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1.  Genome-wide association study of genetic predictors of overall survival for non-small cell lung cancer in never smokers 
Cancer research  2013;73(13):4028-4038.
To identify the genetic factors that influence overall survival in never smokers who have non-small cell lung cancer (NSCLC), we performed a consistency meta-analysis study utilizing genome-wide association approaches for overall survival in 327 never smoker NSCLC patients from the MD Anderson Cancer Center and 293 cases from the Mayo Clinic. We then performed a two-pronged validation of the top 25 variants that included additional validation in 1,256 NSCLC patients from Taiwan and assessment of expression quantitative trait loci (eQTL) and differential expression of genes surrounding the top loci in 70 tumors and matched normal tissues. A total of 94 loci were significant for overall survival in both MD Anderson and Mayo studies in the consistency meta-analysis phase, with the top 25 variants reaching a p-value of 10−6. Two variants of these 25 were also significant in the Taiwanese population: rs6901416 (HR:1.44, 95%CI:1.01-2.06) and rs10766739 (HR:1.23, 95%CI:1.00-1.51). These loci resulted in a reduction in median survival time of at least 8 and 5 months in three populations, respectively. An additional six variants (rs4237904, rs7976914, rs4970833, rs954785, rs485411, and rs10906104) were validated through eQTL analysis that identified significant correlations with expression levels of six genes (LEMD3, TMBIM, ATXN7L2, SHE, ITIH2, and NUDT5, respectively) in normal lung tissue. These genes were also significantly differentially expressed between the tumor and normal lung. These findings identify several novel, candidate prognostic markers for NSCLC in never smokers, with eQTL analysis suggesting a potential biological mechanism for a subset of these observed associations.
doi:10.1158/0008-5472.CAN-12-4033
PMCID: PMC3719971  PMID: 23704207
2.  MicroRNA-Related Genetic Variants Associated with Clinical Outcomes in Early Stage Non-Small Cell Lung Cancer Patients 
Cancer research  2013;73(6):1867-1875.
Given the density of single nucleotide polymorphisms (SNPs) in the human genome and the sensitivity of single nucleotide changes in microRNA (miRNA) functionality and processing, we asked whether polymorphisms within miRNA processing pathways and binding sites may influence non-small cell lung cancer (NSCLC) patients’ prognosis. We genotyped 240 miRNA-related SNPs in 535 stage I and II NSCLC patients to determine associations with overall recurrence and survival, as well as effect in specific treatment subgroups. After correcting for multiple comparisons, the G allele of FZD4:rs713065 displayed a significant association with decreased risk of death in surgery-only patients (HR:0.46, 95%CI:0.32-0.65). DROSHA:rs6886834 variant A allele (HR:6.38, 95%CI:2.49-16.31) remained significant for increased risk of recurrence in the overall and surgery-only populations, respectively. FAS:rs2234978 G allele remained significantly associated with survival in all patients (HR:0.59, 95%CI:0.44-0.77), while borderline significant in subgroups (surgery only: HR:0.59, 95%CI:0.42-0.84; surgery plus chemo: HR:0.19, 95%CI:0.07-0.46). Luciferase assays demonstrated that the FAS SNP created a miR-651 functional binding site. Survival tree analysis was performed to classify patients into distinct risk subgroups based on their risk genotype combinations. These results indicate that miRNA-related polymorphisms may be associated with NSCLC patients’ clinical outcomes through altered miRNA regulation of target genes.
doi:10.1158/0008-5472.CAN-12-0873
PMCID: PMC3602350  PMID: 23378343
NSCLC; recurrence; overall survival; early stage; miRNA; binding site; single nucleotide polymorphism
3.  CXCR2 expression in tumor cells is a poor prognostic factor and promotes invasion and metastasis in lung adenocarcinoma 
Cancer research  2012;73(2):571-582.
CXCR2 in non-small cell lung cancer (NSCLC) has been studied mainly in stromal cells and is known to increase tumor inflammation and angiogenesis. Here, we examined the prognostic importance of CXCR2 in NSCLC and the role of CXCR2 and its ligands in lung cancer cells. The effect of CXCR2 expression on tumor cells was studied using stable knockdown clones derived from a murine KRAS/p53-mutant lung adenocarcinoma cell line with high metastatic potential and an orthotopic syngeneic mouse model and in vitro using a CXCR2 small molecule antagonist (SB225002). CXCR2 protein expression was analyzed in tumor cells from 262 NSCLC. Gene expression profiles for CXCR2 and its ligands (CXCR2 axis) were analyzed in 52 human NSCLC cell lines and 442 human lung adenocarcinomas. Methylation of CXCR2 axis promoters was determined in 70 human NSCLC cell lines. Invasion and metastasis were decreased in CXCR2 knockdown clones in vitro and in vivo. SB225002 decreased invasion in vitro. In lung adenocarcinomas, CXCR2 expression in tumor cells was associated with smoking and poor prognosis. CXCR2 axis gene expression profiles in human NSCLC cell lines and lung adenocarcinomas defined a cluster driven by CXCL5 and associated with smoking, poor prognosis and RAS pathway activation. Expression of CXCL5 was regulated by promoter methylation. The CXCR2 axis may be an important target in smoking-related lung adenocarcinoma.
doi:10.1158/0008-5472.CAN-12-0263
PMCID: PMC3548940  PMID: 23204236
lung cancer; prognosis; metastasis; CXCR2; chemokine
4.  Treatment with HIF-1α Antagonist PX-478 Inhibits Progression and Spread of Orthotopic Human Small Cell Lung Cancer and Lung Adenocarcinoma in Mice 
Introduction
PX-478 is a potent small-molecule inhibitor of HIF-1α. In preclinical studies, it had antitumor activity against various solid tumors in subcutaneous xenografts but had no measurable activity against a non-small cell lung cancer (NSCLC) xenograft. To determine the effectiveness of PX-478 against lung tumors, we investigated HIF-1α expression in several lung cancer cell lines, both in vitro and in vivo, and treated orthotopic mouse models of human lung cancer with PX-478.
Methods
Cells from two human lung adenocarcinoma cell models (PC14-PE6 and NCI-H441) or two human small cell lung cancer (SCLC) models (NCI-H187 and NCI-N417) were injected into the left lungs of nude mice and were randomized 16 to 18 days after injection with daily oral treatment with PX-478 or vehicle for 5 days.
Results
In the PC14-PE6 NSCLC model, treatment with 20 mg/kg PX-478 significantly reduced the median primary lung tumor volume by 87% (p = 0.005) compared with the vehicle-treated group. PX-478 treatment also markedly reduced mediastinal metastasis and prolonged survival. Similar results were obtained in a second NSCLC model. In SCLC models, PX-478 was even more effective. In the NCI-H187 model, the median primary lung tumor volume was reduced by 99% (p = 0.0001). The median survival duration was increased by 132%. In the NCI-N417 model, the median primary lung tumor volume was reduced by 97% (p = 0.008).
Conclusions
We demonstrated that the PX-478, HIF-1α inhibitor, had significant antitumor activity against two orthotopic models of lung adenocarcinomas and two models of SCLC. These results suggest the inclusion of lung cancer patients in phase I clinical trials of PX-478.
doi:10.1097/JTO.0b013e3181dc211f
PMCID: PMC3782111  PMID: 20512076
Hypoxia; HIF-1α; PX-478; Orthotopic model; Lung cancer
5.  Global evaluation of Eph receptors and ephrins in lung adenocarcinomas identifies EphA4 as an inhibitor of cell migration and invasion 
Molecular cancer therapeutics  2012;11(9):2021-2032.
The Eph family of receptors is the largest family of receptor tyrosine kinases, but it remains poorly studied in lung cancer. Our aim was to systematically explore the human Eph receptors and their ligands, the ephrins, in lung adenocarcinoma. The prognostic impact of Eph receptor and ephrin gene expression was analyzed using 2 independent cohorts of lung adenocarcinoma. Gene expression profiles in lung adenocarcinoma versus normal adjacent lung were studied in 3 independent cohorts and in cell lines. Gene expression profiles were validated with quantitative polymerase chain reaction (qPCR) and Western blotting in cell lines. Functional studies to assess the role of Eph receptor A4 (EphA4) were performed in vitro. The biological effects of EphA4 in lung cancer cell lines were assayed following overexpression and knockdown. Of the 11 Eph receptors and 8 ephrins analyzed, only EphA4 and ephrin A1 gene expression were consistently associated with an improved outcome in patients with lung adenocarcinoma. Expression levels of EphA4 by microarray correlated well with expression levels measured by qPCR and Western blotting. EphA4 overexpression reduced cell migration and invasion but did not affect cell cycle, apoptosis, or drug sensitivity. Surprisingly, EphA4 was expressed at higher levels in cancer versus non-cancer tissues and cell lines. EphA4 gene expression is associated with an improved outcome in patients with resected lung adenocarcinoma, likely by affecting cancer cell migration and invasion.
doi:10.1158/1535-7163.MCT-12-0030
PMCID: PMC3438283  PMID: 22807579
non-small cell lung cancer; adenocarcinoma; Eph receptor; ephrin; prognosis
6.  Systematic evaluation of apoptotic pathway gene polymorphisms and lung cancer risk 
Carcinogenesis  2012;33(9):1699-1706.
We adopted a two-stage study design to screen 927 single nucleotide polymorphisms (SNPs) located in 73 apoptotic-pathway genes in a case-control study and then performed a fast-track validation of the significant SNPs in a replication population to identify sequence variations in the apoptotic pathway modulating lung cancer risk. Fifty-five SNPs showed significant associations in the discovery population comprised of 661 lung cancer cases and 959 controls. Six of these SNPs located in three genes (Bcl-2, CASP9 and ANKS1B) were validated in a replication population with 1154 cases and 1373 controls. Additive model was the best-fitting model for five SNPs (rs1462129 and rs255102 of Bcl-2, rs6685648 of CASP9 and rs1549102, rs11110099 of ANKS1B) and recessive model was the best fit for one SNP (rs10745877 of ANKS1B). In the analysis of joint effects with subjects carrying no unfavorable genotypes as the reference group, those carrying one, two, and three or more unfavorable genotypes had an odds ratio (OR) of 2.22 [95% confidence interval (CI) = 1.08–4.57, P = 0.03], 2.70 (95% CI = 1.33–5.49; P = 0.006) and 4.13 (95% CI = 2.00–8.57; P = 0.0001), respectively (P for trend = 6.05E-06). The joint effect of unfavorable genotypes was also validated in the replication population. The SNPs identified are located in or near key genes known to play important roles in apoptosis regulation, supporting the strong biological relevance of our findings. Future studies are needed to identify the causal SNPs and elucidate the underlying molecular mechanisms.
doi:10.1093/carcin/bgs192
PMCID: PMC3514904  PMID: 22665367
7.  EGFR and K-Ras Mutations and Resistance of Lung Cancer to IGF-1R Tyrosine Kinase Inhibitors 
Cancer  2012;118(16):3993-4003.
Background
Most patients with non–small cell lung cancer (NSCLC) have responded poorly to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We investigated the involvement of insulin-like growth factor 1 receptor (IGF-1R) signaling in primary resistance to EGFR TKIs and the molecular determinants of resistance to IGF-1R TKIs.
Methods
Phosphorylated IGF-1R/insulin receptor (pIGF-1R/IR) was immunohistochemically evaluated in a NSCLC tissue microarray. We analyzed the antitumor effects of an IGF-1R TKI (PQIP or OSI-906), either alone or in combination with a small-molecular inhibitor (PD98059 or U0126) or with siRNA targeting K-Ras or MAPK/extracellular signal-regulated kinase kinase (MEK), in vitro and in vivo in NSCLC cells with variable histologic features and EGFR or K-Ras mutations.
Results
pIGF-1R/IR expression in NSCLC specimens was associated with a history of tobacco smoking, squamous cell carcinoma histology, mutant (mut) K-Ras, and wild-type (wt) EGFR, all of which have been strongly associated with poor response to EGFR TKIs. IGF-1R TKIs exhibited significant antitumor activity in NSCLC cells with wt EGFR and wt K-Ras but not in those with mutations in these genes. Introduction of mut K-Ras attenuated the effects of IGF-1R TKIs on NSCLC cells expressing wt K-Ras. Conversely, inactivation of MEK restored sensitivity to IGF-TKIs in cells carrying mut K-Ras.
Conclusions
The mutation status of both EGFR and K-Ras could be predictive markers of response to IGF-1R TKIs. Also, MEK antagonism can abrogate primary resistance of NSCLC cells to IGF-1R TKIs.
doi:10.1002/cncr.26656
PMCID: PMC3674414  PMID: 22359227
EGFR; K-Ras; IGF-1R; lung cancer; TKI
8.  Genetic variants in the PI3K/PTEN/AKT/MTOR pathway predict head and neck cancer patient second primary tumor/recurrence risk and response to retinoid chemoprevention 
Clinical Cancer Research  2012;18(13):3705-3713.
Purpose
The development of second primary tumors (SPT) or recurrence alters prognosis for curatively-treated head and neck squamous cell carcinoma (HNSCC) patients. 13-cis-retnoic acid (13-cRA) has been tested as a chemoprevention agent in clinical trials with mixed results. Therefore, we investigated if genetic variants in the PI3K/PTEN/AKT/MTOR pathway could serve as biomarkers to identify which patients are at high risk of an SPT/recurrence while also predicting response to 13-cRA chemoprevention.
Experimental Design
A total of 137 pathway SNPs were genotyped in 440 patients from the Retinoid Head and Neck Second Primary Trial and assessed for SPT/recurrence risk and response to 13-cRA. Risk models were created based on epidemiology, clinical, and genetic data.
Results
Twenty-two genetic loci were associated with increased SPT/recurrence risk with six also being associated with a significant benefit following chemoprevention. Combined analysis of these high-risk/high-benefit loci identified a significant (P = 1.54×10−4) dose-response relationship for SPT/recurrence risk, with patients carrying 4–5 high-risk genotypes having a 3.76-fold (95%CI:1.87–7.57) increase in risk in the placebo group (n=215). Patients carrying 4–5 high-risk loci showed the most benefit from 13-cRA chemoprevention with a 73% reduction in SPT/recurrence (95%CI:0.13–0.58) compared to those with the same number of high-risk genotypes who were randomized to receive placebo. Incorporation of these loci into a risk model significantly improved the discriminatory ability over models with epidemiology, clinical, and previously identified genetic variables.
Conclusions
These results demonstrate that loci within this important pathway could identify individuals with a high-risk/high-benefit profile and are a step towards personalized chemoprevention for HNSCC patients.
doi:10.1158/1078-0432.CCR-11-3271
PMCID: PMC3404728  PMID: 22577058
9.  Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers: The Selenium and Vitamin E Cancer Prevention Trial (SELECT) 
Context
Secondary analyses of two randomized controlled trials (RCTs) and supportive epidemiologic and preclinical indicated the potential of selenium and vitamin E for preventing prostate cancer.
Objective
To determine whether selenium or vitamin E or both could prevent prostate cancer with little or no toxicity in relatively healthy men.
Design, Setting, and Participants
Randomization of a planned 32,400 men to selenium, vitamin E, selenium plus vitamin E, and placebo in a double-blinded fashion. Participants were recruited and followed in community practices, local hospitals and HMOs, and tertiary cancer centers in the United States, Canada and Puerto Rico. Baseline eligibility included 50 years or older (African American) or 55 years or older (all others), a serum prostate-specific antigen (PSA) ≤ 4 ng/mL, and a digital rectal examination (DRE) not suspicious for prostate cancer. Between 2001 and 2004, 35,533 men (10% more than planned because of a faster-than-expected accrual rate) were randomly assigned to the four study arms, which were well balanced with respect to all potentially important risk factors.
Interventions
Oral selenium (200 µg/day from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/day of all rac-α-tocopheryl acetate) and matched selenium placebo, or the two combined or placebo plus placebo for a planned minimum of 7 and maximum of 12 years.
Main Outcome Measures
Prostate cancer (as determined by routine community diagnostic standards) and prespecified secondary outcomes including lung, colorectal and overall cancer.
Results
Study supplements were discontinued at the recommendation of the Data and Safety Monitoring Committee at a planned 7-year interim analysis because the evidence convincingly demonstrated no benefit from either study agent (p < 0.0001) and no possibility of a benefit to the planned degree with additional follow-up. As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17 and 7.33). Hazard ratios (number of prostate cancers, 99% confidence intervals [CIs]) for prostate cancer were 1.13 for vitamin E (n=473; CI, 0.91–1.41), 1.04 for selenium (n=432; CI, 0.83–1.30), and 1.05 for the combination (n=437; CI, 0.83–1.31) compared with placebo (n=416). There were no significant differences (all p-values > 0.15) in any prespecified cancer endpoints. There were nonsignificant increased risks of prostate cancer in the vitamin E arm (p=0.06; relative risk [RR]=1.13; 99% CI, 0l95–1.35) and of Type 2 diabetes mellitus in the selenium arm (p=0.16; RR=1.07; 99% CI, 0.94–1.22), but they were not observed in the combination arm.
Conclusion
Selenium or vitamin E, alone or in combination, did not prevent prostate cancer in this population at the doses and formulations used.
doi:10.1001/jama.2008.864
PMCID: PMC3682779  PMID: 19066370
10.  Prognostic impact of Insulin Receptor Expression on Survival of Patients with Nonf-Small Cell Lung Cancer 
Cancer  2011;118(9):2454-2465.
Background
The purpose of this study was to characterize insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) expression in patients with non-small cell lung cancer (NSCLC).
Methods
A total of 459 patients who underwent curative resection of NSCLC were studied (median follow-up duration, 4.01 years). Expression of the IR and IGF-1R protein in tumor specimens was assessed immunohistochemically using tissue microarrays.
Results
The cytoplasmic IR score was higher in patients with adenocarcinoma (ADC) than in those with squamous cell carcinoma (SCC) whereas cytoplasmic IGF-1R score was higher in patients with SCC than those with ADC. Neither IR nor IGF-1R expression was associated with sex, smoking history, or clinical stage. Patients with positive IR or IGF-1R expression levels had poor recurrence-free (RFS) (3.8 vs. 3.3 years; 3.8 vs. 2.0 years, respectively), but similar overall survival (OS). Patients with high expression levels of IR and IGF-1R had shorter RFS and OS compared to those with low levels of IR and/or IGF-1R expression. Finally, a multivariate analysis revealed the impact of IR, but not of IGF-1R, as an independent predictive marker of NSCLC survival: hazard ratio (HR) for OS, 1.005 (95% confidence interval [CI], 1.001 – 1.010], HR for RFS, 1.005 (95% CI, 1.001 – 1.009), when IR score was tested as a continuous variable.
Conclusions
Overexpression of IR predicts a poor survival among patients with NSCLC, especially those with SCC. These results might serve as future guidance to the clinical trials involving IR or IGR-1R targeting agents.
doi:10.1002/cncr.26492
PMCID: PMC3298843  PMID: 21952750
Carcinoma; Non-Small-Cell Lung; Receptor; Insulin; Receptor; IGF Type 1; Prognosis; Survival
12.  Effect of KRAS Oncogene Substitutions on Protein Behavior: Implications for Signaling and Clinical Outcome 
Background
Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in cancer cell growth and resistance to therapy. Most mutations occur at codons 12 and 13. In colorectal cancer, the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy. However, in non–small cell lung cancer (NSCLC), the evidence that KRAS mutation is a predictive factor is conflicting.
Methods
We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and tumor gene expression. Transcriptome microarray studies of patient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation. Molecular modeling was used to study the conformations of wild-type and mutant KRas proteins. Kaplan–Meier curves and Cox regression were used to analyze survival data. All statistical tests were two-sided.
Results
Patients whose tumors had either mutant KRas-Gly12Cys or mutant KRas-Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas (P = .046, median survival = 1.84 months) compared with all other mutant KRas (median survival = 3.35 months) or wild-type KRas (median survival = 1.95 months). NSCLC cell lines with mutant KRas-Gly12Asp had activated phosphatidylinositol 3-kinase (PI-3-K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling, whereas those with mutant KRas-Gly12Cys or mutant KRas-Gly12Val had activated Ral signaling and decreased growth factor–dependent Akt activation. Molecular modeling studies showed that different conformations imposed by mutant KRas may lead to altered association with downstream signaling transducers.
Conclusions
Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.
doi:10.1093/jnci/djr523
PMCID: PMC3274509  PMID: 22247021
13.  Common genetic variants in cell cycle pathway are associated with survival in stage III–IV non-small-cell lung cancer 
Carcinogenesis  2011;32(12):1867-1871.
Cell cycle progression contributes to the cellular response to DNA-damaging factors, such as chemotherapy and radiation. We hypothesized that the genetic variations in cell cycle pathway genes may modulate treatment responses and affect survival in patients with advanced non-small-cell lung cancer (NSCLC). We genotyped 374 single-nucleotide polymorphisms (SNPs) from 49 cell cycle-related genes in 598 patients with stages III–IV NSCLC treated with first-line platinum-based chemotherapy with/without radiation. We analyzed the individual and combined associations of these SNPs with survival and evaluated their gene–gene interactions using survival tree analysis. In the analysis of survival in all the patients, 39 SNPs reached nominal significance (P < 0.05) and 4 SNPs were significant at P <0.01. However, none of these SNPs remained significant after correction for multiple comparisons at a false discovery rate of 10%. In stratified analysis by treatment modality, after adjusting for multiple comparisons, nine SNPs in chemotherapy alone and one SNP in chemoradiation remained significant. The most significant SNP in chemotherapy group was CCNB2:rs1486878 [hazard ratio (HR) = 1.69, 95% confidence interval (CI), 1.25–2.30, P = 0.001]. TP73: rs3765701 was the only significant SNP in chemoradiation group (HR = 1.87; 95% CI = 1.35–2.59, P = 1.8 × 10−4). In cumulative analysis, we found a significant gene-dosage effect in patients receiving chemotherapy alone. Survival tree analysis demonstrated potential higher order gene–gene and gene–treatment interactions, which could be used to predict survival status based on distinct genetic signatures. These results suggest that genetic variations in cell cycle pathway genes may affect the survival of patients with stages III–IV NSCLC individually and jointly.
doi:10.1093/carcin/bgr217
PMCID: PMC3220611  PMID: 21965272
14.  Akt/mammalian target of rapamycin counteract the antitumor activities of cixutumumab an anti-insulin-like growth factor I receptor monoclonal antibody 
Molecular cancer therapeutics  2011;10(12):2437-2448.
Recent reports have shown limited anticancer therapeutic efficacy of insulin-like growth factor receptor (IGF-1R)-targeted monoclonal antibodies (mAbs), but the resistance mechanisms have not been completely identified. Because cooperation between epidermal growth factor receptor (EGFR) and IGF-IR could cause resistance to inhibitors of individual RTKs, we investigated the involvement of EGFR signaling in resistance to IGF-1R mAb and the underlying mechanisms of action. Most head and neck squamous cell carcinoma (HNSCC) tissues had co-expression of total and phosphorylated IGF-1R and EGFR at high levels compared to paired adjacent normal tissues. Treatment with cixutumumab (IMC-A12), a fully humanized IgG1 mAb, induced activation of Akt and mammalian target of rapamycin (mTOR), resulting in de novo synthesis of EGFR, Akt1, and survivin proteins and activation of the EGFR pathway in cixutumumab-resistant HNSCC and non-small cell lung cancer (NSCLC) cells. Targeting mTOR and EGFR pathways by treatment with rapamycin and cetuximab (an anti-EGFR mAb), respectively, prevented cixutumumab-induced expression of EGFR, Akt, and survivin and induced synergistic antitumor effects in vitro and in vivo. These data show that resistance to IGF-1R inhibition by mAbs is associated with Akt/mTOR-directed enhanced synthesis of EGFR, Akt1, and survivin. Our findings suggest that Akt/mTOR might be effective targets to overcome the resistance to IGF-1R mAbs in HNSCC and NSCLC.
doi:10.1158/1535-7163.MCT-11-0235
PMCID: PMC3237768  PMID: 21980128
EGFR; IGF-IR; head and neck squamous cell carcinoma; survivin; cixutumumab
15.  Phase III Trial of Selenium to Prevent Prostate Cancer in Men with High-Grade Prostatic Intraepithelial Neoplasia: SWOG S9917 
The threat of prostate cancer (PC) and the significant and often negative impact of its treatment underscore the importance of prevention. High-grade prostatic intraepithelial neoplasia (HGPIN) has been identified as a potential premalignant lesion marking an increased risk of PC, and substantial evidence suggests that men with HGPIN are in need of PC prevention. In vitro, in vivo, epidemiologic, and clinical trial evidence that selenium supplementation protects against PC motivated the study we report here: A double-blind, randomized, placebo-controlled trial of selenium 200 (mcg/day) as selenomethionine in men with HGPIN. The primary endpoint was progression of HGPIN to PC over a three-year period. This NCI Intergroup trial was coordinated by the Southwest Oncology Group (SWOG). Of 619 enrolled patients, 423 randomized men with HGPIN (212, selenium; 211, placebo) were eligible (by central pathology review) and included in the primary analysis. Three-year cancer rates were 36.6% (placebo) versus 35.6% (selenium; P = 0.73, adjusted). The majority of patients who developed cancer on trial (70.8%, selenium, and 75.5%, placebo) had a Gleason score of ≤ 6; there were no differences in Gleason scores between the two arms. Subset analyses included the finding of a nonsignificantly reduced PC risk (relative risk = 0.82; 95% confidence interval, 0.40–1.69) in selenium versus placebo patients in the lowest quartile of baseline plasma selenium level (< 106 ng/ml). Overall, and in all other subsets defined by baseline blood selenium levels, selenium supplementation had no effect on PC risk. The 36% PC rate in men with HGPIN indicates the association of this lesion with an elevated PC risk. Future study in this setting should focus on selenium-deficient populations and selenium pharmacogenetics.
doi:10.1158/1940-6207.CAPR-10-0343
PMCID: PMC3208719  PMID: 21896650
Chemoprevention; selenium; prostate cancer; intraepithelial neoplasia; prevention; clinical trials
16.  Repeat polymorphisms in estrogen metabolism genes and prostate cancer risk: results from the Prostate Cancer Prevention Trial 
Carcinogenesis  2011;32(10):1500-1506.
The etiology of prostate cancer remains elusive, although steroid hormones probably play a role. Considering the carcinogenic potential of estrogen metabolites as well as altered intraprostatic estrogen biosynthesis during the development of prostate cancer, we investigated associations between repeat polymorphisms of three key estrogen-related genes (CYP11A1, CYP19A1, UGT1A1) and risk of prostate cancer in the Prostate Cancer Prevention Trial (PCPT), designed to test finasteride versus placebo as a chemoprevention agent. Using data and specimens from 1154 cases and 1351 controls who were frequency matched on age, family history of prostate cancer and PCPT treatment arm, we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) separately in the placebo and finasteride arms. Among men in the placebo arm, CYP19A1 7/8 genotype carriers had a significantly higher risk of prostate cancer compared with those with the 7/7 genotype (OR = 1.70, 95% CI = 1.16–2.5), regardless of Gleason grade. This genotype was also associated with elevated serum estrogen levels. For the (TA)n repeat polymorphism in UGT1A1, the heterozygous short (<7 repeats)/long (≥7 repeats) genotype was significantly associated with the risk of low-grade prostate cancer (OR = 1.34, 95% CI = 1.05–1.70) compared with the short/short genotype. No significant association was found with CYP11A1. These associations were not observed among men in the finasteride arm. The results indicate that repeat polymorphisms in genes involved in estrogen biosynthesis and metabolism may influence risk of prostate cancer but that their effects may be modified by factors altering hormone metabolism, such as finasteride treatment.
doi:10.1093/carcin/bgr139
PMCID: PMC3179424  PMID: 21771722
17.  Genetic variations in the transforming growth factor-beta pathway as predictors of survival in advanced non-small cell lung cancer 
Carcinogenesis  2011;32(7):1050-1056.
The magnitude of benefit is variable for advanced non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy. The purpose of this study is to determine whether genetic variations in the transforming growth factor-beta (TGF-β) pathway are associated with clinical outcomes in NSCLC patients receiving first-line platinum-based chemotherapy. Five hundred and ninety-eight advanced-stage NSCLC patients who received first-line platinum-based chemotherapy with or without radiotherapy were recruited at the MD Anderson Cancer Center between 1995 and 2007. DNA from blood was genotyped for 227 single nucleotide polymorphisms (SNPs) in 23 TGF-β pathway-related genes to evaluate their associations with overall survival. In individual SNP analysis, 22 variants were significantly associated with overall survival, of which the strongest associations were found for BMP2:rs235756 [hazard ratio (HR) = 1.45; 95% confidence interval (CI), 1.11–1.90] and SMAD3:rs4776342 (HR = 1.25; 95% CI, 1.06–1.47). Fifteen and 18 genetic loci displayed treatment-specific associations for chemotherapy and chemoradiation, respectively, identifying a majority of the cases who would be predicted to respond favorably to a specific treatment regimen. BMP2:rs235753 and a haplotype in SMAD3 were associated with overall survival for both treatment modalities. Cumulative effect analysis showed that multiple risk genotypes had a significant dose-dependent effect on overall survival (Ptrend = 2.44 x 10−15). Survival tree analysis identified subgroups of patients with dramatically different median survival times of 45.39 versus 13.55 months and 18.02 versus 5.89 months for high- and low- risk populations when treated with chemoradiation and chemotherapy, respectively. These results suggest that genetic variations in the TGF-β pathway are potential predictors of overall survival in NSCLC patients treated with platinum-based chemotherapy with or without radiation.
doi:10.1093/carcin/bgr067
PMCID: PMC3128559  PMID: 21515830
18.  Genome-Wide Association Study of Survival in Non–Small Cell Lung Cancer Patients Receiving Platinum-Based Chemotherapy 
Background
Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non–small cell lung cancer (NSCLC).
Methods
To identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307 260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided.
Results
SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10−6), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10−7). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10−6) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35).
Conclusion
These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients.
doi:10.1093/jnci/djr075
PMCID: PMC3096796  PMID: 21483023
19.  Novel Chromosomal Rearrangements and breakpoints at the t(6;9) in Salivary Adenoid Cystic Carcinoma: association with MYB-NFIB chimeric fusion, MYB expression, and clinical outcome 
Objective
To investigate the molecular-genetic heterogeneity associated with the t(6:9) in adenoid cystic carcinoma (ACC) and correlate the findings with patient clinical outcome.
Experimental Design
Multi-molecular and genetic techniques complemented with massive pair-ended sequencing and SNP array analyses were used on tumor specimens from 30 new and 52 previously RT-PCR analyzed fusion transcript negative ACCs. MYB mRNA expression level was determined by quantitative RT-PCR. The results of 102 tumors (30 new and 72 previously reported cases) were correlated with the clinicopathologic factors and patients’ survival.
Results
The FISH analysis showed 34/82 (41.5%) fusion positive tumors and molecular techniques identified fusion transcripts in 21 of the 82 (25.6%) tumors. Detailed FISH analysis of 11 out the 15 tumors with gene fusion without transcript formation showed translocation of NFIB sequences to proximal or distal sites of the MYB gene. Massive pair-end sequencing of a subset of tumors confirmed the proximal translocation to an NFIB sequence and led to the identification of a new fusion gene (NFIB-AIG1) in one of the tumors. Overall, MYB-NFIB gene fusion rate by FISH was in 52.9% while fusion transcript forming incidence was 38.2%. Significant statistical association between the 5′ MYB transcript expression and patient survival was found.
Conclusions
We conclude that: 1) t(6;9) results in a complex genetic and molecular alterations in ACC, 2) MYB-NFIB gene fusion may not always be associated with chimeric transcript formation, 3) non-canonical MYB, NFIB gene fusions occur in a subset of tumors, 4) high MYB expression correlates with worse patient survival.
doi:10.1158/1078-0432.CCR-11-1870
PMCID: PMC3225955  PMID: 21976542
Gene fusion; Gene fusion; chromosomal translocations; salivary gland carcinomas; molecular alterations
20.  Does the level of prostate cancer risk affect cancer prevention with finasteride? 
Urology  2008;71(5):854-857.
Objectives
Finasteride reduced the risk of prostate cancer by 24.8% in the Prostate Cancer Prevention Trial; whether this represents treatment or prevention and who is most likely to benefit are unknown. We sought to clarify these issues by this investigation.
Methods
We fit a logistic regression model to men in the placebo group of the PCPT using risk factors for prostate cancer at entry to predict prostate cancer during the subsequent 7 years of study. Men in the two treatment groups were categorized into quintiles of risk of prostate cancer based on the predictive logistic model. A second model was fit evaluating finasteride’s effect on prostate cancer for each subgroup defined by quartiles of baseline PSA. The magnitude of the prevention effect of finasteride on prostate cancer was then evaluated across risk and PSA strata.
Results
Finasteride significantly reduced prostate cancer risk for all risk quintiles. For quintiles 1 through 5, odds ratios were 0.72, 0.52, 0.64, 0.66, and 0.71, respectively (all p≤0.05). For quartiles of risk of entry PSA (< 0.7 ng/mL, 0.7–1.1 ng/mL, 1.1–1.7 ng/mL, and 1.8–3.0 ng/mL), odds ratios increased (smaller treatment effect) as PSA increased: 0.60, 0.62, 0.66, and 0.69 respectively, but remained significant for all strata (each p<0.001).
Conclusions
Finasteride significantly reduced prostate cancer risk, regardless of the level of this risk, estimated either by multivariable risk or by PSA stratum; this suggests that finasteride exerts both treatment and preventive effects. All men undergoing PSA screening should be informed of the potential for finasteride to reduce their risk of prostate cancer.
doi:10.1016/j.urology.2008.01.025
PMCID: PMC2692669  PMID: 18455628
Prostate neoplasms; prostate specific antigen; risk; finasteride; prevention
21.  RANDOMIZED PHASE II TRIAL OF INHALED BUDESONIDE VERSUS PLACEBO IN HIGH-RISK INDIVIDUALS WITH CT SCREEN-DETECTED LUNG NODULES 
Background
Screening-CT identifies small peripheral lung nodules, some of which may be pre- or early invasive neoplasia. Secondary endpoint analysis of a previous chemoprevention trial in individuals with bronchial dysplasia showed reduction in size of peripheral nodules by inhaled budesonide.
Methods
We performed a randomized, double-blind, placebo-controlled phase IIb trial of inhaled budesonide in current and former smokers with CT-detected lung nodules that were persistent for at least one year. A total of 202 individuals received inhaled budesonide 800 µg twice daily or placebo for one year. The primary endpoint was the effect of treatment on target nodule size in a per-person analysis after one year.
Results
The per-person analysis showed no significant difference between the budesonide and placebo arms (response rate 2% and 1%, respectively). Although the per-lesion analysis revealed a significant effect of budesonide on regression of existing target nodules (p=0.02), the appearance of new lesions was similar in both groups and thus the significance was lost in the analysis of all lesions. The evaluation by nodule type revealed a non-significant trend toward regression of non-solid and partially solid lesions after budesonide treatment. Budesonide was well tolerated with no unexpected side effects identified.
Conclusions
Treatment with inhaled budesonide for one year did not significantly affect peripheral lung nodule size. There was a trend toward regression of non-solid and partially solid nodules after budesonide treatment. Since a subset of these nodules is more likely to represent precursors of adenocarcinoma, additional follow-up is needed. (ClinicalTrials.gov number, NCT00321893)
doi:10.1158/1940-6207.CAPR-10-0182
PMCID: PMC3017323  PMID: 21163939
chemoprevention; lung cancer; helical CT; budesonide
22.  Transition of a Clinical Trial into Translational Research: The Prostate Cancer Prevention Trial Experience 
The Prostate Cancer Prevention Trial (PCPT) was a phase III randomized, double-blind, placebo-controlled clinical trial of finasteride in 18,882 men. Clinical data, blood and tissue specimens were collected at baseline and throughout the study which offered an opportunity to investigate hypotheses related to the biology underlying the PCPT findings as well as the etiology and risk of prostate cancer. Five individual but inter-related projects were brought together under an overall program project with the underlying theme of the genetic, metabolic and environmental factors associated with the risks of prostate cancer overall and high grade prostate cancer and the effects of these factors on the efficacy of finasteride as a cancer preventive agent. All projects with serum-based measures use a single shared nested case-control sample of participants so that each subject provides a more complete biomarker and genetic profile for the evaluation of joint effects of these factors. There are a number of strengths of this project including (1) the control group contains only men who are negative for biopsy-detected cancer (2) the statistical methods to evaluate associations of risk factors with disease are shared across all projects (3) the large number of cancer cases with fully characterized genetic, metabolic and behavioral exposures (4) a central pathology core histopathologically classified the prostate cancer, and (5) the cases identified during the PCPT reflect the characteristics of the current cases that are being detected in the PSA screening era making the results contemporary and highly relevant.
doi:10.1158/1940-6207.CAPR-09-0256
PMCID: PMC3058741  PMID: 21149329
23.  MicroRNA-related genetic variations as predictors for risk of second primary tumor and/or recurrence in patients with early-stage head and neck cancer 
Carcinogenesis  2010;31(12):2118-2123.
Second primary tumor (SPT) and/or recurrence negatively impact the prognosis of patients with curatively treated early-stage head and neck cancer. MicroRNAs (miRNAs) play important roles in cancer development. We explored whether the variations of miRNA-related pathway were associated with the risk of SPT/recurrence in patients with early-stage head and neck cancer. This study includes 150 early-stage head and neck cancer patients with SPT/recurrence and 300 patients without SPT/recurrence. Two hundred and thirty-five tagging and potentially functional single-nucleotide polymorphisms (SNPs) were genotyped from eight miRNA biogenesis pathway genes and 135 miRNA-targeted genes. Eighteen miRNA-related SNPs were significantly associated with the risk of SPT/recurrence. The most significant SNP was rs3747238, a miRNA-binding site SNP in SMC1B. The variant homozygous genotype of this SNP was associated with a 1.74-fold increased risk [95% confidence interval (CI) 1.19–2.54; P = 0.004]. Cumulative effect analysis showed joint effects for the number of unfavorable genotype in patients. Survival tree analysis further identified the high-order gene–gene interactions and categorized the study subjects into low-, medium- and high-risk groups. Patients in the high-risk group had a 4.84-fold increased risk (95% CI: 3.11–7.51; P = 2.45 × 10−12) and a shorter event-free median survival time of 37.9 months (log rank P = 2.28 × 10−13). Our results suggested that miRNA-related genetic polymorphisms may be used individually and jointly to predict the risk of SPT/recurrence of early-stage head and neck cancer patients.
doi:10.1093/carcin/bgq177
PMCID: PMC3105587  PMID: 20819778
24.  BUDESONIDE VERSUS PLACEBO IN HIGH-RISK POPULATION WITH SCREEN-DETECTED LUNG NODULES: RATIONALE, DESIGN AND METHODOLOGY 
Contemporary clinical trials  2010;31(6):612-619.
Background
Screening-CT is able to discover small peripheral lung nodules. The nature of these nodules is uncertain but it is reasonable that some of them, in particular the non solid ones, could represent precancerous lesions. A previous trial showed a reduction in size of peripheral nodules by inhaled budesonide in subjects with bronchial dysplasia.
Objective
The primary objective of the study was the evaluation of the effect of Budesonide as a chemopreventive agent for lung lesions. The primary endpoint was the modification of lung lesions at ld-CT scan (according to RECIST criteria) after one year of treatment in a person-specific analysis.
Methods
We performed a randomized, double-blind, placebo controlled trial to evaluate whether inhaled budesonide was able to reduce size and number of persistent, undetermined CT-detected lung nodules in high-risk asymptomatic subjects currently undergoing a five-year CT scan screening program at the European Institute of Oncology.
Results
Trial enrollment started in April 2006 and ended in July 2007 with the randomization of 202 current or former smokers with stable CT detected lung nodules set to receive budesonide 800µg or placebo twice-daily for 12 months.
Conclusion
Our trial represents the first phase II study of a chemopreventive intervention focusing on the peripheral lung, where the majority of lung cancers arise. The research was nested into a screening project with clear advantages in participant accrual and reduction of costs. This paper describes the rationale and design of the study, thus focusing on the methodology and operational aspects of the clinical trial. (Clinicaltrials.gov number. NCT00321893)
doi:10.1016/j.cct.2010.08.006
PMCID: PMC2962433  PMID: 20719253
budesonide; lung cancer; chemoprevention; low dose CT scan; screening
25.  Phase II Study of Dasatinib in Patients With Advanced Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2010;28(30):4609-4615.
Purpose
Src family kinases (SFKs) promote cancer progression and are commonly expressed in non–small-cell lung cancer (NSCLC), but the clinical effects of SFK inhibition in NSCLC are unknown. We conducted a phase II trial of the SFK inhibitor dasatinib for advanced NSCLC. We tested the hypotheses that the activation of epidermal growth factor receptor (EGFR) or SFK or modulation of serum cytokines may predict a response to dasatinib.
Patients and Methods
Patients received dasatinib as first-line therapy. Response was measured by tumor size on computed tomography scans and by metabolic activity on positron emission tomography scans. Tissue samples taken before patients received dasatinib were tested for EGFR and Kras mutation and phosphorylated SFK expression.
Results
Thirty-four patients were enrolled. The overall disease control rate (partial responses plus stable disease) for dasatinib was 43%. One patient had a partial response to therapy. Eleven patients (32%) had a metabolic response to dasatinib. SFK activation and EGFR and Kras mutations in tumor tissue did not predict response to dasatinib. Significant toxicities included fatigue and dyspnea. The presence of a pleural effusion before dasatanib therapy predicted the development of a clinically significant effusion during therapy.
Conclusion
Dasatinib as a single agent had modest clinical activity that was lower than that generally observed in patients with NSCLC who receive chemotherapy. Pleural effusion was an expected and problematic toxicity that was successfully treated with steroids, diuretics, and dose interruptions. Marked activity in one patient and prolonged stable disease in four others suggested a potential subpopulation of patients with dasatinib-sensitive NSCLC.
doi:10.1200/JCO.2010.30.5474
PMCID: PMC2974341  PMID: 20855820

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