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1.  A translational, pharmacodynamic and pharmacokinetic phase IB clinical study of everolimus in resectable non-small cell lung cancer 
Purpose
Altered PI3K/mTOR pathway is implicated in lung cancer but mTOR inhibitors have failed to demonstrate efficacy in advanced lung cancer. We studied the pharmacodynamic effects of everolimus in resectable non-small cell lung cancer (NSCLC) to inform further development of these agents in lung cancer.
Experimental Design
We enrolled 33 patients and obtained baseline tumor biopsy and FDG-PET/CT imaging followed by everolimus treatment (5 or 10 mg daily, up to 28 days), or without intervening treatment for controls. Target modulation by everolimus was quantified in vivo and ex vivo by comparing metabolic activity on paired PET scans and expression of active phosphorylated forms of mTOR, Akt, S6, eIF4e, p70S6K, 4EBP1 and total Bim protein between pretreatment and post treatment tissue samples.
Results
There were 23 patients on the treatment arm and 10 controls; median age 64 years; 22 (67%) were adenocarcinomas. There was a dose-dependent reduction in metabolic activity (SUVmax: 29.0%, −21%, −24%; p=0.014), tumor size (10.1%, 5.8%, −11.6%; p=0.047), and modulation of S6 (−36.1, −13.7, −77.0; p=0.071) and pS6 (−41.25, −61.57, −47.21; p=0.063) in patients treated in the control, 5mg and 10mg cohorts respectively. Targeted DNA sequencing in all patients along with exome and whole transcriptome RNA-seq in an index patient with hypersensitive tumor was employed to further elucidate the mechanism of everolimus activity.
Conclusion
This “window-of-opportunity” study demonstrated measurable, dose-dependent, biologic, metabolic and antitumor activity of everolimus in early stage NSCLC.
doi:10.1158/1078-0432.CCR-14-1998
PMCID: PMC4401630  PMID: 25673697
Lung cancer; everolimus; biomarker; PET; pharmacodynamic
2.  HPV16 oncoprotein regulates the translocation of β-catenin via activation of EGFR 
Cancer  2014;121(2):214-225.
Background
To understand the mechanism of frequent and early lymph node metastasis in high risk human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC), we investigated whether β-catenin is regulated by 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. Expression and subcellular localization of β-catenin and EGFR activation were also studied in HPV-positive and -negative head and neck SCC cell lines by Western blot analysis. HPV16 E6 siRNA was used to elucidate the effect of 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.
Results
Our results showed that membrane weighted index (WI) of β-catenin was inversely correlated with p16 positivity (p<0.001) and lymph node metastasis (p=0.026), while nuclear staining of β-catenin was associated with p16-positive OPSCC (p<0.001). A low level of membrane β-catenin expression was significantly associated with disease free and overall survival (p<0.0001 in both cases). Furthermore, the membrane WI of EGFR was inversely correlated with p16 positivity (p<0.001) and positively correlated with membrane β-catenin (p<0.001). Our in vitro study showed that HPV16 E6 repression led to reductions of phosphoEGFR, and nuclear β-catenin, which were also observed after erlotinib treatment, and inhibition of invasion.
Conclusions
Our findings suggest that HPV16 E6 mediates the translocation of β-catenin to the nucleus, which may be regulated by activated EGFR.
doi:10.1002/cncr.29039
PMCID: PMC4293285  PMID: 25209444
HPV; oropharyngeal squamous cell carcinoma; β-catenin; EGFR; lymph node metastasis
3.  A Phase II Trial and Pharmacokinetic Study of Oxaliplatin in Children with Refractory Solid Tumors: A Children's Oncology Group Study 
Pediatric blood & cancer  2010;55(3):440-445.
Background
Platinating agents are used in the treatment of a spectrum of childhood cancers. Oxaliplatin, a third generation platinum compound, may provide less toxicity and be more effective. A phase 2 study was performed to estimate the response rate to single agent oxaliplatin in patients with refractory pediatric solid tumors, and to further describe the toxicities and pharmacokinetics of the drug in this population.
Patients and Methods
Subjects, ≤ 21 years of age at original diagnosis, received oxaliplatin (130 mg/m2) intravenously every 21 days. Prior platinum exposure was acceptable. Histologies included: Ewing sarcoma/peripheral PNET, osteosarcoma, rhabdomyosarcoma, neuroblastoma, high and low grade astrocytoma, brain stem glioma, ependymoma, hepatoblastoma and selected rare tumors. A two-stage design, enrolling 10+10 subjects, was used for each disease stratum. Limited sampling pharmacokinetic studies were performed.
Results
Of 124 eligible subjects (75 males), 113 were evaluable for response and 69 (62%) had received platinum previously. Only one objective response was observed, a partial response in a 6 year old child with ependymoma. An additional 13 subjects with various other solid tumors had stable disease, receiving a median (range) of 13.5 (2-17) cycles. Five subjects completed 17 treatment cycles. Thrombocytopenia was the most common toxicity observed. The median (range) terminal half-life and clearance for ultrafiltrable platinum were 293 (187 to 662 hours) and 14.0 (1.9 to 24.9 L/hr/m2), respectively (n=49).
Conclusions
Although reasonably well tolerated, oxaliplatin administered as a single agent has limited activity in pediatric patients with relapsed or refractory solid tumors.
doi:10.1002/pbc.22544
PMCID: PMC4665115  PMID: 20658614
oxaliplatin; phase II study; pediatric; refractory solid tumor; pharmacokinetics
4.  Randomized Trial of Hydroxychloroquine for Newly-diagnosed Chronic Graft-versus-Host Disease in Children: A Children’s Oncology Group Study 
The Children’s Oncology Group conducted a multi-center Phase III trial for chronic GVHD (cGVHD). The double-blind placebo-controlled randomized study evaluated hydroxychloroquine added to standard therapy for children with newly-diagnosed cGVHD. The study also used a novel grading and response scoring system and evaluated clinical laboratory correlates of cGVHD. The primary endpoint was complete response (CR) after 9 months of therapy. Fifty-four patients (27 on each arm) were enrolled prior to closure due to slow accrual. The CR rate was 28% in the hydroxychloroquine arm vs. 33% in the placebo arm (OR=0.77, 95% CI: 0.20–2.93, p=0.75) for 42 evaluable patients. For 41 patients with severity assessment at enrollment, 20 (49%) were severe and 18 (44%) moderate according to the NIH Consensus Conference global scoring system. The CR rate was 15% for severe cGVHD and 44% for moderate cGVHD (OR=0.24, 95% CI: 0.05–1.06, p = 0.07). Although the study could not resolve the primary question, it provided important information for future cGVHD study design in this population.
doi:10.1016/j.bbmt.2011.05.016
PMCID: PMC4627789  PMID: 21689773
Chronic graft-versus-host disease; GVHD; randomized; hydroxychloroquine
5.  Genistein Enhances the Efficacy of Cabazitaxel Chemotherapy in Metastatic Castration-Resistant Prostate Cancer Cells 
The Prostate  2013;73(15):1681-1689.
BACKGROUND
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.
METHODS
The in vitro and in vivo effect of genistein in enhancing the response of mCRPC cells to cabazitaxel chemotherapy was evaluated in experimental models.
RESULTS
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.
CONCLUSION
This study provided the first preclinical evidence supporting that genistein could be beneficial in improving cabazitaxel chemotherapy in mCRPC.
doi:10.1002/pros.22705
PMCID: PMC4499861  PMID: 23999913
genistein; cabazitaxel; prostate cancer; experimental model; chemoresistance
6.  Combination of Anti-HER3 Antibody MM-121/SAR256212 and Cetuximab Inhibits Tumor Growth in Preclinical Models of Head and Neck Squamous Cell Carcinoma (HNSCC) 
Molecular cancer therapeutics  2014;13(7):1826-1836.
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.
doi:10.1158/1535-7163.MCT-13-1093
PMCID: PMC4090261  PMID: 24748655
Cetuximab; MM-121; HNSCC; HER3; EGFR
7.  Targeted Iron-Oxide Nanoparticle for Photodynamic Therapy and Imaging of Head and Neck Cancer 
ACS Nano  2014;8(7):6620-6632.
Photodynamic therapy (PDT) is a highly specific anticancer treatment modality for various cancers, particularly for recurrent cancers that no longer respond to conventional anticancer 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 β1. 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 nontargeted IO-Pc 4 and targeted Fmp-IO-Pc 4 NPs accumulated in xenograft tumors with higher concentrations than nonformulated 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 nontargeted 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.
doi:10.1021/nn501652j
PMCID: PMC4155749  PMID: 24923902
iron-oxide nanoparticle; Fmp-IO-Pc 4; photodynamic therapy; head and neck cancer; magnetic resonance imaging; integrin β1
8.  HPV-associated lung cancers: an international pooled analysis 
Carcinogenesis  2014;35(6):1267-1275.
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 = 3249 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 and 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 with HPV18, except in North America. HPV16/18-positive lung cancer was less likely observed among White race (adjusted odds ratio [OR] = 0.33, 95% confidence interval [CI] = 0.12–0.90), whereas 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.
doi:10.1093/carcin/bgu038
PMCID: PMC4043241  PMID: 24523449
9.  Predictive Power of Pretreatment Prognostic Factors in Children with Hepatoblastoma: A Report from the Children’s Oncology Group 
Pediatric blood & cancer  2009;53(6):1016-1022.
Background
PRETEXT is used to stratify risk in children with hepatoblastoma by the Liver Tumor Strategy Group (SIOPEL) of the International Society of Pediatric Oncology (SIOP). A recent analysis excluding patients that did not survive neoadjuvant chemotherapy, concluded that PRETEXT was superior to Children’s Oncology Group (COG) stage for predicting survival. Puzzled by this result, we made a similar comparison of PRETEXT and COG stage. This time, however, we include all patients, and we compare predictive value at diagnosis, instead of after neoadjuvant chemotherapy.
Methods
Hepatoblastoma patients in INT-0098 were retrospectively reviewed for PRETEXT and other potential prognostic factors including pathologic subtype, and alpha-fetoprotein (AFP).
Results
5-year overall survival by PRETEXT was 88.9%, 84.5%, 71.6%, and 30.9%, for PRETEXT I, II, III, and IV, respectively. The 5-year overall survival rates by COG Stage were 100%, 97.5%, 100%, 70.2%, and 39.3% for Stage I pure fetal histology (PFH), Stage I unfavorable histology (UH = not PFH), Stage II, Stage III, and Stage IV, respectively. PRETEXT added significant additional prognostic information within the COG Stage III, but not COG Stage IV. Additional prognostic factors statistically significant for an increased risk of death were small-cell-undifferentiated (SCU) histologic subtype and AFP<100 at diagnosis.
Conclusions
PRETEXT, COG stage, SCU histology, and AFP<100, as assessed at diagnosis, are important determinants of survival that will allow us to better develop common international criteria for risk stratification. Common risk stratification is an essential prerequisite to establish effective cooperation across the ocean in this field of rare tumors.
doi:10.1002/pbc.22088
PMCID: PMC4408767  PMID: 19588519
hepatoblastoma; stage; PRETEXT; alpha-fetoprotein (AFP); small cell undifferentiated histology; prognostic factors; overall survival; surgical margin
10.  CHRONIC HEALTH CONDITIONS AND HEALTH-RELATED QUALITY OF LIFE IN SURVIVORS OF CHILDHOOD ACUTE MYELOID LEUKEMIA (AML): A Report from the Children's Oncology Group 
Pediatric blood & cancer  2013;61(4):729-736.
Background
Therapy for childhood acute myeloid leukemia (AML) has historically included chemotherapy with or without autologous bone marrow transplant (autoBMT) or allogeneic hematopoietic stem cell transplantation (alloBMT). We sought to compare health-related quality-of-life (HRQOL) outcomes between these treatment groups.
Procedure
Five-year survivors of AML diagnosed before age 21 and enrolled and treated from 1979 to 1995 on one of 4 national protocols were interviewed. These survivors or proxy caregivers completed a health questionnaire and an HRQOL measure.
Results
Of 180 survivors, 100 were treated with chemotherapy only, 26 with chemotherapy followed by autoBMT, and 54 with chemotherapy followed by alloBMT. Median age at interview was 20 years (range 8 to 39). Twenty-one percent reported a severe or life-threatening chronic health condition (chemotherapy-only 16% vs. autoBMT 21% vs. alloBMT 33%; p=0.02 for chemotherapy-only vs. alloBMT). Nearly all (95%) reported excellent, very good or good health. Reports of cancer-related pain and anxiety did not vary between groups. HRQOL scores among 136 participants ≥ 14 years of age were similar among groups and to the normative population, though alloBMT survivors had a lower physical mean summary score (49.1 alloBMT vs. 52.2 chemotherapy-only; p=0.03). Multivariate analyses showed the presence of severe chronic health conditions to be a strong predictor of physical but not mental mean summary scores.
Conclusions
Overall HRQOL scores were similar among treatment groups, although survivors reporting more health conditions or cancer-related pain had diminished HRQOL. Attention to chronic health conditions and management of cancer-related pain may improve QOL.
doi:10.1002/pbc.24881
PMCID: PMC4190066  PMID: 24285698
pediatric; bone marrow transplantation; acute myeloid leukemia; late effects; chronic health condition; quality of life
11.  Chemoprevention of Head and Neck Cancer with Celecoxib and Erlotinib: Results of a Phase Ib and Pharmacokinetic Study 
Purpose
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.
Patients and Methods
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.
Results
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.
Conclusion
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.
doi:10.1158/1940-6207.CAPR-13-0215
PMCID: PMC4351876  PMID: 24085777
12.  Diagnostic Accuracy of Ultrasonic Histogram Features to Evaluate Radiation Toxicity of the Parotid Glands 
Academic radiology  2014;21(10):1304-1313.
Rationale and Objectives
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).
Materials and Methods
Thirty-four patients, who have developed xerostomia after RT for head-and-neck cancer, were enrolled. Radiation-induced xerostomia was defined by the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer morbidity scale. Ultrasound scans were performed on each patient’s parotids bilaterally. The 34 patients were stratified into the acute-toxicity groups (16 patients, ≤3 months after treatment) and the late-toxicity group (18 patients, >3 months after treatment). A separate control group of 13 healthy volunteers underwent similar ultrasound scans of their parotid glands. Six sonographic features were derived from the echo-intensity histograms to assess acute and late toxicity of the parotid glands. The quantitative assessments were compared to a radiologist’s clinical evaluations. The diagnostic accuracy of these ultrasonic histogram features was evaluated with the receiver operating characteristic (ROC) curve.
Results
With an area under the ROC curve greater than 0.90, several histogram features demonstrated excellent diagnostic accuracy for evaluation of acute and late toxicity of parotid glands. Significant differences (P < .05) in all six sonographic features were demonstrated between the control, acute-toxicity, and late-toxicity groups. However, subjective radiologic evaluation cannot distinguish between acute and late toxicity of parotid glands.
Conclusions
We demonstrated that ultrasound histogram features could be used to measure acute and late toxicity of the parotid glands after head-and-neck cancer RT, which may be developed into a low-cost imaging method for xerostomia monitoring and assessment.
doi:10.1016/j.acra.2014.05.017
PMCID: PMC4345172  PMID: 25088832
Xerostomia; ultrasound; parotid gland; radiation toxicity; sonographic features
13.  Escalation with Overdose Control using All Toxicities and Time to Event Toxicity Data in Cancer Phase I Clinical Trials 
Contemporary clinical trials  2014;37(2):322-332.
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.
doi:10.1016/j.cct.2014.02.004
PMCID: PMC4046505  PMID: 24530487
Escalation with Overdose Control; Maximum Tolerated Dose; Multiple Toxicities; Quasi-continuous; Normalized Equivalent Toxicity Score; Toxicity Score System; Time to Toxicity Event; Phase I Clinical Trial
14.  Anaplastic lymphoma kinase (ALK) gene alteration in signet ring cell carcinoma of the gastrointestinal tract 
Objectives:
ALK-EML4 translocation is an established driver aberration in non-small cell lung cancer (NSCLC), with reported predilection for cases with signet ring histology. We assessed the presence of anaplastic lymphoma kinase (ALK) gene rearrangements in signet ring cancers arising in the stomach and colon.
Methods:
Histologically confirmed cases of signet ring adenocarcinoma of the stomach or the colon were identified. The presence of the classic ALK and EML4 fusion gene was initially determined by fluorescence in-situ hybridization (FISH) technique. Immunohistochemistry (IHC) was performed using two previously validated antibodies, ALK1 clone (1:100; DAKO) and 5A4 (Novocastra, Leica Biosystems) along with positive controls of ALK-translocated lung cancer.
Results:
We employed 42 cases of signet ring carcinoma diagnosed between 2001 and 2011; 25 gastric and 17 colon cancer. Median age 63.3 years; male/female 17/25; race, black 47.5%, white 47.5%, others, 5%; stage I, 21.4%; stage II, 31%; stage III, 26.2%; stage IV, 21.4%. One of 42 cases (2.3%) was positive for ALK translocation by FISH using the standard criteria of at least 15% positive cells for the break-apart signal (50–70 cells enumerated per case). Using a less restrictive cut-off of 10% positive cells, 7 cases (16%) were considered possibly positive. None of the ‘possibly positive’ cases was found to harbor ALK translocation by another molecular testing approach (IHC). IHC with two previously validated monoclonal antibodies showed 0 of 42 (0%) cases positive.
Conclusions:
ALK gene rearrangement is very rare in gastrointestinal cancers and enrichment strategy focusing on signet ring cell histology did not significantly improve the detection rate.
doi:10.1177/1758834014567117
PMCID: PMC4346214  PMID: 25755678
ALK rearrangement; ALK-EML4 fusion; colon; signet ring cell cancer; stomach
15.  Luteolin nanoparticle in chemoprevention – in vitro and in vivo anticancer activity 
Cancer prevention (chemoprevention) by using naturally occurring dietary agents has gained immense interest due to 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 towards 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 4.13μM, and that of luteolin was 6.96μM. In H292 cells, the IC50 of luteolin was 15.56μM, and Nano-Luteolin was 14.96μM. 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.
doi:10.1158/1940-6207.CAPR-13-0230
PMCID: PMC3888883  PMID: 24403290
Cancer; chemoprevention; luteolin; nanotechnology; nanomedicine
16.  P38 MAPK contributes to resistance and invasiveness of HER2-overexpressing breast cancer 
Current medicinal chemistry  2014;21(4):501-510.
Intrinsic or acquired resistance to the HER2-targeted therapy trastuzumab is a clinical concern in the treatment of patients with HER2-over-expressing metastatic breast cancers. We demonstrate here that multiple models of intrinsic and acquired resistance exhibit increased phosphorylation of p38 MAPK. Kinase inhibition of p38 rescued trastuzumab sensitivity in cells with acquired resistance. In addition, knockdown of p38 increased sensitivity to trastuzumab in an intrinsically resistant cell line. We previously reported that expression of growth differentiation factor 15 (GDF15) is increased in trastuzumab-resistant HER2-overexpressing breast cancer cells. In this study, we found that exogenous GDF15 or stable overexpression of GDF15 stimulated p38 phosphorylation in HER2-positive cells, suggesting a possible mechanism by which p38 is activated in resistant cells. GDF15 stable clones showed significantly increased invasiveness, which was rescued by p38 kinase inhibition, suggesting that p38 plays a role in the pro-invasive phenotype conferred by GDF15. Importantly, immunohistochemical analysis of a breast tumor tissue array indicated a significant (p=0.0053) correlation between HER2 and phosphorylated p38 specifically in GDF15-positive tissues. Our results suggest that p38 signaling drives trastuzumab resistance and invasiveness in HER2-overexpressing breast cancer. Upstream growth factor signals that have previously been implicated in trastuzumab resistance, such as GDF15, may contribute to the increased phosphorylation of p38 found in resistant cells.
PMCID: PMC4262834  PMID: 24251561
breast cancer; HER2; invasion; p38; trastuzumab
17.  Poly (ADP) ribose polymerase enzyme inhibitor, veliparib, potentiates chemotherapy and radiation in vitro and in vivo in small cell lung cancer 
Cancer Medicine  2014;3(6):1579-1594.
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.
doi:10.1002/cam4.317
PMCID: PMC4298385  PMID: 25124282
Carboplatin; cisplatin; etoposide; PARP; SCLC; veliparib (ABT-888)
18.  Targeted Iron-Oxide Nanoparticle for Photodynamic Therapy and Imaging of Head and Neck Cancer 
ACS nano  2014;8(7):6620-6632.
Photodynamic therapy (PDT) is a highly specific anticancer treatment modality for various cancers, particularly for recurrent cancers that no longer respond to conventional anticancer 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 β1. 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 nontargeted IO-Pc 4 and targeted Fmp-IO-Pc 4 NPs accumulated in xenograft tumors with higher concentrations than nonformulated 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 nontargeted 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.
doi:10.1021/nn501652j
PMCID: PMC4155749  PMID: 24923902
iron-oxide nanoparticle; Fmp-IO-Pc 4; photodynamic therapy; head and neck cancer; magnetic resonance imaging; integrin β1
19.  High-Risk Medulloblastoma: A Pediatric Oncology Group Randomized Trial of Chemotherapy Before or After Radiation Therapy (POG 9031) 
Journal of Clinical Oncology  2013;31(23):2936-2941.
Purpose
To compare event-free survival (EFS) in children with high-risk medulloblastoma randomly assigned to receive either chemotherapy before radiation or chemotherapy after radiation.
Patients and Methods
One hundred twelve patients were randomly assigned to each arm. Criteria used to categorize patients as high risk included M1-4 disease by modified Chang staging classification, T3b/T4 disease, or greater than 1.5 cm3 of residual tumor after surgery. Postoperatively, children with high-risk medulloblastoma were randomly assigned to two arms, either chemotherapy entailing three cycles of cisplatin and etoposide before radiation (chemotherapy first [CT1]) or the same chemotherapy regimen after radiation (radiation therapy first [RT1]). Both groups received consolidation chemotherapy consisting of vincristine and cyclophosphamide.
Results
The median follow-up time was 6.4 years. Five-year EFS was 66.0% in the CT1 arm and 70.0% in the RT1 arm (P = .54), and 5-year overall survival in the two groups was 73.1% and 76.1%, respectively (P = .47). In the CT1 arm, 40 of the 62 patients with residual disease achieved either complete or partial remission.
Conclusion
Five-year EFS did not differ significantly whether, after surgery, patients received chemotherapy before or after radiotherapy.
doi:10.1200/JCO.2012.43.9984
PMCID: PMC3732312  PMID: 23857975
20.  Phase II Study of Docetaxel in Combination with Everolimus for Second- or Third-Line Therapy of Advanced Non-Small-Cell Lung Cancer 
We conducted a phase II study of docetaxel in combination with everolimus, a mammalian target of rapamycin (mTOR) inhibitor, for salvage therapy of advanced non–small-cell lung cancer (NSCLC) based on promising preclinical and early-phase clinical data. Patients with advanced-stage NSCLC treated with one or two previous systemic therapy regimens were given docetaxel (60 mg/m2) and everolimus (5 mg orally once daily on days 1–19) every 3 weeks. Archived tumor specimens were evaluated for markers of mTOR pathway activation (total and phosphorylated mTOR, Akt, S6, eIF4e, and 4EBP1). Twenty-eight patients were enrolled (median age: 62 years; male: 13; Caucasians: 19; adenocarcinoma: 20; performance status 0, 3; performance status 1, 23; 1 previous regimen, 16). A median of 3.5 cycles of therapy was administered. Two patients experienced partial response and 15 had stable disease (clinical benefit rate, 70%). The 6-month progression-free survival rate was 5%, and the median overall survival was 9.6 months. Low pAkt expression correlated with clinical benefit rate (p = 0.01) but not with progression-free survival or overall survival. The combination of everolimus and docetaxel was tolerated well, but the efficacy was relatively modest in an unselected population of patients with NSCLC.
doi:10.1097/JTO.0b013e318282709c
PMCID: PMC4126230  PMID: 23407561
Non–small-cell lung cancer; Docetaxel; Everolimus
21.  Progesterone and vitamin D: improvement after traumatic brain injury in middle-aged rats 
Hormones and behavior  2013;64(3):10.1016/j.yhbeh.2013.06.009.
Progesterone (PROG) and vitamin D hormone (VDH) have both shown promise in treating traumatic brain injury (TBI). Both modulate apoptosis, inflammation, oxidative stress, and excitotoxicity. We investigated whether 21 days of VDH deficiency would alter cognitive behavior after TBI and whether combined PROG and VDH would improve behavioral and morphological outcomes more than either hormone alone in VDH-deficient middle-aged rats given bilateral contusions of the medial frontal cortex. PROG (16 mg/kg) and VDH (5 µg/kg) were injected intraperitoneally 1 hour post-injury. Eight additional doses of PROG were injected subcutaneously over 7 days post-injury. VDH deficiency itself did not significantly reduce baseline behavioral functions or aggravate impaired cognitive outcomes. Combination therapy showed moderate improvement in preserving spatial and reference memory but was not significantly better than PROG monotherapy. However, combination therapy significantly reduced neuronal loss and the proliferation of reactive astrocytes, and showed better efficacy compared to VDH or PROG alone in preventing MAP-2 degradation. VDH+PROG combination therapy may attenuate some of the potential long-term, subtle, pathophysiological consequences of brain injury in older subjects.
doi:10.1016/j.yhbeh.2013.06.009
PMCID: PMC3833454  PMID: 23896206
Aging; Combination treatments; Functional repair; Progesterone; Traumatic brain injury; Vitamin D deficiency; Vitamin D3 hormone
22.  Acetylated Tubulin (AT) as a Prognostic Marker in Squamous Cell Carcinoma of the Head and Neck 
Head and Neck Pathology  2013;8(1):66-72.
Acetylated tubulin (AT) expression has been proposed as a marker for sensitivity to taxane chemotherapy. We wanted to explore AT as a prognostic marker in squamous cell carcinoma of the head and neck (SCCHN). We assessed AT expression in archival tissue from our institutional tissue bank of primary SCCHN specimens. We also examined AT expression on pre-therapy tissues of patients with SCCHN receiving induction chemotherapy with docetaxel, cisplatin and 5FU (TPF IC). AT expression was assessed on archival cases of SCCHN with (N = 63) and without (N = 82) locoregional lymph node metastases (LNM). The predominant tumor site was oral cavity (52 %). Immunohistochemistry staining was based on staining intensity and percentage of tumor cells stained to create a weighted index (WI). A total of nine patients who received TPF IC were evaluable for response by RECIST and also had pre-therapy tissues available. A significant independent correlation between AT and tumor grade (p = 0.001) and primary location (p = 0.008) was noted. There was a trend of higher AT in patients with presence of LNM (p = 0.052) and a trend in improved OS for patients with an AT WI below the median compared to those above the median for patients with no LNM (p = 0.054). For patients treated with induction TPF, we observed an inverse correlation between AT expression and response to TPF IC (p = 0.0071). AT expression is correlated with tumor grade and primary site. There was an observed trend correlating AT with presence nodal metastases. The observed inverse correlation with response to taxane based chemotherapy needs validation in a larger sample size.
doi:10.1007/s12105-013-0476-6
PMCID: PMC3950380  PMID: 23881549
Taxane sensitivity; Acetylated tubulin; Head and neck cancer; Induction therapy; Nodal metastases
23.  RRM2 Regulates Bcl-2 in Head and Neck and Lung Cancers: A Potential Target for Cancer Therapy 
Purpose
Ribonucleotide reductase subunit M2 (RRM2) plays an active role in tumor progression. Recently, we reported that depletion of RRM2 by systemic delivery of a nanoparticle carrying RRM2-specific siRNA suppresses head and neck tumor growth. The aim of this study is to clarify the underlying mechanism by which RRM2 depletion inhibits tumor growth.
Methods
siRNA-mediated gene silencing was performed to downregulate RRM2. Immunoblotting, RT-PCR, confocal microscopy, tissue fractionation, gene overexpression and knockdown were employed to analyze critical apoptosis signaling. Conventional immunohistochemistry (IHC) and quantum dot-based IHF were applied to detect RRM2 and Bcl2 expression and localization in tissue samples from patients and mice.
Results
Knockdown of RRM2 led to apoptosis through the intrinsic pathway in head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cell lines. We demonstrated that Bcl-2 is a key determinant controlling apoptosis, both in vitro and in vivo and that RRM2 depletion significantly reduces Bcl-2 protein expression. We observed that RRM2 regulates Bcl-2 protein stability, with RRM2 suppression leading to increased Bcl-2 degradation, and identified their co-localization in HNSCC and NSCLC cells. In a total of 50 specimens each from HNSCC and NSCLC patients, we identified the co-localization of Bcl-2 and RRM2 and found a significant positive correlation between their expression in HNSCC (R=0.98, p<0.0001) and NSCLC (R=0.92, p<0.0001) tumor tissues.
Conclusion
Our novel findings add to the knowledge of RRM2 in regulating expression of the anti-apoptotic protein Bcl-2 and reveal a critical link between RRM2 and Bcl-2 in apoptosis signaling.
doi:10.1158/1078-0432.CCR-13-0073
PMCID: PMC3747783  PMID: 23719266
RRM2; Bcl-2; RNAi; Apoptosis
24.  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
25.  Clinical Efficacy of Targeted Biologic Agents as Second-Line Therapy of Advanced Thyroid Cancer 
The Oncologist  2013;18(12):1262-1269.
The authors report an experience using biologic agents as second-line treatment for advanced thyroid cancer and show that patients derived a modest additional benefit in comparison to the front-line treatment. The findings are relevant for the clinical management of patients and for future studies of second-line targeted therapy of thyroid cancer.
Learning Objectives
List the therapeutic opportunities with tyrosine kinase inhibitors for advanced thyroid cancer, especially in the frontline setting.Describe and discuss the current knowledge and experience with salvage therapy with biologic agents for thyroid cancer.
Introduction.
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.
Methods.
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.
Results.
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).
Conclusion.
Patients with advanced thyroid cancer derived meaningful clinical benefit from additional therapy with a biologic agent following disease progression on front-line targeted therapy.
doi:10.1634/theoncologist.2013-0250
PMCID: PMC3868420  PMID: 24153240
Thyroid cancer; Biologic agents; Second-line

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