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3.  Dose Escalation with Overdose Control using a Quasi-Continuous Toxicity Score in Cancer Phase I Clinical Trials 
Contemporary clinical trials  2012;33(5):949-958.
SUMMARY
Escalation with overdose control (EWOC) is a Bayesian adaptive design for selecting dose levels in cancer Phase I clinical trials while controlling the posterior probability of exceeding the maximum tolerated dose (MTD). EWOC has been used by clinicians to design many cancer Phase I clinical trials, see e.g [1-4]. However, this design treats the toxicity response as a binary indicator of dose limiting toxicity (DLT) and does not account for the number and specific grades of toxicities experienced by patients during the trial. Chen et al. (2010) proposed a novel toxicity score system to fully utilize all toxicity information using a normalized equivalent toxicity score (NETS). In this paper, we propose to incorporate NETS into EWOC using a quasi-Bernoulli likelihood approach to design cancer Phase I clinical trials. We call the design escalation with overdose control using normalized equivalent toxicity score (EWOC-NETS). Simulation results show that this design has good operating characteristics and improves the accuracy of MTD, trial efficiency, therapeutic effect, and overdose control relative to EWOC which is used as a representative of designs treating toxicity response as a binary indicator of DLT. We illustrate the performance of this design using real trial data in identifying the Phase II dose.
doi:10.1016/j.cct.2012.04.007
PMCID: PMC4046335  PMID: 22561391
Escalation with Overdose Control; Maximum Tolerated Dose; Multiple Toxicities; Quasi-continuous; Normalized Equivalent Toxicity Score; Toxicity Score System
4.  Prognostic impact of Fas-associated death domain, a key component in death receptor signaling, is dependent on the presence of lymph node metastasis in head and neck squamous cell carcinoma 
Cancer Biology & Therapy  2013;14(4):365-369.
FAS-associated death domain (FADD) is a key adaptor protein that bridges a death receptor (e.g., death receptor 5; DR5) to caspase-8 to form the death-inducing signaling complex during apoptosis. The expression and prognostic impact of FADD in head and neck squamous cell carcinoma (HNSCC) have not been well studied. This study focuses on detecting FADD expression and analyzing its prognostic impact in primary and metastatic HNSCCs. We found a significant increase in FADD expression in primary tumors with lymph node metastasis (LNM) in comparison with primary tumors with no LNM. This increase was significantly less in the matched LNM tissues. Both univariate and multivariable analyses indicated that lower FADD expression was significantly associated with better disease-free survival and overall survival in HNSCC patients with LNM although FADD expression did not significantly affect survival of HNSCC patients without LNM . When combined with DR5 or caspase-8 expression, patients with LNM expressing both low FADD and DR5 or both low FADD and caspase-8 had significantly better prognosis than those expressing both high FADD and DR5 or both high FADD and caspase-8. However, the expression of both low FADD and caspase-8 was significantly linked to worse overall survival compared with both high FADD and caspase-8 expression in HNSCC patients without LNM. Hence, we suggest that FADD alone or together with DR5 and caspase-8 participates in metastatic process of HNSCC.
doi:10.4161/cbt.23636
PMCID: PMC3667877  PMID: 23358467
FADD; caspase-8; death receptor 5; head and neck cancer; immunohistochemistry
5.  Escalation with Overdose Control Using Time to Toxicity for Cancer Phase I Clinical Trials 
PLoS ONE  2014;9(3):e93070.
Escalation with overdose control (EWOC) is a Bayesian adaptive phase I clinical trial design that produces consistent sequences of doses while controlling the probability that patients are overdosed. However, this design does not take explicitly into account the time it takes for a patient to exhibit dose limiting toxicity (DLT) since the occurrence of DLT is ascertained within a predetermined window of time. Models to estimate the Maximum Tolerated Dose (MTD) that use the exact time when the DLT occurs are expected to be more precise than those where the variable of interest is categorized as presence or absence of DLT, given that information is lost in the process of categorization of the variable. We develop a class of parametric models for time to toxicity data in order to estimate the MTD efficiently, and present extensive simulations showing that the method has good design operating characteristics relative to the original EWOC and a version of time to event EWOC (TITE-EWOC) which allocates weights to account for the time it takes for a patient to exhibit DLT. The methodology is exemplified by a cancer phase I clinical trial we designed in order to estimate the MTD of Veliparib (ABT-888) in combination with fixed doses of gemcitabine and intensity modulated radiation therapy in patients with locally advanced, un-resectable pancreatic cancer.
doi:10.1371/journal.pone.0093070
PMCID: PMC3963973  PMID: 24663812
6.  Receiver operating characteristic curve analysis of circulating blood dendritic cell precursors and T cells predicts response to extracorporeal photopheresis in patients with chronic graft-versus-host disease 
Transfusion  2010;50(11):2424-2431.
BACKGROUND
One proposed mechanism of extracorporeal photopheresis (ECP) in reducing chronic graft-versus-host disease (cGVHD) is alteration in numbers of circulating dendritic cells (DCs). This hypothesis was tested by correlating numbers of DC precursors and T cells in the blood before and during ECP therapy with response of cGVHD.
STUDY DESIGN AND METHODS
Twenty-five patients with cGVHD were treated with ECP. Data were collected with emphasis on blood cellular markers, clinical response to ECP, and overall survival.
RESULTS
Fourteen patients (56%) responded and had better 2-year survival than nonresponders (88% vs. 18%, p = 0.003). Responders had higher baseline circulating myeloid DC (mDC) and plasmacytoid DC precursors and CD4+ and CD8+ T cells compared with nonresponders. Receiver operating characteristic curve analyses showed that the best baseline cutoff values to predict response to ECP were mDC counts of 3.7 cells/µL (79% sensitivity, 82% specificity) and CD4+ T-cell counts of 104 cells/µL (71% sensitivity, 82% specificity). CD4+ T cells declined in responders over time, but not in nonresponders, and no significant changes were seen in CD8 T-cell or DC numbers over a 12-month period in responder or nonresponder groups.
CONCLUSIONS
Higher baseline numbers of circulating DCs and T cells may predict clinical response to ECP in patients with cGVHD.
doi:10.1111/j.1537-2995.2010.02712.x
PMCID: PMC3926317  PMID: 20529004
7.  Detection of Live Circulating Tumor Cells by a Class of Near-Infrared Heptamethine Carbocyanine Dyes in Patients with Localized and Metastatic Prostate Cancer 
PLoS ONE  2014;9(2):e88967.
Tumor cells are inherently heterogeneous and often exhibit diminished adhesion, resulting in the shedding of tumor cells into the circulation to form circulating tumor cells (CTCs). A fraction of these are live CTCs with potential of metastatic colonization whereas others are at various stages of apoptosis making them likely to be less relevant to understanding the disease. Isolation and characterization of live CTCs may augment information yielded by standard enumeration to help physicians to more accurately establish diagnosis, choose therapy, monitor response, and provide prognosis. We previously reported on a group of near-infrared (NIR) heptamethine carbocyanine dyes that are specifically and actively transported into live cancer cells. In this study, this viable tumor cell-specific behavior was utilized to detect live CTCs in prostate cancer patients. Peripheral blood mononuclear cells (PBMCs) from 40 patients with localized prostate cancer together with 5 patients with metastatic disease were stained with IR-783, the prototype heptamethine cyanine dye. Stained cells were subjected to flow cytometric analysis to identify live (NIR+) CTCs from the pool of total CTCs, which were identified by EpCAM staining. In patients with localized tumor, live CTC counts corresponded with total CTC numbers. Higher live CTC counts were seen in patients with larger tumors and those with more aggressive pathologic features including positive margins and/or lymph node invasion. Even higher CTC numbers (live and total) were detected in patients with metastatic disease. Live CTC counts declined when patients were receiving effective treatments, and conversely the counts tended to rise at the time of disease progression. Our study demonstrates the feasibility of applying of this staining technique to identify live CTCs, creating an opportunity for further molecular interrogation of a more biologically relevant CTC population.
doi:10.1371/journal.pone.0088967
PMCID: PMC3925210  PMID: 24551200
8.  A Folate Receptor-Targeting Nanoparticle Minimizes Drug Resistance in a Human Cancer Model 
ACS nano  2011;5(8):6184-6194.
Resistance to chemotherapy is a major obstacle in cancer therapy. The main purpose of this study is to evaluate the potential of a folate receptor-targeting nanoparticle to overcome/minimize drug resistance and to explore the underlying mechanisms. This is accomplished with enhanced cellular accumulation and retention of paclitaxel (one of the most effective anticancer drugs in use today and a well-known P-glycoprotein (P-gp) substrate) in a P-gp-overexpressing cancer model. The folate receptor-targeted nanoparticle, HFT-T, consists of a heparin-folate-paclitaxel (HFT) backbone with an additional paclitaxel (T) loaded in its hydrophobic core. In vitro analyses demonstrated that the HFT-T nanoparticle was superior to free paclitaxel or non-targeted nanoparticle (HT-T) in inhibiting proliferation of P-gp-overexpressing cancer cells (KB-8-5), partially due to its enhanced uptake and prolonged intracellular retention. In a subcutaneous KB-8-5 xenograft model, HFT-T administration enhanced the specific delivery of paclitaxel into tumor tissues and remarkably prolonged retention within tumor tissues. Importantly, HFT-T treatment markedly retarded tumor growth in a xenograft model of resistant human squamous cancer. Immunohistochemical analysis further indicated that increased in vivo efficacy of HFT-T nanoparticles was associated with a higher degree of microtubule stabilization, mitotic arrest, antiangiogenic activity, and inhibition of cell proliferation. These findings suggest that when the paclitaxel delivered as an HFT-T nanoparticle, the drug is better retained within the P-gp-overexpressing cells than the free form of paclitaxel. These results indicated that the targeted HFT-T nanoparticle may be promising in minimizing P-gp related drug resistance and enhancing therapeutic efficacy compared with the free form of paclitaxel.
doi:10.1021/nn200739q
PMCID: PMC3773705  PMID: 21728341
Targeting nanoparticle; paclitaxel; Folate receptor; drug resistance; chemotherapy
9.  The Pivotal Role of Integrin β1 in Metastasis of Head and Neck Squamous Cell Carcinoma 
Purpose
This study aimed to understand the prognostic value of integrin β1 expression in head and neck squamous cell carcinoma (HNSCC) and the mechanism underlying its association with metastatic HNSCC.
Experimental Design
Archival HNSCC tissues including 99 non-metastatic primary tumors and 101 metastatic primary tumors were examined for the association of integrin β1 expression with metastasis and disease prognosis by appropriate statistical methods. Fluorescence activated cell sorting was used to separate the integrin β1high/+ cell population from the integrin β1low/− population in HNSCC cell lines. These two populations and integrin β1 shRNA knock-down HNSCC cells were examined for the effect of integrin β1 on invasion in vitro and on lymph node and lung metastases in a xenograft mouse model. Expression and activation of matrix metalloproteinases (MMPs) were examined by zymography.
Results
Statistical analysis showed that integrin β1 expression was significantly higher in the metastatic primary tumors than in the non-metastatic tumors (42.6% vs 24.8%, p<0.0001 and p<0.0001 by univariate and multivariate analyses, respectively). In patients with lymph node metastasis, integrin β1 expression was inversely correlated with overall survival (p=0.035). The integrin β1 knock-down or integrin β1low/− HNSCC cells showed a significant reduction in lymph node and lung metastases in vivo (p<0.001 and p<0.05, respectively). Significantly reduced matrigel invasion capability was also found in integrin β1 knock-down or integrin β1low/− HNSCC cells (p< 0.01). Finally, zymography results showed integrin β1 affected HNSCC invasion by regulating MMP-2 activation.
Conclusion
These findings indicate that integrin β1 has a major impact on HNSCC prognosis through its regulation of metastasis.
doi:10.1158/1078-0432.CCR-11-3127
PMCID: PMC3462074  PMID: 22829201
10.  A Pragmatic Approach Using MRI to Treat Ischemic Strokes of Unknown Onset Time in a Thrombolytic Trial 
Purpose
Toward the goal of designing a clinical trial using imaging parameters to treat stroke patients with unknown onset time, we investigated the timing of changes on MRI in patients with well-defined stroke onset.
Methods
Hypothesis generating (n=85) and confirmatory (n=111) samples were scored by blinded readers for FLAIR hyperintensity in diffusion-positive regions. Reader measured signal intensity ratio (SIR) of the lesion to contralateral tissue was compared with SIR measured by co-registration.
Results
Lesion conspicuity increased with time on FLAIR (p=0.006). Qualitative assessment of FLAIR-negative vs FLAIR hyperintensity (k= 0.7091, 95% CI 0.61–0.81) showed good interrater agreement. Subtle hyperintensity was less reliably categorized (k=0.59, 95% CI 0.47–0.71). Reader measured SIR <1.15 can identify patients within the treatable time window of 4.5 hours (positive predictive value= 0.90). The SIR was greater for right hemisphere lesions (p=0.04) for a given reported time from stroke symptom onset.
Conclusion
The SIR on FLAIR provides a quantitative tool to identify early ischemic strokes. In developing SIR thresholds, right hemisphere lesions may confound the accurate estimate of stroke onset time. Image co-registration for thrombolytic trial enrollment is not necessary. A SIR < 1.15 on FLAIR yields a practical estimate of stroke onset within 4.5 hours.
doi:10.1161/STROKEAHA.111.630947
PMCID: PMC3464959  PMID: 22693129
DWI= Diffusion Weighted Imaging; FLAIR= Fluid Attenuation Inversion Recovery; Thrombolysis; Stroke
11.  HFT-T, a Targeting Nanoparticle, Enhances Specific Delivery of Paclitaxel to Folate Receptor-Positive Tumors 
ACS nano  2009;3(10):3165-3174.
Non-specific distribution of chemotherapeutic drugs (such as paclitaxel) is a major factor contributing to side effects and poor clinical outcomes in the treatment of human head and neck cancer. To develop novel drug delivery systems with enhanced efficacy and minimized adverse effects, we synthesized a ternary conjugate heparin-folic acid-paclitaxel (HFT), loaded with additional paclitaxel (T). The resulting nanoparticle, HFT-T, is expected to retain the antitumor activity of paclitaxel and specifically target folate receptor (FR)-expressing tumors, thereby increasing the bioavailability and efficacy of paclitaxel. In vitro experiments found that HFT-T selectively recognizes FR-positive human head and neck cancer cell line KB-3-1, displaying higher cytotoxicity compared to the free form of paclitaxel. In a subcutaneous KB-3-1 xenograft model, HFT-T administration enhanced the specific delivery of paclitaxel into tumor tissues and remarkably improved antitumor efficacy of paclitaxel. The average tumor volume in the HFT-T treatment group was 92.9±78.2mm3 vs 1670.3±286.1mm3 in the mice treated with free paclitaxel. Furthermore, paclitaxel tumors showed a resurgence of growth after several weeks of treatment, but this was not observed with HFT-T. This indicates that HFT-T could be more effective in preventing tumors from developing drug resistance. No significant acute in vivo toxicity was observed. These results indicate that specific delivery of paclitaxel with a ternary structured nanoparticle (HFT-T) targeting FR-positive tumor is a promising strategy to enhance chemotherapy efficacy and minimize adverse effects.
doi:10.1021/nn900649v
PMCID: PMC3733355  PMID: 19761191
Targeting nanoparticle; specific drug delivery; folate receptor; paclitaxel; chemotherapy
12.  Comparison of Quantum Dot Technology with Conventional Immunohistochemistry in Examining Aldehyde Dehydrogenase 1A1 as a Potential Biomarker for Lymph Node Metastasis of Head and Neck Cancer 
European Journal of Cancer  2012;48(11):1682-1691.
This study explored whether expression of aldehyde dehydrogenase 1 (ALDH1A1) in the primary tumor correlated with lymph node metastasis (LNM) of squamous cell carcinoma of the head and neck (HNSCC). We used both quantum dot (QD)-based immunohistofluorescence (IHF) and conventional immunohistochemistry (IHC) to quantify ALDH1A1 expression in primary tumor samples taken from 96 HNSCC patients, 50 with disease in the lymph nodes and 46 without. The correlation between the quantified level of ALDH1A1 expression and LNM in HNSCC patients was evaluated with univariate and multivariate analysis. The prognostic value of ALDH1A1 was examined by Kaplan-Meier analysis and Wald test. ALDH1A1 was highly correlated with LNM in HNSCC patients (p < 0.0001 by QD-based IHF and 0.039 by IHC). The two methods (QD-based IHF and conventional IHC) for quantification of ALDH1A1 were found to be comparable (R = 0.75, p < 0.0001), but QD-IHF was more sensitive and objective than IHC. The HNSCC patients with low ALDH1A1 expression had a higher 5-year survival rate than those with high ALDH1A1 level (p = 0.025). Our study suggests that ALDH1A1 is a potential biomarker for predicting LNM in HNSCC patients, though it is not an independent prognostic factor for survival of HNSCC patients. Furthermore, QD-IHF has advantages over IHC in quantification of ALDH1A1 expression in HNSCC tissues.
doi:10.1016/j.ejca.2011.12.029
PMCID: PMC3381072  PMID: 22341992
Aldehyde dehydrogenase 1; biomarker; metastasis; immunohistochemistry; head and neck cancer; quantum dot; nanotechnology
13.  Med1 plays a critical role in the development of tamoxifen resistance 
Carcinogenesis  2012;33(4):918-930.
Understanding the molecular pathways that contribute to the development of tamoxifen resistance is a critical research priority as acquired tamoxifen resistance is the principal cause of poor prognosis and death of patients with originally good prognosis hormone-responsive breast tumors. In this report, we provide evidence that Med1, an important subunit of mediator coactivator complex, is spontaneously upregulated during acquired tamoxifen-resistance development potentiating agonist activities of tamoxifen. Phosphorylated Med1 and estrogen receptor (ER) are abundant in tamoxifen-resistant breast cancer cells due to persistent activation of extracellular signal-regulated kinases. Mechanistically, phosphorylated Med1 exhibits nuclear accumulation, increased interaction with ER and higher tamoxifen-induced recruitment to ER-responsive promoters, which is abrogated by inhibition of Med1 phosphorylation. Stable knockdown of Med1 in tamoxifen-resistant cells not only reverses tamoxifen resistance in vitro but also in vivo. Finally, higher expression levels of Med1 in the tumor significantly correlated with tamoxifen resistance in ER-positive breast cancer patients on adjuvant tamoxifen monotherapy. In silico analysis of breast cancer, utilizing published profiling studies showed that Med1 is overexpressed in aggressive subsets. These findings provide what we believe is the first evidence for a critical role for Med1 in tamoxifen resistance and identify this coactivator protein as an essential effector of the tamoxifen-induced breast cancer growth.
doi:10.1093/carcin/bgs105
PMCID: PMC3324449  PMID: 22345290
14.  The Sequence Dependence of Cell Growth Inhibition by EGFR-Tyrosine Kinase Inhibitor ZD1839, Docetaxel and Cisplatin in Head and Neck Cancer 
Head & neck  2009;31(10):1263-1273.
Background
This study was to explore whether the efficacy of the EGFR tyrosine kinase inhibitor ZD1839 (Z, Iressa, gefitinib) plus chemotherapeutic agents docetaxel (D) and cisplatin (P) may benefit from sequencing of the combination.
Methods
Three head and neck cancer cell lines were used to study the effect of various combinations of and relative sequencing of D, P, and Z in cell growth inhibition. A population pharmacokinetic stimulation study was conducted on Z in silico, and used to together with the growth inhibition data to derive principles for future in vivo use of this drug combination.
Results
The inhibitory effects of Z on combinations of D and P were sequence dependent. Treatment simultaneously with DPZ or with DP followed by Z (DP→Z) showed synergistic effects in all three cell lines. However, sequencing with Z followed by DP (Z→DP), gave an antagonistic effect, suggesting that D and P should be administered when the effect of Z is low. The induction of apoptosis was also sequence dependent. The in silico pharmacokinetic study suggested the feasibility of deriving a 5 day on 2 day off regimen for Z, in which D and P administration commences when levels of Z are low, allowing levels of Z to accumulate sufficiently during the remainder of the cycle.
Conclusion
These data suggests that it is feasible to design clinical trials with these settings to maximize the efficacy of this combined drug regimen.
doi:10.1002/hed.21103
PMCID: PMC3600558  PMID: 19399750
EGFR; cytotoxic agent; docetaxel; cisplatin; apoptosis; head and neck cancer
15.  The Integrated Web Portal for Escalation with Overdose Control (EWOC) 
In this paper, we present the design and implementation of a novel web portal for the cancer phase I clinical trial design method Escalation with Overdose Control (EWOC). The web portal has two major components: a web-based dose finding calculator; and a standalone and downloadable dose finding software which can be installed on Windows operating systems. The web-based dose finding calculator uses industry standards and is a database-driven and distributed computing platform for designing and conducting dose finding in cancer phase I clinical trials utilizing EWOC methodology. The web portal is developed using open source software: PHP, JQuery, R and OpenBUGS. It supports any standard browsers with internet connection. The web portal can be accessed at: http://biostatistics.csmc.edu.
doi:10.2174/1874431120130427001
PMCID: PMC3706802  PMID: 23847696
EWOC; Bayesian method; cancer phase I clinical trial; maximum tolerated dose; open source.
16.  Phase I and pharmacokinetic study of everolimus, an mTOR inhibitor, in combination with docetaxel for recurrent/refractory non-small cell lung cancer 
Cancer  2010;116(16):3903-3909.
Purpose
Everolimus is a novel inhibitor of the mammalian target of rapamycin (mTOR) pathway, which is aberrantly activated in non-small cell lung cancer (NSCLC). We conducted a phase I and pharmacokinetic study of everolimus and docetaxel for recurrent NSCLC.
Methods
Patients with advanced stage NSCLC and progression following prior platinum-based chemotherapy were eligible. Sequential cohorts were treated with escalating doses of docetaxel (day 1) and everolimus (PO daily, days 1–19), every 3 weeks. Pharmacokinetic (PK) sampling of everolimus and docetaxel were done in cycle 1. The primary endpoint was determination of the recommended phase II doses (RP2D) of the combination.
Results
Twenty-four patients were enrolled. Median age, 62 yrs; Females, 11; number of prior regimens, 1(n=13), 2 (n=6), ≥3 (n=5) ECOG PS 0(n=6), 1(n=17). The dose-limiting toxicities (DLT) were fever with grade 3/4 neutropenia, grade 3 fatigue and grade 3 mucositis. None of the 7 patients treated at the RP2D (docetaxel 60 mg/m2 and everolimus 5 mg daily) experienced DLT. Everolimus area under the concentration time curve (AUC) was not different with 60 or 75 mg/m2 docetaxel. Mean ±SD AUC-based accumulation factors (R) for everolimus on days 8 and 15 were 1.16 ± 0.37 and 1.42 ± 0.42, respectively. Docetaxel day 1 half-life was 9.4 ± 3.4 hours. Among 21 patients evaluable, 1 had a partial response, and 10 had disease stabilization.
Conclusions
The RP2D of docetaxel and everolimus for combination therapy are 60 mg/m2 and 5 mg PO daily, respectively. Promising anti-cancer activity has been noted.
doi:10.1002/cncr.25264
PMCID: PMC2940062  PMID: 20564143
Everolimus; docetaxel; phase I; pharmacokinetics; non-small cell lung cancer
17.  Adiponectin Modulates C-Jun N-Terminal Kinase and Mammalian Target of Rapamycin and inhibits hepatocellular carcinoma 
Gastroenterology  2010;139(5):1762-1773.e5.
Background & Aims
Epidemiological studies have shown that obesity is a risk factor for hepatocellular carcinoma (HCC). Lower adiponectin levels are associated with poor prognosis in obese HCC patients hence it is plausible that adiponectin acts as a negative regulator of HCC. Here, we investigated the effects of adiponectin on HCC development and elucidated the underlying molecular mechanisms.
Methods
We utilized various in vitro assays using Huh7 and HepG2 HCC cells to examine the signal transduction pathways involved in protective function of adiponectin in HCC. These studies were followed by in vivo approaches using HCC xenografts and tumor analysis. Results from in vitro and in vivo findings were corroborated using human HCC tissue micro-array (TMA) and analysis of clinicopathological characteristics.
Results
Adiponectin treatment resulted in increased apoptosis of HCC cells via activation of caspase-3. Adiponectin increased phosphorylation of c-Jun-N-terminal kinase (JNK) and inhibition of JNK-phosphorylation inhibited adiponectin-induced apoptosis and caspase-3 activation. Adiponectin increased phosphorylation of AMP-activated protein kinase (AMPK) and tumor suppressor TSC2 and inhibited mammalian target of rapamycin (mTOR) phosphorylation. Inhibition of AMPK phosphorylation not only inhibited adiponectin-induced JNK phosphorylation but also effectively blocked biological effects of adiponectin. In vivo study showed that adiponectin treatment substantially reduced liver tumorigenesis in nude mice. Importantly, analysis of adiponectin expression levels in TMA of human HCC patients revealed an inverse correlation of adiponectin expression with tumor size.
Conclusions
These novel findings show protective role of adiponectin in liver tumorigenesis and could help explain poor prognosis of obese HCC patients who typically have low adiponectin levels.
doi:10.1053/j.gastro.2010.07.001
PMCID: PMC2967590  PMID: 20637208
Hepatocellular carcinoma; Adiponectin; TSC2; mTOR
18.  Role of COX-2 in tumor progression and survival of head and neck squamous cell carcinoma 
Inhibition of cyclooxygenase-2 (COX-2) pathways may have significant implications for the prevention and treatment of head and neck squamous cell carcinoma (HNSCC). COX-2 is overexpressed in both premalignant lesions and invasive HNSCC. We examined COX-2 expression by immunohistochemistry in normal tissues, different stages of premalignant lesions, and carcinoma in-situ (CIS). We also evaluated the correlation between COX-2 expression and clinical characteristics of HNSCC patients. Tissue specimens were obtained from: premalignant lesions from 25 subjects enrolled in a biochemoprevention trial; tumor samples collected at diagnosis from 38 HNSCC patients enrolled in an induction chemotherapy trial; and normal control tissues from 10 non-cancer, non-smoking subjects. COX-2 was expressed in early and intermediate stages of premalignant lesions, increasing first in the basal and parabasal layers, then lower spinous, and upper spinous layers. This correlation was noted in normal epithelium (p<0.0001), histologically normal in-field samples (p<0.0001), low-grade dysplasia (p=0.024), and moderate-grade dysplasia (p=0.009), but was lost in the majority of high-grade dysplasia/CIS (p=0.896). COX-2 expression was also noted to increase progressively through the early stages of premalignancy, and to decrease in severe/CIS stage and invasive carcinoma. COX-2 expression in tumors from patients treated with induction chemotherapy was correlated with overall survival after controlling for clinical variables. These findings elucidate the differential expression pattern of COX-2 in stages of head and neck premalignant lesions and invasive carcinoma, supporting the rationale for COX-2 inhibition as an important strategy for cancer chemoprevention. Further validation of COX-2 expression is needed in prospective ongoing chemoprevention trials.
doi:10.1158/1940-6207.CAPR-09-0077
PMCID: PMC2910364  PMID: 19737986
COX-2; Head and neck cancer; premalignancy; chemoprevention; cyclooxygenase 2
19.  Analysis of Death Receptor 5 and Caspase-8 Expression in Primary and Metastatic Head and Neck Squamous Cell Carcinoma and Their Prognostic Impact 
PLoS ONE  2010;5(8):e12178.
Death receptor 5 (DR5) and caspase-8 are major components in the extrinsic apoptotic pathway. The alterations of the expression of these proteins during the metastasis of head and neck squamous cell carcinoma (HNSCC) and their prognostic impact have not been reported. The present study analyzes the expression of DR5 and caspase-8 by immunohistochemistry (IHC) in primary and metastatic HNSCCs and their impact on patient survival. Tumor samples in this study included 100 primary HNSCC with no evidence of metastasis, 100 primary HNSCC with lymph node metastasis (LNM) and 100 matching LNM. IHC analysis revealed a significant loss or downregulation of DR5 expression in primary tumors with metastasis and their matching LNM compared to primary tumors with no evidence of metastasis. A similar trend was observed in caspase-8 expression although it was not statistically significant. Downregulation of caspase-8 and DR5 expression was significantly correlated with poorly differentiated tumors compared to moderately and well differentiated tumors. Univariate analysis indicates that, in HNSCC with no metastasis, higher expression of caspase-8 significantly correlated with better disease-free survival and overall survival. However, in HNSCC with LNM, higher caspase-8 expression significantly correlated with poorer disease-free survival and overall survival. Similar results were also generated when we combined both DR5 and caspase-8. Taken together, we suggest that both DR5 and caspase-8 are involved in regulation of HNSCC metastasis. Our findings warrant further investigation on the dual role of caspase-8 in cancer development.
doi:10.1371/journal.pone.0012178
PMCID: PMC2922336  PMID: 20808443
20.  Examining expression of folate receptor in squamous cell carcinoma of the head and neck as a target for a novel nanotherapeutic drug 
Head & neck  2009;31(4):475-481.
Background
Nanotechnology-based drug delivery approaches may help increase therapeutic efficacy and decrease side effects of chemotherapeutics. We investigated expression levels of folate receptor (FR) in squamous cell carcinoma of the head and neck (SCCHN) to evaluate FR as a target for nanotherapy.
Methods
FR expression levels in archival SCCHN tissues were analyzed by immunohistochemistry and correlated with clinical parameters.
Results
FR was detected in 45% of primary tumors and 40% of corresponding lymph node metastases (LNM). FR expression in primary tumors of the metastatic group strongly correlated with the corresponding LNM (p=0.0002). FR expression was inversely correlated with disease-free survival in non-metastatic (p=0.0048), metastatic (p=0.0127), and LNM (p <0.001) groups, and with overall survival in the LNM group (p <0.0001).
Conclusions
FR is expressed in a significant proportion of primary SCCHN and corresponding LNM tissues, and correlates with worse clinical outcome. These findings provide support for FR-mediated nanotherapeutics in SCCHN.
doi:10.1002/hed.21003
PMCID: PMC2658731  PMID: 19072997
folate receptor; nanotechnology; head and neck cancer; squamous cell carcinoma
21.  caGrid-Enabled caBIGTM Silver Level Compatible Head and Neck Cancer Tissue Database System 
There are huge amounts of biomedical data generated by research labs in each cancer institution. The data are stored in various formats and accessed through numerous interfaces. It is very difficult to exchange and integrate the data among different cancer institutions, even among different research labs within the same institution, in order to discover useful biomedical knowledge for the healthcare community. In this paper, we present the design and implementation of a caGrid-enabled caBIGTM silver level compatible head and neck cancer tissue database system. The system is implemented using a set of open source software and tools developed by the NCI, such as the caCORE SDK and caGrid. The head and neck cancer tissue database system has four interfaces: Web-based, Java API, XML utility, and Web service. The system has been shown to provide robust and programmatically accessible biomedical information services that syntactically and semantically interoperate with other resources.
doi:10.2174/1874431101004010171
PMCID: PMC3095113  PMID: 21589853
caBIGTM compatible level; caCORE SDK; caGrid; head and neck cancer; cancer tissue database; model driven architecture; semantic interoperability.
22.  BAP1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization 
Cancer research  2008;68(17):6953-6962.
BAP1 (BRCA1-associated protein-1), a deubiquitinating enzyme of unknown cellular function, is mutated in breast and lung cancers. In this study, we have demonstrated for the first time that BAP1 has tumor suppressor activity in vivo by showing that BAP1 can suppress tumorigenicity of lung cancer cells in athymic nude mice. We show that BAP1 fulfills another criterion of a genuine tumor suppressor because cancer-associated mutations in BAP1 result in a protein deficient in deubiquitinating activity. We show for the first time that one of the two predicted nuclear targeting motifs is required for nuclear localization of BAP1 and that a truncation mutant found in a lung cancer cell line results in BAP1 that fails to localize to the nucleus. Furthermore, we demonstrate that deubiquitinating activity and nuclear localization are both required for BAP1-mediated tumor suppression in nude mice. We show that BAP1 exerts its tumor suppressor functions by affecting the cell cycle; speeding the progression through the G1/S checkpoint and inducing cell death via a process that has characteristics of both apoptosis and necrosis. Surprisingly, BAP1-mediated growth suppression is independent of wild-type BRCA1. Since deubiquitinating enzymes are components of the ubiquitin proteasome system, this pathway has emerged as an important target for anti-cancer drugs. The identification of the deubiquitinating enzyme BAP1 as a tumor suppressor may lead to further understanding of how the ubiquitin proteasome system contributes to cancer and aid in the identification of new targets for cancer therapy.
doi:10.1158/0008-5472.CAN-08-0365
PMCID: PMC2736608  PMID: 18757409
BAP1; BRCA1; ubiquitin; cancer
23.  Synergistic inhibition of head and neck tumor growth by green tea (−)-epigallocatechin-3-gallate and EGFR tyrosine kinase inhibitor 
One of the mechanisms of the antitumor activity of green tea (−)-epigallocatechin-3-gallate (EGCG) is associated with its effect on epidermal growth factor receptor (EGFR)-mediated signaling transduction pathways. We investigated whether combining EGCG with the EGFR-tyrosine kinase inhibitor (EGFR-TKI) erlotinib may augment erlotinib-induced cell growth inhibition of squamous cell carcinoma of the head and neck (SCCHN) in a mouse xenograft model. In vitro studies with 5 head and neck cancer cell lines revealed that synergistic cell growth inhibition by the combination of EGCG and erlotinib was associated with significantly greater inhibition of pEGFR and pAKT, increased activation of caspases 9, 3 and PARP compared to the inhibition induced by EGCG or erlotinib alone. Erlotinib inhibited phosphorylation of EGFR, stabilizing EGFR at the plasma membrane, whereas EGCG induced EGFR internalization and ubiquitin-degradation, ultimately undermining EGFR signaling. The efficacy of the combination treatment was investigated with nude mice (n = 25) orally gavaged with vehicle control, EGCG, erlotinib or the combination at the same doses for 7 days, followed by subcutaneous injection with Tu212 cells. Animals were continuously administered the agents 5 days weekly for 7 weeks. The combined treatment resulted in significantly greater inhibition of tumor growth and delayed tumor progression as a result of increased apoptosis, decreased cell proliferation and reduced pEGFR and pAKT compared to the single agent treatment groups. Our results suggest a synergistic antitumor effect of a combined treatment with EGCG and erlotinib, and provide a promising regimen for future chemoprevention and treatment of SCCHN.
doi:10.1002/ijc.23585
PMCID: PMC2555987  PMID: 18546267
squamous cell carcinoma of the head and neck; (−)-epigallocatechin-3-gallate; erlotinib
24.  Targeted Cancer Gene Therapy Using a Hypoxia Inducible Factor–Dependent Oncolytic Adenovirus Armed with Interleukin-4 
Cancer research  2007;67(14):6872-6881.
There is a need for novel therapies targeting hypoxic cells in tumors. These cells are associated with tumor resistance to therapy and express hypoxia inducible factor-1 (HIF-1), a transcription factor that mediates metabolic adaptation to hypoxia and activates tumor angiogenesis. We previously developed an oncolytic adenovirus (HYPR-Ad) for the specific killing of hypoxic/HIF-active tumor cells, which we now armed with an interleukin-4 gene (HYPR-Ad-IL4). We designed HYPR-Ad-IL4 by cloning the Ad E1A viral replication and IL-4 genes under the regulation of a bidirectional hypoxia/HIF-responsive promoter. The IL-4 cytokine was chosen for its ability to induce a strong host antitumor immune response and its potential antiangiogenic activity. HYPR-Ad-IL4 induced hypoxia-dependent IL-4 expression, viral replication, and conditional cytolysis of hypoxic, but not normoxic cells. The treatment of established human tumor xenografts with HYPR-Ad-IL4 resulted in rapid and maintained tumor regression with the same potency as that of wild-type dl309-Ad. HYPR-Ad-IL4–treated tumors displayed extensive necrosis, fibrosis, and widespread viral replication. Additionally, these tumors contained a distinctive leukocyte infiltrate and prominent hypoxia. The use of an oncolytic Ad that locally delivers IL-4 to tumors is novel, and we expect that HYPR-Ad-IL4 will have broad therapeutic use for all solid tumors that have hypoxia or active HIF, regardless of tissue origin or genetic alterations.
doi:10.1158/0008-5472.CAN-06-3244
PMCID: PMC2262867  PMID: 17638898

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