Zhengjia Chen

Georgia Department of Public Health, Marietta, Georgia, United States

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Publications (106)498.39 Total impact

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    ABSTRACT: The aim of this study is to examine the reproducibility of anti-1-amino-3-[(18)F]fluorocyclobutane-1-carboxylic acid (anti-3-[(18)F]FACBC) quantitative measurements in key background structures and untreated malignant lesions.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 10/2014; · 2.47 Impact Factor
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    ABSTRACT: BACKGROUND To understand the mechanism of frequent and early lymph node metastasis in high-risk human papillomavirus (HPV)–associated oropharyngeal squamous cell carcinoma (OPSCC), this study investigated whether β-catenin is regulated by the HPV oncoprotein and contributes to OPSCC metastasis.METHODS Expression levels of p16, β-catenin, and epidermal growth factor receptor (EGFR) were examined in OPSCC samples (n = 208) by immunohistochemistry. The expression and subcellular localization of β-catenin and EGFR activation were also studied in HPV-positive and HPV-negative head and neck squamous cell carcinoma cell lines with western blot analysis. HPV16 E6 small interfering RNA was used to elucidate the effect of the HPV oncoprotein on β-catenin translocation. The involvement of EGFR in β-catenin translocation was confirmed by treatment with erlotinib. Moreover, the invasive capacity was evaluated after HPV16 E6/E7 repression.RESULTSThe results showed that the membrane weighted index of β-catenin was inversely correlated with p16 positivity (P < .001) and lymph node metastasis (P = .026), whereas nuclear staining of β-catenin was associated with p16-positive OPSCC (P < .001). A low level of membrane β-catenin expression was significantly associated with disease-free and overall survival (P < .0001 in both cases). Furthermore, the membrane weighted index of EGFR was inversely correlated with p16 positivity (P < .001) and positively correlated with membrane β-catenin (P < .001). The in vitro study showed that HPV16 E6 repression led to reductions of phospho-EGFR and nuclear β-catenin, which were also observed after erlotinib treatment, and inhibition of invasion.CONCLUSIONS The findings suggest that HPV16 E6 mediates the translocation of β-catenin to the nucleus, which may be regulated by activated EGFR. Cancer 2014. © 2014 American Cancer Society.
    Cancer 09/2014; · 5.20 Impact Factor
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    ABSTRACT: BACKGROUND Platinum-based therapy combined with cetuximab is standard first-line therapy for recurrent or metastatic squamous cell carcinoma of the head and neck (RMSCCHN). Preclinical studies have suggested that mammalian target of rapamycin inhibitors may overcome resistance to epidermal growth factor receptor blockers and may augment cetuximab antitumor activity. We conducted a phase 1b trial of carboplatin, cetuximab, and everolimus for untreated RMSCCHN.METHODS Patients received carboplatin (area under the curve = 2 mg/ml/min; 3 weeks on, 1 week off), cetuximab (with a loading dose of 400 mg/m2 and then 250 mg/m2 weekly), and dose-escalating everolimus (2.5, 5.0, 7.5, and 10 mg/day) with a 3+3 design. After 4 cycles, patients without progression continued cetuximab/everolimus until progression or intolerable toxicity. Patients (age ≥ 18 years) had previously untreated, unresectable RMSCCHN not amenable to radiotherapy and an Eastern Cooperative Oncology Group performance status of 0 to 2.RESULTSThe study enrolled 20 patients (male/female = 18/2) with RMSCCHN; the median age was 65 years (44-75 years). Thirteen patients received everolimus (male/female = 92%). Two of 6 patients receiving 2.5 mg/day experienced dose-limiting toxicity (DLT) with grade 3 hyponatremia and nausea. In 7 patients receiving de-escalated everolimus (2.5 mg every other day), grade 3 hyperglycemia produced DLT in 1 of 6 patients. The objective response rate (RR) was 61.5% (all partial responses). Progression-free survival (PFS) was 8.15 months. The pharmacokinetics of everolimus was described with a 2-compartment mixed-effects model. There was a significant correlation between tumor p-p44/42 staining and response (P = .044) and a marginally significant correlation between phosphorylated mammalian target of rapamycin and overall survival.CONCLUSIONS The maximum tolerated dose of everolimus with cetuximab and carboplatin was 2.5 mg every other day. The regimen was associated with an encouraging RR and PFS, and this suggested possible clinical efficacy in a select group of patients with squamous cell carcinoma of the head and neck. Cancer 2014. © 2014 American Cancer Society.
    Cancer 08/2014; · 5.20 Impact Factor
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    ABSTRACT: To investigate the diagnostic accuracy of ultrasound histogram features in the quantitative assessment of radiation-induced parotid gland injury and to identify potential imaging biomarkers for radiation-induced xerostomia (dry mouth)-the most common and debilitating side effect after head-and-neck radiotherapy (RT).
    Academic Radiology 08/2014; 21(10):1304–1313. · 1.91 Impact Factor
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    ABSTRACT: Poly (ADP) ribose polymerase (PARP) plays a key role in DNA repair and is highly expressed in small cell lung cancer (SCLC). We investigated the therapeutic impact of PARP inhibition in SCLC. In vitro cytotoxicity of veliparib, cisplatin, carboplatin, and etoposide singly and combined was determined by MTS in 9 SCLC cell lines (H69, H128, H146, H526, H187, H209, DMS53, DMS153, and DMS114). Subcutaneous xenografts in athymic nu/nu mice of H146 and H128 cells with relatively high and low platinum sensitivity, respectively, were employed for in vivo testing. Mechanisms of differential sensitivity of SCLC cell lines to PARP inhibition were investigated by comparing protein and gene expression profiles of the platinum sensitive and the less sensitive cell lines. Veliparib showed limited single-agent cytotoxicity but selectively potentiated (≥50% reduction in IC50) cisplatin, carboplatin, and etoposide in vitro in five of nine SCLC cell lines. Veliparib with cisplatin or etoposide or with both cisplatin and etoposide showed greater delay in tumor growth than chemotherapy alone in H146 but not H128 xenografts. The potentiating effect of veliparib was associated with in vitro cell line sensitivity to cisplatin (CC = 0.672; P = 0.048) and DNA-PKcs protein modulation. Gene expression profiling identified differential expression of a 5-gene panel (GLS, UBEC2, HACL1, MSI2, and LOC100129585) in cell lines with relatively greater sensitivity to platinum and veliparib combination. Veliparib potentiates standard cytotoxic agents against SCLC in a cell-specific manner. This potentiation correlates with platinum sensitivity, DNA-PKcs expression and a 5-gene expression profile.
    Cancer Medicine 08/2014;
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    ABSTRACT: Photodynamic therapy (PDT) is a highly specific anti-cancer treatment modality for various cancers, particularly for recurrent cancers which no longer respond to conventional anti-cancer therapies. PDT has been under development for decades, but light-associated toxicity limits its clinical applications. To reduce the toxicity of PDT, we recently developed a targeted nanoparticle (NP) platform that combines a second-generation PDT drug, Pc 4, with a cancer targeting ligand, and iron oxide (IO) NPs. Carboxyl functionalized IO NPs were first conjugated with a fibronectin-mimetic peptide (Fmp) which binds integrin 1. Then the PDT drug Pc 4 was successfully encapsulated into the ligand-conjugated IO NPs to generate Fmp-IO-Pc 4. Our study indicated that both non-targeted IO-Pc 4 and targeted Fmp-IO-Pc 4 NPs accumulated in xenograft tumors with higher concentrations than non-formulated Pc 4. As expected, both IO-Pc 4 and Fmp-IO-Pc 4 reduced the size of HNSCC xenograft tumors more effectively than free Pc 4. Using a 10-fold lower dose of Pc 4 than that reported in the literature, the targeted Fmp-IO-Pc 4 NPs demonstrated significantly greater inhibition of tumor growth than non-targeted IO-Pc 4 NPs. These results suggest that the delivery of a PDT agent Pc 4 by IO NPs can enhance treatment efficacy and reduce PDT drug dose. The targeted IO-Pc 4 NPs have great potential to serve as both a magnetic resonance imaging (MRI) agent and PDT drug in the clinic.
    ACS Nano 06/2014; · 12.03 Impact Factor
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    ABSTRACT: The EGFR monoclonal antibody cetuximab is the only approved targeted agent for treating head and neck squamous cell carcinoma (HNSCC). Yet resistance to cetuximab has hindered its activity in this disease. Intrinsic or compensatory HER3 signaling may contribute to cetuximab resistance. To investigate the therapeutic benefit of combining MM-121/SAR256212, an anti-HER3 monoclonal antibody, with cetuximab in HNSCC, we initially screened twelve HNSCC cell lines for total and phosphorylated levels of the four HER receptors. We also investigated the combination of MM-121 with cetuximab in preclinical models of HNSCC. Our results revealed that HER3 is widely expressed and activated in HNSCC cell lines. MM-121 strongly inhibited phosphorylation of HER3 and AKT. When combined with cetuximab, MM-121 exerted a more potent anti-tumor activity through simultaneously inhibiting the activation of HER3 and EGFR and consequently the downstream PI3K/AKT and ERK pathways in vitro. Both high and low doses of MM-121 in combination with cetuximab significantly suppressed tumor growth in xenograft models and inhibited activations of HER3, EGFR, AKT and ERK in vivo. Our current work is the first report on this new combination in HNSCC and supports the concept that HER3 inhibition may play an important role in future therapy of HNSCC. Our results open the door for further mechanistic studies to better understand the role of HER3 in resistance to EGFR inhibitors in HNSCC.
    Molecular Cancer Therapeutics 04/2014; · 5.60 Impact Factor
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    ABSTRACT: Colorectal cancer has a distinct clinicopathologic presentation in younger patients. The aim of this paper was to evaluate the outcome of younger (age below 50 y) and older patients with stage IV (advanced) colorectal cancer in the modern era of combination chemotherapy. Cases of metastatic colorectal cancer reported in Surveillance, Epidemiology, and End Results registry (1973 to 2008) were reviewed. Demographics, tumor characteristics, and overall and cancer-specific survivals in patients below 50 and above 50 years of age were compared by Cox proportional hazard analyses. Joinpoint regression analysis was used to evaluate secular trends in 2-year survival. Younger patients had a greater proportion of negative clinicopathologic features (male sex, African American ethnicity, and signet ring or mucinous histology). In multivariate analysis, older age, male sex, African American ethnicity, right-sided tumors, and signet ring histology were associated with higher mortality risk. Younger patients had improved survival (hazard ratio 0.72; 95% confidence interval: 0.70-0.75) compared with older patients, whereas all patients experienced increased 2-year survival by joinpoint analysis beginning in 1999-2000. The results confirm decreased mortality from advanced colorectal cancer in the era of modern combination chemotherapy in younger and older patients. Younger age, non-right-sided tumors, and absence of signet ring histology significantly associate with better survival.
    American journal of clinical oncology 03/2014; · 2.21 Impact Factor
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    ABSTRACT: Human papillomavirus (HPV) is the etiologic risk factor for cervical cancer. Some studies have suggested an association with a subset of lung tumors, but the etiologic link has not been firmly established. We performed an international pooled analysis of cross-sectional studies (27 datasets, n = 3,249 patients) to evaluate HPV DNA prevalence in lung cancer and to investigate viral presence according to clinical and demographic characteristics. HPV16/18 were the most commonly detected, but with substantial variation in viral prevalence between geographic regions. The highest prevalence of HPV16/18 was observed in South & Central America, followed by Asia, North America and Europe (Adjusted prevalence rates = 22%, 5%, 4% and 3% respectively). Higher HPV16 prevalence was noted in each geographic region compared to HPV18, except in North America. HPV16/18-positive lung cancer was less likely observed among White race (Adjusted OR = 0.33, 95% CI = 0.12-0.90), while no associations were observed with gender, smoking history, age, histology or stage. Comparisons between tumor and normal lung tissue show that HPV was more likely to be present in lung cancer rather than normal lung tissues (OR = 3.86, 95% CI = 2.87-5.19). Among a subset of patients with HPV16-positive tumors, integration was primarily among female patients (93%, 13/14), while the physical status in male cases (N = 14) was inconsistent. Our findings confirm that HPV DNA is present in a small fraction of lung tumors, with large geographic variations. Further comprehensive analysis is needed to assess whether this association reflects a causal relationship.
    Carcinogenesis 02/2014; · 5.64 Impact Factor
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    ABSTRACT: Cancer prevention (chemoprevention) by using naturally occurring dietary agents has gained immense interest because of the broad safety window of these compounds. However, many of these compounds are hydrophobic and poorly soluble in water. They frequently display low bioavailability, poor systemic delivery, and low efficacy. To circumvent this problem, we explored a novel approach toward chemoprevention using nanotechnology to deliver luteolin, a natural compound present in green vegetables. We formulated water-soluble polymer-encapsulated Nano-Luteolin from hydrophobic luteolin, and studied its anticancer activity against lung cancer and head and neck cancer. In vitro studies demonstrated that, like luteolin, Nano-Luteolin inhibited the growth of lung cancer cells (H292 cell line) and squamous cell carcinoma of head and neck (SCCHN) cells (Tu212 cell line). In Tu212 cells, the IC50 value of Nano-Luteolin was 4.13 μmol/L, and that of luteolin was 6.96 μmol/L. In H292 cells, the IC50 of luteolin was 15.56 μmol/L, and Nano-Luteolin was 14.96 μmol/L. In vivo studies using a tumor xenograft mouse model demonstrated that Nano-Luteolin has a significant inhibitory effect on the tumor growth of SCCHN in comparison to luteolin. Our results suggest that nanoparticle delivery of naturally occurring dietary agents like luteolin has many advantages and may have potential application in chemoprevention in clinical settings. Cancer Prev Res; 7(1); 65-73. ©2013 AACR.
    Cancer Prevention Research 01/2014; 7(1):65-73. · 4.89 Impact Factor
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    ABSTRACT: Background Platinum compounds remain the most widely utilized systemic agents in combination with radiation for treating SCCHN in the concurrent setting. Despite recent interest in using taxanes in this setting, there is a lack of randomized clinical trials to support this approach. We conducted a systematic review of published clinical trials of taxane-containing versus standard non-taxane-based regimens used in definitive treatment of SCCHN. Methods Trials published between 1994 and 2012 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). All prospective studies were independently identified by two authors for inclusion. Studies were excluded if induction therapy was part of the regimen or if targeted agents were used. Trials using cisplatin- or carboplatin-based regimens and paclitaxel or docetaxel were included. Demographic data, treatment response, locoregional failure free rate (LFFR), progression-free and overall survival (PFS, OS) and toxicities were extracted and analyzed using Comprehensive Meta Analysis software (Version 2.0). Outcome data were pooled and reported as weighted response rate (RR), PFS and OS. Results A total of 790 studies were retrieved and 42 studies with 3120 patients were included: 804 patients were treated with taxanes (80% males, median age 57 years) and 2316 with non-taxanes (86% males, median age 56 years). Progression free survival was not different between the two groups. Weighted median survival was compared from those studies that reported these data; taxanes = 36.7 months (N = 197) versus non-taxanes = 25 months (N = 503), P < 0.001. Toxicity (grade 3 and above) was higher in non-taxane containing trials. Conclusions The improved overall survival observed supports the choice of taxane-based regimens in the concurrent setting but may also reflect the predominance of single arm multi-agent phase II trials in the taxane arm. Our findings urge the need for better standardization of taxane-based regimens.
    Oral Oncology. 01/2014;
  • Zhengjia Chen, Xinjia Chen
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    ABSTRACT: In this article, we propose rigorous sample size methods for estimating the means of random variables, which require no information of the underlying distributions except that the random variables are known to be bounded in a certain interval. Our sample size methods can be applied without assuming that the samples are identical and independent. Moreover, our sample size methods involve no approximation. We demonstrate that the sample complexity can be significantly reduced by using a mixed error criterion. We derive explicit sample size formulae to ensure the statistical accuracy of estimation.
    Journal of Statistical Planning and Inference 01/2014; · 0.71 Impact Factor
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    ABSTRACT: The primary purposes of Phase I cancer clinical trials are to determine the maximum tolerated dose (MTD) and the treatment schedule of a new drug. Phase I trials usually involve a small number of patients so that fully utilizing all toxicity information including time to event toxicity data is key to improving the trial efficiency and the accuracy of MTD estimation. Chen et al. [1] proposed a novel normalized equivalent toxicity score (NETS) system to fully utilize multiple toxicities per patient instead of a binary indicator of dose limiting toxicity (DLT). Cheung and Chappell [2] developed the time to toxicity event (TITE) approach to incorporate time to toxicity event data. Escalation with Overdose Control (EWOC) is an adaptive Bayesian Phase I design which can allow rapid dose escalation while controlling the probability of overdosing patients [3]. In this manuscript, we use EWOC as a framework and integrate it with the NETS system and the TITE approach to develop an advanced Phase I design entitled EWOC-NETS-TITE. We have conducted simulation studies to compare its operating characteristics using selected derived versions of EWOC because EWOC itself has already been extensively compared with common Phase I designs [3]. Simulation results demonstrate that EWOC-NETS-TITE can substantially improve the trial efficiency and accuracy of MTD determination as well as allow patients to be entered in a staggered fashion to significantly shorten trial duration. Moreover, user-friendly software for EWOC-NETS-TITE is under development.
    Contemporary clinical trials 01/2014; · 1.51 Impact Factor
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    ABSTRACT: Docetaxel treatment is the only first-line chemotherapy with a survival benefit in metastatic castration-resistant prostate cancer (PCa). Nonetheless, most patients become docetaxel resistant and inevitably progress with no cure. In this study, we investigated the potential of pomegranate extract (PE) in targeting metastatic castration-resistant PCa and improving docetaxel chemotherapy. The in vitro and in vivo effect of POMx, a PE formula currently approved for clinical trials, in metastatic castration-resistant PCa cells was evaluated in experimental models. We demonstrated that POMx exhibited potent in vitro cytotoxicity in metastatic castration-resistant PCa cells. Mechanistic studies identified survivin as a novel molecular target that may mediate the anti-cancer activity of POMx, presumably through the inhibition of signal transducer and activator of transcription 3. The in vivo administration of POMx treatment effectively inhibited survivin, induced apoptosis, retarded C4-2 tumor growth in skeleton and significantly enhanced the efficacy of docetaxel in athymic nude mice. These results provide the first preclinical evidence that POMx may be effective in treating metastatic castration-resistant PCa and enhancing the efficacy of docetaxel chemotherapy. Prostate © 2013 Wiley Periodicals, Inc.
    The Prostate 12/2013; · 3.84 Impact Factor
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    ABSTRACT: Ampullary (AMP-A) and duodenal adenocarcinomas (DA) are rare tumors. The literature regarding treatment and outcome is very limited. The objective of this project is to compare the outcomes of AMP-A and DA. The records for AMP-A and DA patients between July 1995 and July 2012 at Emory University were reviewed for demographics, pathology, treatment, and survival. Survival rates were estimated by Kaplan-Meier method and compared with log-rank test. A Cox proportional hazard model was fitted to estimate the adjusted effect of AMP-A versus DA on overall survival (OS). Ninety-five AMP-A and 66 DA patients were identified. No significant difference between patients with DA and AMP-A was observed for age, gender, or grade. DA presented with larger tumors and higher stages. Treatment included surgery, surgery followed by adjuvant therapy or chemotherapy alone. No OS difference was observed when controlled for stage. AMP-A was sub-classified into intestinal (IAMP), pancreaticobiliary (PBAMP), and unspecified types. IAMP tended to present at a higher grade (P = 0.045) than PBAMP. No OS difference between the IAMP and PBAMP was observed. After accounting for stage, OS was not significantly different for AMP-A and DA patients. There was no OS difference comparing PBAMP with IAMP. J. Surg. Oncol. © 2013 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 12/2013; · 2.64 Impact Factor
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    ABSTRACT: Triple Negative subset of (TN) Breast Cancers (BC), a close associate of the basal-like subtype (with limited discordance) is an aggressive form of the disease which convey unpredictable, and poor prognosis due to limited treatment options and lack of proven effective targeted therapies. We conducted an expression study of 240 formalin-fixed, paraffin-embedded (FFPE) primary biopsies from two cohorts, including 130 TN tumors, to identify molecular mechanisms of TN disease. The annotation of differentially expressed genes in TN tumors contained an overrepresentation of canonical Wnt signaling components in our cohort and others. These observations were supported by upregulation of experimentally induced oncogenic Wnt/beta-catenin genes in TN tumors, recapitulated using targets induced by Wnt3A. A functional blockade of Wnt/beta-catenin pathway by either a pharmacological Wnt-antagonist, WntC59, sulidac sulfide, or beta-catenin (functional read out of Wnt/beta-catenin pathway) SiRNA mediated genetic manipulation demonstrated that a functional perturbation of the pathway is causal to the metastasis- associated phenotypes including fibronectin-directed migration, F-actin organization, and invasion in TNBC cells. A classifier, trained on microarray data from beta-catenin transfected mammary cells, identified a disproportionate number of TNBC breast tumors as compared to other breast cancer subtypes in a meta-analysis of 11 studies and 1,878 breast cancer patients, including the two cohorts published here. Patients identified by the Wnt/beta-catenin classifier had a greater risk of lung and brain, but not bone metastases. These data implicate transcriptional Wnt signaling as a hallmark of TNBC disease associated with specific metastatic pathways.
    BMC Cancer 11/2013; 13(1):537. · 3.33 Impact Factor
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    ABSTRACT: FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, and irinotecan) as compared with gemcitabine in pancreatic cancer (PC) has superior activity and increased toxicity. The bolus 5-FU contributes to the toxicity. We hypothesized that the elimination of bolus 5-FU and use of hematopoietic growth factor will improve the safety profile without compromising the activity of FOLFIRINOX. Sixty patients with PC treated with modified FOLFIRINOX (no bolus 5-FU) were reviewed. Patients were divided into metastatic or nonmetastatic (locally advanced or borderline resectable) disease. Toxicity, response rate, progression-free survival, and overall survival were evaluated. Nonmetastatic and metastatic disease were present in 24 (40%) and 36 (60%) patients, respectively. The incidence of grade 4 neutropenia, grade 3/4 diarrhea, and fatigue were 3%, 13%, and 13%, respectively. Response rate was 30%. The median progression-free survival for nonmetastatic disease was 13.7 months (95% confidence interval [CI], 9.6-24.6 months), and that for metastatic disease was 8.5 months (95% CI, 3.7-11.0 months), respectively. The median overall survival for nonmetastatic disease was 17.8 months (95% CI, 9.9 months to not estimable), and that for metastatic disease was and 9.0 months (95% CI, 7.1 months to not estimable), respectively. Modified FOLFIRINOX has an improved safety profile with maintained efficacy in metastatic PC. Modified FOLFIRINOX has promising activity in nonmetastatic disease.
    Pancreas 11/2013; 42(8):1311-5. · 2.95 Impact Factor
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    ABSTRACT: Targeted biologic agents showed clinically meaningful efficacy as front-line therapy for advanced radioiodine-refractory and medullary thyroid cancer. The clinical benefit of these agents beyond the front line has yet to be established. We assessed the clinical benefit of targeted agents in patients with advanced differentiated and medullary thyroid cancer treated at a single academic cancer center. We determined efficacy and compared front-line and second-line benefit using biochemical and anatomic response, time to treatment failure, and progression-free survival (PFS). Statistical differences were assessed by t test and chi-square test. Survival curves were generated by the Kaplan-Meier method. Differences in survival were assessed using the log-rank test, and a p value <.05 was considered significant. We identified 39 patients with advanced differentiated and medullary thyroid cancer treated with targeted biologic agents. Median age was 56.3 years. Overall, 25 men and 14 women participated. Histology showed 23% medullary and 77% differentiated cancer. Nineteen patients progressed on front-line therapy and subsequently received second-line therapy. Targeted agents conferred clinically meaningful benefit in the second-line setting in terms of biochemical response (13.3%), clinical benefit (83.3%), median time to treatment failure (4.0 months; 95% confidence interval: 2.6-8.2), and median PFS (4.6 months; 95% confidence interval: 3.2-8.2). Second-line benefit (median PFS) was more modest in comparison to the front-line setting in both genders (women: 3 months vs. 12.2 months; men: 6 months vs. 19.7 months), in differentiated cancers (4.1 months vs. 15.7 months), and with vascular targeting agents (4.4 months vs. 20.1 months). Patients with advanced thyroid cancer derived meaningful clinical benefit from additional therapy with a biologic agent following disease progression on front-line targeted therapy.
    The Oncologist 10/2013; · 4.10 Impact Factor
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    ABSTRACT: Epidermal growth factor receptor (EGFR) and cyclooxygenase 2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions. 36 subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. Erlotinib was escalated following a standard 3+3 design at 50, 75, and 100mg orally daily and celecoxib was fixed at 400mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6 and 12 months. Erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400mg BID was 50mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response 43%, partial response 14%, stable disease 29%, disease progression 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (~308L) and CL/F (8.3L/hr) compared to previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6hr. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated.
    Cancer Prevention Research 10/2013; · 4.89 Impact Factor
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    ABSTRACT: Cabazitaxel (Jevtana) has been approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, most patients progress and become chemoresistant, which remains a major challenge in the management of advanced PCa. In this study, we investigated whether genistein, an isoflavone abundant in soy products, could sensitize mCRPC cells to cabazitaxel treatment in experimental models. The in vitro and in vivo effect of genistein in enhancing the response of mCRPC cells to cabazitaxel chemotherapy was evaluated in experimental models. Genistein increases the expression of pro-apoptotic protein Bax, activates apoptotic signals, and enhances the response to cabazitaxel treatment in mCRPC cells. In a PC3-luciferase xenograft model, the combined treatment with genistein and cabazitaxel significantly retarded the growth of mCRPC when compared to vehicle control, cabazitaxel, or genistein. Tissue staining confirmed the in vivo effect of genistein on the induction of Bax and activation of apoptosis. This study provided the first preclinical evidence supporting that genistein could be beneficial in improving cabazitaxel chemotherapy in mCRPC. Prostate © 2013 Wiley Periodicals, Inc.
    The Prostate 09/2013; · 3.84 Impact Factor

Publication Stats

939 Citations
498.39 Total Impact Points


  • 2014
    • Georgia Department of Public Health
      Marietta, Georgia, United States
  • 2010–2014
    • Emory University
      • • Department of Biostatistics and Bioinformatics
      • • Department of Hematology and Medical Oncology
      • • Department of Urology
      Atlanta, Georgia, United States
  • 2013
    • Hospital Universitario Ruiz y Paez
      Bolívar, Estado Bolívar, Venezuela
  • 2011
    • Moffitt Cancer Center
      • Department of Cancer Epidemiology
      Tampa, Florida, United States
  • 2005–2010
    • Children's Oncology Group
      Monrovia, California, United States
  • 2004–2009
    • University of Southern California
      • • Keck School of Medicine
      • • Department of Preventive Medicine
      Los Angeles, California, United States
    • University of California, Los Angeles
      Los Angeles, California, United States