organ functions and signed informed consent. Patients received carboplatin at an AUC of 5 mg/mL.min and paclitaxel 180 mg/m2 on day 1 every 3 weeks. RESULTS Between January 2001 and July 2003, 25 elderly patients with NSCLC (median: 76y, range: 70-83y) were enrolled to this study. There were 4 stage IIIB, 17 stage IV and 4 other medically inoperable patients. The median number of treatment cycles was 3 (range 1-4). There were 1 complete response and 6 partial response for an objective response rate (ORR) of 25% (95%CI: 12-40%). The median survival was 11.3 months and the 1-year survival rates were 37%. Hematological toxicities with grade 3/4 were as follows; 32%/8% for leukopenia, 28%/40% for neutropenia, 4% for anemia. Non-hematological toxicities with grade 3 were: arthralgia/myalgia 16% of patients, neuropathy 12% and infections 20%. Efficacy and toxicity analyses were also conducted on patients over age 75 years (n=15). ORR for patients > 75 years were 26% and no evidence of excessive toxicity were observed when compared with patients < 75 years. CONCLUSION This carboplatin/paclitaxel combination chemotherapy is an active first-line treatment option with a favorable toxic profile for elderly patients with advanced/metastatic NSCLC. No significant financial relationships to disclose.

Pneumothorax in a Patient with Unilateral Pulmonary Artery Agenesis

A 17-year-old Japanese woman presented with right chest pain and exertional dyspnea. The patient had a history of isolated unilateral absence of the right pulmonary artery (UAPA) and pulmonary hypertension from early childhood. Chest radiography revealed right-sided pneumothorax and a small lung volume with mediastinal and tracheal shift to the right as well as right diaphragm elevation (Picture 1). Computed tomography revealed pneumothorax and multiple thinwalled bullae only in the right lung, and absence of the right main pulmonary artery (Picture 2). The pneumothorax improved without any invasive procedures, such as needle aspiration or chest tube drainage (Picture 3). In comparison to

Population Pharmacokinetics and Adverse Events of Erlotinib in Japanese Patients with Non-small-cell Lung Cancer: Impact of Genetic Polymorphisms in Metabolizing Enzymes and Transporters

Determinants of interindividual variability in erlotinib pharmacokinetics (PK) and adverse events remain to be elucidated. This study with 50 Japanese non-small-cell lung cancer patients treated with oral erlotinib at a standard dose of 150 mg aimed to investigate whether genetic polymorphisms affect erlotinib PK and adverse events. Single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, and GSTT1) or efflux transporters (ABCB1, and ABCG2) were analyzed as covariates in a population PK model. The ABCB1 1236C>T (rs1128503) polymorphism, not ABCB1*2 haplotype (1236TT-2677TT-3455TT, rs1128503 TT-rs2032582 TT-rs1045642 TT), was a significant covariate for the apparent clearance (CL/F), with the TT genotype showing a 29.4% decrease in CL/F as compared with the CC and the CT genotypes. A marginally higher incidence of adverse events (mainly skin rash) was observed in the TT genotype group; however, patients with high plasma erlotinib exposure did not always experience skin rash. None of the other SNPs affected PK or adverse events. The ABCB1 genotype is a potential predictor for erlotinib adverse events. Erlotinib might be used with careful monitoring of adverse events in patients with ABCB1 polymorphic variants.

O1-4-4Association of the bevacizumab pharmacokinetics with efficacy and toxicity in advanced non-small cell lung cancer

lung, and it was significantly associated with shorter survival rate after curative surgery. In addition, URST1 was expressed in 64 of 96 (66.7%) oral cancers, but not in oral mucosa, and it was significantly correlated with poor prognosis after surgery. Multivariate analysis confirmed that URST1 expression was an independent prognostic factor for oral cancer. Suppression of URST1 expression by siRNA or treatment with synthesized inhibitor specific for URST1 activity inhibited mitosis and growth of lung or oral cancer cell lines. Our results suggest that URST1 could be a prognostic biomarker and therapeutic target for aerodigestive cancers such as lung or oral cancers.