Afshin Dowlati

Hackensack University Medical Center, Хакенсак, New Jersey, United States

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Publications (141)979.89 Total impact

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    ABSTRACT: Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with, number NCT01721759. Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7-22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2-4·8), and median duration of response was not reached (95% CI 8·31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7-10·9). 20 (17%) of 117 patients reported grade 3-4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. Bristol-Myers Squibb. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 02/2015; DOI:10.1016/S1470-2045(15)70054-9 · 24.73 Impact Factor
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    ABSTRACT: CD30 is a cytokine receptor belonging to the tumor necrosis factor superfamily (TNFRSF8) that acts as a regulator of apoptosis. The presence of CD30 antigen is important in the diagnosis of Hodgkin's disease and anaplastic large cell lymphoma. There have been sporadic reports of CD30 expression in non-lymphoid tumors, including malignant mesothelioma. Given the remarkable success of brentuximab vedotin, an antibody-drug conjugate directed against CD30 antigen, in lymphoid malignancies, we undertook a study to examine the incidence of CD30 in mesothelioma and to investigate the ability to target CD30 antigen in mesothelioma. Mesothelioma tumor specimens (N = 83) were examined for CD30 expression by immunohistochemistry. Positive CD30 expression was noted in 13 mesothelioma specimens, primarily those of epithelial histology. There was no significant correlation of CD30 positivity with either tumor grade, stage or survival. Examination of four mesothelioma cell lines (H28, H2052, H2452, and 211H) for CD30 expression by both FACS analysis and confocal microscopy showed that CD30 antigen localized to the cell membrane. Brentuximab vedotin treatment of cultured mesothelioma cells produced a dose-dependent decrease in cell growth and viability at clinically relevant concentrations. Our studies validate the presence of CD30 antigen in a subgroup of epithelial-type mesothelioma tumors and indicate that selected mesothelioma patients may derive benefit from brentuximab vedotin treatment. Copyright © 2015, American Association for Cancer Research.
    Molecular Cancer Therapeutics 01/2015; DOI:10.1158/1535-7163.MCT-14-0972 · 6.11 Impact Factor
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    ABSTRACT: Unlike lung adenocarcinoma, little progress has been made in the treatment of squamous cell lung carcinoma (SCC). The Cancer Genome Atlas (TCGA) has recently reported that receptor tyrosine kinase signaling pathways are altered in 26% of SCC tumors, validating the importance of downstream Signal Transducers and Activators of Transcription 3 (STAT3) activity as a prime therapeutic target in this cancer. In the present report we examine the status of an endogenous inhibitor of STAT3, called Protein Inhibitor of Activated STAT3 (PIAS3), in SCC and its potential role in this disease. We examine PIAS3 expression in SCC tumors and cell lines by immunohistochemistry of a tissue microarray and western blotting. PIAS3 mRNA expression and survival data are analyzed in the TCGA data set. SCC cell lines are treated with curcumin to regulate PIAS3 expression and cell growth. PIAS3 protein expression is decreased in a majority of lung SCC tumors and cell lines. Analysis of PIAS3 mRNA transcript levels demonstrated that low PIAS3 levels predicted poor survival; Cox regression analysis revealed a hazard ratio of 0.57 (95% CI: 0.37-0.87), indicating a decrease in the risk of death by 43% for every unit elevation in PIAS3 gene expression. Curcumin treatment increased endogenous PIAS3 expression and decreased cell growth and viability in Calu-1 cells, a model of SCC. Our results implicate PIAS3 loss in the pathology of lung SCC and raise the therapeutic possibility of upregulating PIAS3 expression as a single target that can suppress signaling from the multiple receptor tyrosine kinase receptors found to be amplified in SCC. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
    Cancer Medicine 01/2015; 4(3). DOI:10.1002/cam4.372
  • International journal of radiation oncology, biology, physics 11/2014; 90(5). DOI:10.1016/j.ijrobp.2014.08.170 · 4.18 Impact Factor
  • International journal of radiation oncology, biology, physics 11/2014; 90(5). DOI:10.1016/j.ijrobp.2014.08.035 · 4.18 Impact Factor
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    ABSTRACT: There are currently no molecular targeted approaches to treat small-cell lung cancer (SCLC) similar to those used successfully against non-small-cell lung cancer. This failure is attributable to our inability to identify clinically-relevant subtypes of this disease. Thus, a more systematic approach to drug discovery for SCLC is needed. In this regard, two comprehensive studies recently published in Nature, the Cancer Cell Line Encyclopedia and the Cancer Genome Project, provide a wealth of data regarding the drug sensitivity and genomic profiles of many different types of cancer cells. In the present study we have mined these two studies for new therapeutic agents for SCLC and identified heat shock proteins, cyclin-dependent kinases and polo-like kinases (PLK) as attractive molecular targets with little current clinical trial activity in SCLC. Remarkably, our analyses demonstrated that most SCLC cell lines clustered into a single, predominant subgroup by either gene expression or CNV analyses, leading us to take a pharmacogenomic approach to identify subgroups of drug-sensitive SCLC cells. Using PLK inhibitors as an example, we identified and validated a gene signature for drug sensitivity in SCLC cell lines. This gene signature could distinguish subpopulations among human SCLC tumors, suggesting its potential clinical utility. Finally, circos plots were constructed to yield a comprehensive view of how transcriptional, copy number and mutational elements affect PLK sensitivity in SCLC cell lines. Taken together, this study outlines an approach to predict drug sensitivity in SCLC to novel targeted therapeutics.
    PLoS ONE 09/2014; 9(9):e106784. DOI:10.1371/journal.pone.0106784 · 3.53 Impact Factor
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    ABSTRACT: There is growing interest in defining the somatic mutations associated with small-cell lung cancer (SCLC). Unfortunately, a serious blockade to genomic analyses of this disease is a limited access to tumors because surgery is rarely performed. We used our clinical/pathologic database of SCLC patients to determine the availability of biopsy specimens that could be used for genomic studies and to identify tumors for initial oncogene analysis.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2014; 9(9):1316-1323. DOI:10.1097/JTO.0000000000000234 · 5.80 Impact Factor
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    ABSTRACT: Erlotinib is a tyrosine kinase inhibitor approved for the treatment of patients with advanced non-small cell lung cancer (NSCLC). In these patients, erlotinib prolongs survival but its benefit remains modest since many tumors express wild-type (wt) epidermal growth factor receptor (EGFR) or develop a second-site EGFR mutation. To test drug combinations that could improve the efficacy of erlotinib, we combined erlotinib with quinacrine, which inhibits the FACT (facilitates chromatin transcription) complex that is required for NF-kappaB transcriptional activity. In A549 (wtEGFR), H1975 (EGFR-L858R/T790M) and H1993 (MET amplification) NSCLC cells, this drug combination was highly synergistic, as quantified by Chou-Talalay combination indices, and slowed xenograft tumor growth. At a sub-IC50 but more clinically attainable concentration of erlotinib, quinacrine, alone or in combination with erlotinib, significantly inhibited colony formation and induced cell cycle arrest and apoptosis. Quinacrine decreased the level of active FACT subunit SSRP1 and suppressed NF-kappaB-dependent luciferase activity. Knockdown of SSRP1 decreased cell growth and sensitized cells to erlotinib. Moreover, transcriptomic profiling showed that quinacrine or combination treatment significantly affected cell cycle-related genes that contain binding sites for transcription factors that regulate SSRP1 target genes. As potential biomarkers of drug combination efficacy, we identified genes that were more strongly suppressed by the combination than by either single treatment, and whose increased expression predicted poorer survival in lung adenocarcinoma patients. This preclinical study shows that quinacrine overcomes erlotinib resistance by inhibiting FACT and cell cycle progression, and supports a clinical trial testing erlotinib alone versus this combination in advanced NSCLC.
    Molecular Cancer Therapeutics 09/2014; 13(9):2203-2214. DOI:10.1158/1535-7163.MCT-14-0013 · 6.11 Impact Factor
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    ABSTRACT: Purpose: Deregulation of STAT3 activation is a hallmark of many cancer cells and the underlying mechanisms are subject to intense investigation. We examined the extent of PIAS3 expression in mesothelioma cells and human tumor samples and determined the functional effects of PIAS3 expression on STAT3 signaling. Experimental design: We evaluated the expression of PIAS3 in mesothelioma tumors from patients and correlated the expression levels with the course of the disease. We also measured the effects of enhanced PIAS3 activity on STAT3 signaling, cellular growth and viability in cultured mesothelioma cells. Results: Gene expression databases revealed that mesotheliomas have the lowest levels of PIAS3 transcripts among solid tumors. PIAS3 expression in human mesothelioma tumors is significantly correlated with overall survival intervals (p = 0.058). The high expression of PIAS3 is predictive of a favorable prognosis and decreases the probability of death within one year after diagnosis by 44%. PIAS3 expression is functionally linked to STAT3 activation in mesothelioma cell lines. STAT3 down regulation with siRNA or enhanced expression of PIAS3 both inhibited mesothelioma cell growth and induced apoptosis. Mesothelioma cells are sensitive to curcumin and respond by the induction of PIAS3. Corroborative evidence has been obtained from STAT3 inhibition experiments. Exposure of the cells to a peptide derived from the PIAS3 protein which interferes with STAT3 function resulted in apoptosis induction and the inhibition of cell growth. Conclusion: These results suggest that PIAS3 protein expression impacts survival in mesothelioma patients and that PIAS3 activation could become a therapeutic strategy.
    Clinical Cancer Research 08/2014; 20(19). DOI:10.1158/1078-0432.CCR-14-1233 · 8.19 Impact Factor
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    Afshin Dowlati, Gary Wildey
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2014; 9(6):750-1. DOI:10.1097/JTO.0000000000000176 · 5.80 Impact Factor
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    ABSTRACT: Our prior phase I study of the combination of vascular endothelial growth factor (VEGF) antibody, bevacizumab, and VEGF receptor (VEGFR) inhibitor, sunitinib, in advanced solid tumors identified an encouraging response evaluation. An expansion phase of this study was thus undertaken to obtain further safety data, response assessment and characterization of pharmacodynamic biomarkers in melanoma, renal, and adrenal carcinoma patients. Patients with metastatic solid tumors received sunitinib (37.5 mg/day 4 weeks on/2 weeks off) and bevacizumab (5 mg/kg intravenously every 2 weeks). Responses were assessed every 2 cycles. Serum levels of angiogenic molecules were measured using ELISA assays. Twenty-two patients were enrolled, including 11 melanoma, 5 renal cell carcinoma (RCC), 5 adrenal cancer, and 1 angiosarcoma. Grade 3 or higher adverse events were observed in 15 patients, including hypertension (41%), thrombocytopenia (23%), and fatigue (14%). Three RCC patients, and 1 melanoma patient developed thrombotic microangiopathy (TMA). Partial response (PR) occurred in 21% patients, including melanoma (2), adrenal (1), and renal (1) carcinomas. Overall, 6 patients demonstrated some reduction in their tumor burden. Serum VEGF and several other proangiogenic proteins declined over the first 4 weeks of treatment whereas the putative VEGF-resistant protein, prokineticin-2, increased over 10-fold. Occurrence of TMA related to dual VEGF/VEGFR inhibition can result from systemic or nephron specific injury even in non-renal malignancies. While the combination of sunitinib and bevacizumab was clinically efficacious in renal cell carcinoma and melanoma, the observance of microangiopathy, even in non-RCC patients, is a significant toxicity that precludes further clinical development.
    Cancer biology & therapy 05/2014; 15(8). DOI:10.4161/cbt.29187 · 3.63 Impact Factor
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    ABSTRACT: Background:We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics.Methods:Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m(-2))/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000. At the MTR, additional patients were enrolled to further evaluate tolerability, and the potential effects of pazopanib and lapatinib, inhibitors of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP2C8 and CYP3A4 substrate.Results:Twenty-six patients were enrolled. Dose-limiting toxicities at the MTR (80/400/1000) included grade 4 thrombosis and grade 3 aspartate aminotransferase elevation. Other toxicities included diarrhoea, neutropenia, fatigue, and liver enzyme elevations. Coadministration of pazopanib 400 mg and lapatinib 1000 mg increased paclitaxel maximum plasma concentration (38%) and area under the curve (37%) relative to paclitaxel alone. One patient with a salivary gland tumour had a partial response; three patients had stable disease (⩾6 months).Conclusions:Pazopanib 400 mg per day and lapatinib 1000 mg per day can be combined with paclitaxel 80 mg m(-2) in 28-day cycles. Coadministration of pazopanib and lapatinib, weak inhibitors of CYP2C8 and CYP3A4, had an inhibitory effect on paclitaxel clearance.British Journal of Cancer advance online publication, 6 May 2014; doi:10.1038/bjc.2014.233
    British Journal of Cancer 05/2014; DOI:10.1038/bjc.2014.233 · 4.82 Impact Factor
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    ABSTRACT: Background: Non-small cell lung cancer (NSCLC) cell lines with epidermal growth factor receptor (EGFR) mutations are very sensitive to EGFR inhibitors such as erlotinib (E). However, the efficacy of E is limited in NSCLC cells harboring wild-type (WT) EGFR or second-site mutation EGFR-L858R/T790M. Various mechanisms of resistance have been described including activation of alternate signaling pathways through activation of MET, PI3K and NF-κB. Quinacrine (Q) is member of a group of small molecules called curaxins, which are 9-aminoacridine derivative and known to suppresses NF-κB activity by causing chromatin trapping of the FACT (facilitates chromatin transcription) complex. We evaluated utility of NF-κB inhibition by Q in overcoming the resistance to E in NSCLC cell lines Methods: E resistant NSCLC cell lines, A549 (EGFR WT), H1975 (EGFR-L858R/T790M) and H1993 (Met amplification) were used for drug synergy experiments. MTT assay, flow cytometry, Annexin V/PI staining, western blot and NF-κB luciferase assay were used for analyzing cell proliferation, cell cycle and NF-κB activity. Microarray analysis was performed using the Affymetrix Human Gene 2.0 ST Array. Results: In A549, H1975 and H1993 NSCLC cells, the combination of E and Q is highly synergistic, as quantified by the Chou-Talalay combination indices. Combination treatment significantly inhibited colony formation, induced cell cycle arrest and apoptosis as well as reduced xenograft tumor growth. Upon Q treatment, the FACT subunit SSRP1 disappeared from the soluble protein fraction, and NF-κB dependent luciferase activity was decreased. Knockdown of SSRP1 decreased cell viability and sensitized the cells to E treatment. Whole genome expression analysis of A549 and H1975 cells treated with E only, Q only, or both showed that Q or combination treatment significantly affected genes involved in cell cycle progression or nucleotide metabolism, and many of these genes contain binding sites for transcription factors that regulate SSRP1-enriched genes. Conclusions: We conclude that the combination of Q and E helps overcome E resistance in NSCLC, potentially by targeting FACT and suppressing cell cycle progression.
    2014 American Society of Clinical Oncology Annual Meeting, Chicago; 05/2014
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    ABSTRACT: The treatment of non-acquired immunodeficiency syndrome-defining cancers may be complicated by drug interactions between highly active antiretroviral therapy (HAART) and chemotherapy. This trial is the first by the AIDS Malignancy Consortium to assess targeted therapies and HAART in human immunodeficiency virus-positive patients ( identifier: NCT00890747). In a modified phase 1 study of sunitinib, patients were stratified into 2 treatment arms based on whether they were receiving therapy with ritonavir, a potent CYP3A4 inhibitor. Patients in treatment arm 1 (non-ritonavir HAART) received standard sunitinib dosing (50 mg/day). Treatment arm 2 (ritonavir-based HAART) used a phase 1, 3 + 3 dose escalation design (from 25 mg/day to 50 mg/day). Cycles were comprised of 4 weeks on treatment followed by a 2-week break (6 weeks total). The pharmacokinetics of sunitinib and its active metabolite (N-desethyl sunitinib) were assessed. Nineteen patients were enrolled and were evaluable. Patients on treatment arm 1 tolerated treatment with no dose-limiting toxicity observed. In treatment arm 2, a dose-limiting toxicity was experienced at a dose of 37.5 mg, and an additional 3 of 5 patients experienced grade 3 neutropenia (toxicity graded as per National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]), an uncommon toxicity of sunitinib. No patient achieved a response, but 10 patients had stable disease, including 8 with prolonged disease stability. Efavirenz, a potent inducer of CYP3A4, resulted in increased exposure of N-desethyl sunitinib, whereas ritonavir caused decreased exposure of the metabolite. Hand-foot syndrome was associated with higher steady-state trough concentrations of sunitinib. Patients receiving non-ritonavir-based HAART regimens tolerated standard dosing of sunitinib. Patients receiving ritonavir-based therapy who were treated with a dose of 37.5 mg/day experienced higher toxicities. Dose reductions of sunitinib to 37.5 mg may be warranted in patients receiving ritonavir. Cancer 2013. © 2013 American Cancer Society.
    Cancer 04/2014; 120(8). DOI:10.1002/cncr.28554 · 4.90 Impact Factor
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    ABSTRACT: Background/Purpose This study was designed to evaluate the response and toxicity of sorafenib alone or when combined with carboplatin and paclitaxel in patients with platinum-sensitive, recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer (EOC). Methods Patients with recurrent platinum-sensitive EOC with no more than 2 prior courses of chemotherapy were randomized to single-agent sorafenib 400 mg twice daily or combination sorafenib 400 mg bid (days 2-19) with IV carboplatin (AUC 6) and IV paclitaxel 175 mg/m(2) (S+C/T) every 3 weeks. Single agent sorafenib could cross over to combination upon progression. Results Patients were initially randomized to either arm, however, due to poor accrual, sorafenib arm was prematurely closed. A total of 13 patients were evaluable for response to sorafenib and 23 patients were evaluable for response to S+C/T. Objective response rate (RR) was 15 % for patients on sorafenib vs. 61 % for patients on S+C/T (p = 0.014); stable disease was seen in 62 % and 35 %, respectively. Clinical benefit rate (CBR) at 4 months (mos.) was 69 % for S and 65 % for S+C/T. The median progression free survival was 5.6 months on sorafenib vs. 16.8 months on S+C/T (p = 0.012) and there was no significant difference of overall survival between two arms (p = 0.974) with median overall survival 25.6 months under sorafenib vs. 25.9 months on S+C/T. Patients remained on trial for a median of 7.8 cycles on sorafenib and 5.4 cycles on S+C/T. Conclusion Sorafenib, alone or in combination with carboplatin and paclitaxel, has activity in patients with platinum-sensitive EOC. Sorafenib in combination with carboplatin and paclitaxel improved RR and PFS; however, there were increased grade and frequencies of toxicities.
    Investigational New Drugs 03/2014; DOI:10.1007/s10637-014-0078-5 · 2.93 Impact Factor
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    ABSTRACT: Protein inhibitor of activated STAT3 (PIAS3) is an endogenous inhibitor of STAT3 that negatively regulates STAT3 transcriptional activity and cell growth and demonstrates limited expression in the majority of human squamous cell carcinomas of the lung. In the present study we sought to determine if PIAS3 inhibits cell growth in non-small cell lung cancer (NSCLC) cell lines by inducing apoptosis. Our results demonstrate that over-expression of PIAS3 promotes mitochondrial depolarization, leading to cytochrome c release, caspase 9 and 3 activation and PARP cleavage. This intrinsic pathway activation was associated with decreased Bcl-xL expression and increased Noxa expression and was independent of p53 status. Furthermore, PIAS3 inhibition of STAT3 activity was also p53 independent. Microarray experiments were performed to discover STAT3-independent mediators of PIAS3-induced apoptosis by comparing the apoptotic gene expression signature induced by PIAS3 over-expression with that induced by STAT3 siRNA. The results showed that a subset of apoptotic genes was uniquely expressed only after PIAS3 expression. Thus, PIAS3 may represent a promising lung cancer therapeutic target because of its p53-independent efficacy as well as its potential to synergize with Bcl-2 targeted inhibitors. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 03/2014; 134(5). DOI:10.1002/ijc.28448 · 5.01 Impact Factor
  • Myles Nickolich, Afshin Dowlati
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    ABSTRACT: Small cell lung cancer (SCLC) is a rapidly progressive malignancy with no improvement in survival outcome or change in the standard of care over the past thirty years. In this review, we examine molecular tissue markers, serum/ plasma markers, laboratory data and clinical markers that have been reported to have prognostic influence in SCLC. We discovered that the following held a poor prognosis in limited (LD) and extensive-stage (ED) SCLC: Autocrine growth loop activity via C-kit, gastrin-releasing peptide, or pro-gastrin releasing peptide, high pre-treatment beta fibroblast growth factor, increased cathepsin B or D expression, reduced intracellular fragile histidine triad protein expression, her-2/neu over-expression, high matrix metalloproteinase-11 or -14 activity, loss of function of Rb, elevated serum levels of ALT, CEA, CRP, LDH, or VEGF, hyponatremia, elevated lymphatic/vascular endothelial progenitor, disease extent, male gender, weight loss, anemia, neutrophilia, thrombocytopenia, prolonged PT or aPTT, and superior vena cava syndrome as part of an initial presentation of disease. Hypourecemia, elevated neuron-specific enolase, and age over 70 years conveyed a poorer prognosis in LD and elevated creatinine, higher performance status (> 2), and liver, bone, or brain metastases conveyed a poorer prognosis in ED SCLC. The following conveyed a favorable prognosis in LD and ED SCLC: E-cadherin expression, increased cytoplasmic levels of inhibitor of DNA binding/differentiation-2, increased numbers of tumor-infiltrating lymphocytes, high MAPK activity, normal to elevated albumin levels, female gender, performance status Keywords: Prognostic factors; Small Cell Lung Cancer; Survival Document Type: Research Article Publication date: February 1, 2014 More about this publication? Current Cancer Therapy Reviews publishes frontier reviews on all the latest advances in clinical oncology, cancer therapy and pharmacology. The journal's aim is to publish the highest quality review articles dedicated to clinical research in the field. The journal is essential reading for all researchers and clinicians in cancer therapy. $(document).ready(function() { var shortdescription = $(".originaldescription").text().replace(/\\&/g, '&').replace(/\\, '<').replace(/\\>/g, '>').replace(/\\t/g, ' ').replace(/\\n/g, ''); if (shortdescription.length > 350){ shortdescription = "" + shortdescription.substring(0,250) + "... more"; } $(".descriptionitem").prepend(shortdescription); $(".shortdescription a").click(function() { $(".shortdescription").hide(); $(".originaldescription").slideDown(); return false; }); }); Related content In this: publication By this: publisher In this Subject: Oncology By this author: Nickolich, Myles ; Dowlati, Afshin GA_googleFillSlot("Horizontal_banner_bottom");
    Current Cancer Therapy Reviews 02/2014; 10(1). DOI:10.2174/157339471001140815152154
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    ABSTRACT: Objectives Sorafenib is a multi-tyrosine kinase inhibitor of Raf kinase, VEGFR, and PDGFR. Angiogenesis is important for growth and progression of SCLC. This trial was conducted to evaluate whether the combination of cisplatin and etoposide plus concurrent and sequential sorafenib could prolong survival in patients with previously untreated SCLC. Methods Previously untreated patients with extensive stage SCLC were treated with cisplatin and etoposide days 1, 2, 3 for four cycles, concurrent with sorafenib 200 mg orally bid starting day 1 cycle 1. Patients with no disease progression after four cycles continued sorafenib 400 mg orally bid as maintenance for maximum of 12 months. The primary endpoint was 1 year survival with response rate and safety as secondary endpoints. Results A total of 18 patients were enrolled with 17 evaluable patients. One patient had a complete response, seven patients had a partial response (overall response rate of 47 %) and one patient had stable disease. Overall median survival was 7.4 months and 1 year survival was 25 %. The most common treatment-related adverse events included fatigue, anorexia, rash, diarrhea, neutropenia and weight loss. Grade 5 GI bleeding, pulmonary hemorrhage and neutropenia occurred in one pt (6 %) each. Accrual was halted on the basis of safety profile as well as preliminary efficacy data. Conclusions The combination of platinum based chemotherapy and sorafenib has significant toxicity at current dose levels and is associated with disappointing efficacy data.
    Investigational New Drugs 01/2014; 32(2). DOI:10.1007/s10637-013-0061-6 · 2.93 Impact Factor
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    ABSTRACT: Small-cell lung cancer (SCLC) is a disease for which few recent therapeutic advances have been achieved. SCLC trial design and reporting may have an impact on the interpretation of studies. Furthermore, the use of surrogate end points in SCLC has not been explored. Through examining SCLC trials published in the Journal of Clinical Oncology (JCO) (8471 patients from 66 trials between 1983 and 2010), we examined how SCLC trial reporting and design has evolved, determining if the type I error, power, and sample size calculations were provided. We assessed primary end points for all trials and sought to discover surrogate end points for overall survival (OS). There was increased reporting of statistical design in power (16.7% in 1986-1996 to 77.8% in 2006-2010; P = .001) and type I error (22.2% in 1986-1996 to 72.2% in 2006-2010; P = .005). Of trials published in 1986 to 1996, 72.2% failed to report a primary end point, whereas only 5.56% of trials conducted in 2006 to 2010 failed to do so (P = .004). Of phase II trials, primary end points were identified as response rate (RR) in 65%, OS in 25%, and progression-free survival (PFS) in 10%. There is a strong correlation between RR and both PFS (P = .013) and OS (P = .012) in extensive disease (ED). RR (P = .029) exhibits a negative trend over time, with a dramatic and significant decrease in RR across all studies starting in 2005. A strong correlation exists between PFS and OS for limited disease (LD) (P = .036) and ED (P = .058). We found no change in OS (P = .383) over time.
    Clinical Lung Cancer 12/2013; DOI:10.1016/j.cllc.2013.12.001 · 3.22 Impact Factor
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    ABSTRACT: The epidermal growth factor receptor (EGFR) inhibitor erlotinib is highly effective in non-small cell lung cancer (NSCLC) patients whose tumors express EGFR mutations, e.g., EGFR-L858R or EGFR exon 19 del. However, the efficacy of erlotinib is limited by either primary or secondary resistance, i.e., in patients whose tumors express wild-type EGFR (wtEGFR), or in initially sensitive patients whose tumors develop the second-site mutation EGFR-L858R/T790M or Met amplification after 10-14 months of erlotinib treatment. To improve treatment with erlotinib, we combined it with quinacrine in several erlotinib-resistant NSCLC cells. Quinacrine is a 9-aminoacridine derivative that suppresses nuclear factor-kappa B (NF-κB) by causing chromatin trapping of the FACT (facilitates chromatin transcription) complex. In A549 (wtEGFR), H1975 (EGFR-L858R/T790M), and H1993 (Met amplification) cells, the combination of erlotinib and quinacrine at 5 to 1 or 10 to 1 fixed ratios was highly synergistic, as quantified by the Chou-Talalay combination indices [ED50: 0.61 (0.42-0.81); ED75: 0.53 (0.40-0.67); ED90: 0.63 (0.54-0.71)]. Addition of quinacrine to erlotinib treatment inhibited colony formation and induced significant cell cycle arrest and apoptosis in A549 and H1975 cells. Upon quinacrine treatment, the FACT subunit SSRP1 disappeared from the soluble protein fraction, and NF-κB-dependent luciferase activity was decreased. Knockdown of SSRP1 decreased cell viability and colony formation, and sensitized the cells to erlotinib treatment. Moreover, microarray analysis of A549 and H1975 cells treated with erlotinib only, quinacrine only, or both, showed that quinacrine or combination treatment significantly affected genes involved in cell cycle progression or nucleotide metabolism, and many of these genes contain binding sites for transcription factors that regulate SSRP1-enriched genes. These data support a Phase I/II clinical trial (NCT01839955) that is just beginning, combining erlotinib and quinacrine in wtEGFR NSCLC patients after first-line chemotherapy. To assess synergistic effects in this clinical trial, we identified genes from the microarray analysis that were more significantly suppressed by combination treatment than by either single treatment. We further narrowed them down to those whose increased expression is associated with poorer survival in lung adenocarcinoma patients (HR ranges from 1.58-2.92) as potential biomarkers of drug synergy for the clinical trial. These genes, most of which are involved in various cell cycle processes, included BIRC5, DLGAP5, FOSL1, FOXM1, HIST1H2AK, HIST1H2BM, KIFC1, MKI67, PBK, PLK1, TOP2A, and ZWILCH. We conclude that the combination of quinacrine and erlotinib helps overcome erlotinib resistance in NSCLC, potentially by targeting FACT and suppressing cell cycle progression.
    2013 Molecular Targets and Cancer Therapeutics Meeting, Boston; 11/2013

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7k Citations
979.89 Total Impact Points


  • 2015
    • Hackensack University Medical Center
      Хакенсак, New Jersey, United States
  • 2012–2015
    • Cleveland State University
      Cleveland, Ohio, United States
  • 2001–2014
    • Case Western Reserve University School of Medicine
      • Department of Medicine
      Cleveland, Ohio, United States
  • 1999–2014
    • Case Western Reserve University
      • • Division of Hematology and Oncology
      • • Case Comprehensive Cancer Center
      • • School of Medicine
      Cleveland, Ohio, United States
  • 2005–2008
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
  • 2007
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2002
    • University of Nairobi
      • College of Health Sciences
      Nairobi, Nairobi Province, Kenya
  • 1995–1999
    • University of Liège
      • • Department of Internal Medicine
      • • Department of Pneumology
      • • Department of Gastroenterology
      Luik, Walloon Region, Belgium
  • 1996
    • Centre Hospitalier Universitaire de Liège
      Luik, Walloon, Belgium