bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of gefitinib as a first-line therapy for advanced non-small cell lung cancers with epidermal growth factor receptor (EGFR) gene mutations
Authors: Asahina H. , Yamazaki K. , Kinoshita I. , Ogura S. , Ishida T. , Dosaka-Akita H. , Isobe H. , Nishimura M. 
Published: March 2020

13014 Background: Activating mutations in exon 18–21 of the epidermal growth factor receptor (EGFR) gene have been reported to be a predictor of response to gefitinib. We conducted a phase II study to evaluate the efficacy and safety of gefitinib as a first-line therapy for advanced non-small cell lung cancers (NSCLCs) with EGFR gene mutations. Methods: The primary endpoint was response rate (RR). Eligiblity criteria were stage IIIB or IV chemotherapy naive NSCLC, ECOG PS of 0–2, adequate organ functions, measurable lesions, and written informed consent. First, we examined EGFR gene mutations in exon 18–21 by direct sequencing of PCR products of DNA extracted from paraffin-embedded tissues. Those who had EGFR gene mutations received gefitinib 250 mg daily. This study, with a sample size of 14, had 90% power to support the hypothesis that true RR was ≥70%, and 5% significance to deny the hypothesis that true RR was ≤30%. Assuming an inevaluality rate ≤15%, we projected an accrual of 16 patients. Results: From Nov. 2004 to Jan. 2006, EGFR gene mutations were analyzed in tumor specimens from 82 patients. Twenty patients (24%) had EGFR gene mutations (16 with deletions in or near E746-A750, 4 with L858R). While there were no significant differences between mutation status and age, sex, histology, or the procedures to obtain tumor specimens, EGFR gene mutations were more frequently observed in never-smokers than in smokers (39% vs. 11%, p<0.01). Sixteen patients (median age, 68; male/female, 3/13; adenocarcinoma/SCC, 15/1; current/former/never smoker, 2/1/13) were enrolled and treated with gefitinib. To date, best response is 2 CR, 7 PR, 1 SD and 1 PD (RR, 82%). Two patients had grade 3 toxicities, including 1 skin eruption and 1 liver dysfunction. One patient had grade 1 interstitial lung disease, leading to the termination of gefitinib treatment. Conclusions: Gefitinib is very active and well tolerated as a first-line therapy for advanced NSCLCs with EGFR gene mutations. No significant financial relationships to disclose.
Rapid detection of UGT1A1 polymorphisms by a novel microarray assay: A validation study using 100 samples from patients with lung cancer treated by irinotecan
Authors: Yamada Y. , Shimizu T. , Ozaki T. , Hatashita E. , Kurata T. , Fukuoka M. , Tamura K. 
Published: March 2020

13019 Background: Irinotecan is one of the active drugs for the treatment of colorectal, gastric and lung cancer. SN-38, the active metabolite of irinotecan is metabolized through conjugation by uridine diphosphate glucuronosyl transferase (UGT1A1). Genetic polymorphisms of UGT1A1 in the specific locus have been reported to be significantly related to severe toxicities of Irinotecan. Although the polymorphisms are usually detected by direct sequence (DS) or PCR-restriction fragment length polymorphism (RFLP) analysis, these assays consume time and need deferent PCR product for each exon. We report a novel microarray (MA) technology to detect the UGT1A1 polymorphisms using 100 peripheral blood samples of lung cancer patients treated with irinotecan, and evaluate a consistence ratio in comparison with the confirmed results by RFLP or DS. Methods: One hundred lung cancer patients who had received irinotecan containing chemotherapy were enrolled in this study. Genomic DNA was extracted from whole blood and prepared into 100 ng/5μL. PCR were performed by random primers, and the PCR products were labeled by biotin. The labeled probe have hybridized the MA chips, and patterns of visualized dots informed us the polymorphisms in the deferent locus (*28, *6 *27), simultaneously. Polymorphisms of all samples were also confirmed by RFLP and DS for validation. Results: One homozygous (Hom), 14 heterozygous (Het) and 85 wild type (W) for UGT1A1*28 were confirmed by DS. Five Hom, 25 Het and 70 W for UGT1A1*6, and 1 Het and 99 W for UGT1A1*27 were confirmed by RFLP and DS. A single approach of the novel MA assay have revealed 79.3%, 96.6% and 100% consistence with the confirmed result for each exon (*28, *6 *27), respectively. Individual twice approach of the MA have revealed 94.3%, 98.9% and 100% consistence with the confirmed result for the each exon, respectively. We could assay all samples by the MA and needed only single day for detection. Conclusions: Our newly developed assay for detecting UGT1A1 polymorphisms is rapid, accurate and feasible and has potential to be used for screening before irinotecan in the future prospective clinical trials. No significant financial relationships to disclose.
[18F]fluorothymidine (FLT) PET after 3 days of gefitinib treatment and tumor response in non-small cell lung cancer (NSCLC)
Authors: Sohn H. , Kim S. , Ryu J. , Oh S. , Moon D. , Oh Y. , Shim T. , Kim W. , Suh C. , Lee J. 
Published: March 2020

13031 Background: FLT has been developed as a PET tracer for imaging tumor proliferation. We evaluated whether FLT-PET could predict tumor response only after 3 days of gefitinib treatment. Methods: Nonsmokers with adenocarcinoma of the lung were eligible for this study. FLT-PET was performed at 1 day before and 3 days after the start of gefitinib (250 mg/d) therapy. The maximum standardized uptake value (SUVmax) of the main lung mass was measured, and changes in tumor SUVmax were calculated. After 6 weeks of therapy, response was assessed by chest CT according to WHO criteria. The cutoff value predicting subsequent CT response was obtained by receiver operating characteristic curve analysis. Results: Between Jun. 2005 and Nov. 2005, 22 patients were enrolled. CT response was partial response in 12 (54%), stable disease in 5 (23%), and progressive disease in 5 (23%). As early as 3 days after the initiation of therapy, significant difference in % changes of tumor SUVmax on FLT-PET was observed between responders and nonresponders (−32% v −2.3%, P = .002) ( Table ). When a reduction of tumor SUVmax ≥ 20% was used as a cutoff value for FLT-PET response, CT response could be predicted with positive and negative predictive values of 100% and 83%, respectively. Time to progression was significantly longer in FLT-PET responders than nonresponders (median 5.1 v 1.4 months, P = .011). Conclusions: Using FLT-PET obtained on days 0 and 3 of gefitinib therapy, the response could be early predicted in patients with NSCLC. [Table: see text] No significant financial relationships to disclose.
Insulin-like growth factor-1 receptor/epidermal growth factor receptor (EGFR) heterodimerization and resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer
Authors: Morgillo F. , Hong W. K. , Lee H. 
Published: March 2020

13032 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been used to treat lung cancers, but resistance to these agents has been observed. This study was designed to investigate whether the insulin-like growth factor (IGF)-mediated signaling pathway induces resistance to the EGFR TKIs in lung cancer. Methods: The antitumor activities and action mechanisms of EGFR inhibitors (erlotinib, gefinitib, cetuximab), single or in combination with IGF-IR inhibitors, were assessed in vitro in a subset of non-small-cell lung cancer (NSCLC) cell lines by the MTT assay, flow cytometry-based TUNEL assay, soft agar, confocal microscopy, metabolic labeling, coimmunoprecipitation, and northern and western blot analyses, and in vivo in animal models. Correlation of EGFR and IGF-1R expression was assessed using lung tissues from patients with NSCLC. Results: EGFR TKI inhibited the proliferation and anchorage-dependent and -independent colony-forming ability of NSCLC cells, which induced apoptosis, only when IGF-1R signaling was blocked. Treatment with EGFR TKIs, but not with the EGFR antibody, induced EGFR:IGF-1R heterodimerization on cell surface and activation of the IGF-1R, resulting in the stimulation of PI3K/Akt/ mTOR pathway, promoting the de novo protein biosynthesis of survivin and EGFR, resulting in the survival of NSCLC cells. When IGF-IR and mTOR were blocked, treatment of EGFR-TKIs induced apoptosis in NSCLC cells, resulting in suppression of the NSCLC tumor growth. When we tested the expression of IGF-R and EGFR in human lung tissue, 9/14 tumor samples exhibited increased expression of EGFR and 7/9 samples showed a correlative increases in IGF-IR protein levels compared to their paired normal counterparts. Conclusions: These findings suggest that simultaneous targeting of EGFR and IGF-1R signaling pathways might be an effective therapeutic strategy against NSCLC. No significant financial relationships to disclose.
In vitro chemosensitivity against enzastaurin correlates with gene expression of IL8 and GSK3-beta
Authors: Oberschmidt O. , Eismann U. , Lahn M. M. , Fleeth J. , Lüdtke F. , Struck S. , Schulz L. , Blatter J. , Ma D. , Hanauske A. 
Published: March 2020

13046 Background: Enzastaurin (E) is an active antitumoral agent which selectively inhibits the β-isoform of protein kinase C (PKC-β). The compound blocks the enzyme’s ATP-binding site and signal transmission is abrogated resulting in the inhibition of neovascularization. The aim of the present study was to correlate gene expression with in vitro chemosensitivity of freshly explanted human tumor specimens. Such correlations in tumors taken directly from patients will help to rationally design subsequent clinical trials. Methods: Soft-agar colony forming assays were performed on freshly biopsied tumor cells exposed to various concentrations of E. Corresponding pieces of tumor specimens were shock-frozen and prepared for RNA isolation and cDNA generation followed by multiplex real-time PCR experiments. Gene expression data were correlated against cloning assay results. Results: Gene expression data of PKC-β1, PKC-β2, IL8RA, IL8RB, IL8, GSK3-β, and TGF-β were correlated against in vitro chemosensitivity pattern of E from 66 samples. After 1h-drug exposure gene expressions in sensitive versus resistant specimens were statistically significant with p = 0.013 for IL8 [median copy number (mcn): 1881 vs. 694; n = 66] and p = 0.012 for GSK3-beta (mcn: 1.6 vs. 7.0; n = 66). No correlation was detected for PKC-β1, PKC-β2, IL8RA, and IL8RB. Detection of TGF-β failed in most samples. Conclusions: Low expression of GSK3-β and high expression of IL8 correlate statistically significantly with increased in vitro sensitivity to E in freshly explanted human tumors. These findings may help direct further clinical development of this compound. No significant financial relationships to disclose.
A phase Ib trial of ARQ 501, a selective checkpoint activator, in combination with docetaxel in patients with advanced solid tumors
Authors: Li C. , Nemunaitis J. , Senzer N. , Edelman G. , Glasner S. , Dombal G. , Dovholuk A. , Cunningham C. 
Published: March 2020

13053 Background: ARQ 501 is a DNA damage checkpoint activator. It directly activates DNA damage response pathways without inducing primary DNA damage, resulting in selective apoptosis in a broad range of cancer cells. The cell death pathway of ARQ 501 is mediated by E2F1, and is independent of p53. In preclinical models, ARQ 501 demonstrates potent anticancer activity with a high therapeutic index. In these models, the addition of a variety of cytotoxic agents, including docetaxel, greatly enhances the anti-tumor activity of ARQ 501. Therefore, clinical investigation of this combination is warranted. Methods: Phase 1b dose escalation study in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity of ARQ 501 in combination with docetaxel. Two schedules have been investigated. In one, ARQ 501 was administered for 5 consecutive days with a single docetaxel infusion at 50 to 100 mg/m2 given on day 3. In the other, a single dose of ARQ 501 was given in combination with a single docetaxel infusion on day 1. Both schedules were repeated every 3 weeks. Pharmacokinetic data were collected during study weeks 1 and 4 and tumor evaluations performed every 6 weeks. Results: To date, the first ARQ 501 treatment schedule has been given to 9 evaluable patients, and the second to 7 patients with a wide variety of tumor types. The combination is well tolerated and exhibits favorable, apparently linear, pharmacokinetics. ARQ 501 does not alter docetaxel pharmacokinetic parameters in patients. The most common grade 3 and 4 adverse events are neutropenia (4.9%) and anemia (4.4%). Of the 16 patients receiving at least 8 weeks of treatment, 12 have achieved a response of stable disease or better, including four responses (2 unconfirmed PRs based on RECIST, and 2 responses based on CA-125 decreases). Conclusions: The combination of ARQ 501 with docetaxel demonstrates clinical tolerability, favorable pharmacokinetics, and signs of antitumor activity. Further dose escalation is ongoing to determine a recommended phase II regimen. [Table: see text]
Population pharmacokinetics (PK) of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in cancer patients
Authors: Li J. , Jameson M. B. , Baguley B. C. , Pili R. , Baker S. D. 
Published: March 2020

13076 Background: DMXAA (AS1404) is a small-molecule vascular-disrupting agent that selectively disrupts established tumor blood vessels. It is being evaluated in phase II trials in combination with cytotoxics. DMXAA is extensively metabolized, predominantly by UDP-glucuronosyltransferase (UGT) 2B7 and 1A9, and exhibits concentration-dependent protein binding. The study aim was to develop a population PK model for DMXAA and to examine covariates influencing drug disposition. Methods: 3,050 DMXAA total plasma concentrations were measured in 124 cancer patients receiving DMXAA monotherapy as a 20-min iv infusion weekly or every three weeks at doses from 6 to 4900 mg/m2 in 3 phase I trials. PK models were fitted to the data from all patients simultaneously using the program NONMEM. Potential covariates including age, body weight, height, body surface area (BSA), sex, and liver and kidney function tests were screened with general additive model analysis and tested in the PK model. Results: DMXAA concentration-time profiles after multiple-dose administration were well described by a 3-compartment model with saturable elimination (Michaelis-Menten kinetic) from the central compartment. BSA and sex were significant covariates on the volume of distribution of the central compartment (V1) and the maximum elimination capacity (Vm), respectively, accounting for 10 and 12% of interindividual variation (IIV) in these parameters. Population estimates for Vm, Km (concentration at which half-maximal elimination rate is achieved), and V1 were 122 × (1 + 0.502 × (2-SEX)) (μM/h) [females had lower Vm than males; SEX = 1 for males, 2 for females], 103 μM, and 8.15 × (BSA/1.8)0.69 (L), respectively. In the final model, IIV in Vm was 52%. Conclusions: DMXAA plasma disposition is characterized by a saturable elimination process. BSA-guided dosing for DMXAA is important. Evaluation of other covariates that reflect drug glucuronidation (e.g., UGT polymorphisms) may account for a greater fraction of the substantial unexplained PK variability. The population PK model will aid development of limited PK sampling strategies and investigation of PK-pharmacodynamic relationships in further trials. [Table: see text]
Enzastaurin safety review: Data from phase I and phase II trials
Authors: Watkins V. , Hong S. , Lin B. 
Published: March 2020

13077 Background: Enzastaurin, an oral inhibitor of PKC and PI3K/AKT pathways, blocks tumor angiogenesis, tumor cell proliferation and induces tumor cell death. Enzastaurin has demonstrated promise in phase I and II trials in patients (pts) with various advanced cancers. We report preliminary analysis of safety data of enzastaurin, obtained in previous trials, with particular consideration to long-term therapy. Methods: Data available to date from 3 different non-randomized, single-arm trials in pts with advanced cancers, diffuse large B cell lymphoma and mantle cell lymphoma, were analyzed with regards to treatment emergent adverse events (TEAEs). Severities were defined by NCI guidelines and investigators assessed the relatedness of AEs to enzastaurin. Results: A total of 135 pts (58 F; 77 M), mean age 64 years (range: 24–87) received 20–700 mg oral enzastaurin daily (103 pts at 525 mg). 36 pts were dosed for 0–30 days, 45 for 31–60 days, 35 for 61–180 days and 19 for ≥ 180 days. No deaths were related to enzastaurin. Chromaturia was the most common drug-related event (14%). No drug-related bone marrow suppression, Gr 3 neutropenia, thrombocytopenia or anemia was reported. TEAEs in ≥ 15% pts, or drug-related events ≥ Gr 3 reported in > 1 pt, are listed in the table . Other Gr 3 AEs, including edema, migraine and peripheral motor neuropathy were observed in 1 pt, each. Pts on therapy for ≤ 30 D reported highest number of AEs, consistent with the severity of their disease. Pts with exposure ≥ 180 days did not experience any drug related AE ≥ Gr 3. Conclusions: Enzastaurin is well tolerated across all doses and for extended durations with minimal AEs. In the 19 patients who received oral enzastaurin for ≥ 180 days, there was no indication of increased severity of any event. Given the severity of the disease and the absence of controlled studies for comparison, no event other than chromaturia or fecal discoloration (due to reddish-orange color of the active ingredient) appears to be definitively attributable to enzastaurin by this analysis. [Table: see text] [Table: see text]
Synergistic and selective inhibition of NSCLC cell growth via a caspase-independent cell death pathway by tumor suppressor 101F6 nanoparticles plus vitamin C in vitro and in vivo
Authors: Ohtani S. , Ueda K. , Jayanchandran G. , Xu K. , Minna J. D. , Roth J. A. , Ji L. 
Published: March 2020

13086 Background: 101F6 is a candidate tumor suppressor gene on chromosome 3p21.3, a site of allele loss and genomic alterations were frequently found in many human cancers. We previously showed that enforced expression of wt-101F6 by adenoviral virus significantly inhibited tumor cell growth in 3p21.3-deficient NSCLC cells in vitro and in vivo. How 101F6 exerts this effect is largely unknown. Using a computer-aided structural and functional modeling, we recently identified 101F6 as a member of cytochrome b-561 protein family, which is involved in the regeneration of vitamin C. We hypothesized that under normal physiologic conditions, 101F6 protects cells from oxidative damage by regenerating antioxidant vitamin C and that in 101F6-deficient tumor cells, exogenous 101F6 facilitates vitamin C-mediated cytotoxic H2O2 formation. Methods and Results: We examined endogenous 101F6 expression in human NSCLC cell lines and tissue samples. All normal lung bronchial epithelial cells and fibroblasts but few lung cancers expressed 101F6. We investigated the combined effect of 101F6 and vitamin C on the cell growth: a nanoparticle-mediated wt-101F6 gene transfer plus a sub-pharmacologic concentration of vitamin C synergistically inhibited 3p21.3-deficient NSCLC cell growth but did not affect normal cell growth. We also used a human NSCLC H322 orthotopic lung tumor xenograft mouse model to evaluate the therapeutic efficacy of systemic injection of 101F6 nanoparticles and intraperitoneal injection of vitamin C. The growth of lung tumors was synergistically inhibited by the combination treatment (p<0.001). Furthermore, exogenous 101F6 promoted intracellular vitamin C uptake, leading to the vitamin C-mediated accumulation of H2O2 in the tumor cells, and these two agents synergistically killed the cells through caspase-independent apoptosis and autophagy cell death pathways. Conclusions: The synergistic and selective antitumor effect of 101F6 nanoparticles plus vitamin C may offer a useful tool for lung cancer prevention and intervention. This abstract is supported by grants from NCI (SPORE P50CA70907) and DOD (TARGET, DAMD17002–1-0706). No significant financial relationships to disclose.
Marked synergism of cytotoxic agents with either a prenylation inhibitor or M-TOR inhibitor in acute leukemia cell lines: Potential clinical implications
Authors: Budman D. R. , Calabro A. 
Published: March 2020

13103 Background: The most combinations of anticancer drugs are based upon empiricism. The potential permutations of drugs overwhelm the clinical trials system. Acute leukemia is sensitive to a variety of agents but relapses are common. Targeted agents are attractive new venues of therapy both as single agents and in combination with older agents. Isobologram median effect analysis allows up to three agents to be studied together in vitro to identify interesting combinations. We evaluated a commercially available statin, fluvastatin, to block prenylation which affects a variety of pathways, rapamycin and its experimental analogue RAD001 as M-TOR inhibitors to block downstream of the AKT pathway, and cytotoxic agents. Methods: The human leukemia cell lines AML-193 and KG-1 were obtained from ATTC (Rockville, MD), fluvastatin and RAD001 from Novartis Pharma, and the other agents from Sigma-Aldrich (St. Louis, MO). The IC50 of the single agent was determined by a 72 hr incubation of log growth cells using a MTT assay and the EZ-ED50 program (Perrella Scientific, Conyers, CA). The dosages of all agents were at clinically achievable concentrations. All reported values were the means of at least 3 experiments with each study using 4 wells per point. For isobologram analysis, a minimum of 8 concentrations of drug mixtures were studied above and below the IC50. Median effect CI values less than 1 are synergistic. Results: Doublets of fluvastatin with Ara-C (0.7), daunomycin (0.4), idarubicin (0.7), RAD001 (0.5), or rapamycin (0.3) demonstrated synergy. Doublets of RAD001 with Ara-C (0.3), daunomycin (0.7), or idarubicin (0.5) demonstrated synergy. Triplets of RAD001/daunorubicin/Ara-C, RAD001/daunomycin/fluvastatin, and RAD001/Ara-C/idarubicin all demonstrated marked synergy in both cell lines. Conclusion: A new potential non classical combination for further investigation is RAD001 or rapamycin with an inhibitor of prenylation such as fluvastatin. Additional potential combinations include cytotoxics with either fluvastatin or RAD001, and triplet combinations. No significant financial relationships to disclose.