David S Schrump

NCI-Frederick, Maryland, United States

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Publications (119)589.57 Total impact

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    ABSTRACT: Mithramycin is a neoplastic antibiotic synthesized by various Streptomyces bacteria. It is under investigation as a chemotherapeutic treatment for a wide variety of cancers. Ongoing and forthcoming clinical trials will require pharmacokinetic analysis of mithramycin in humans, both to see if target concentrations are achieved and to optimize dosing and correlate outcomes (response/toxicity) with pharmacokinetics. Two published methods for mithramycin quantitation exist, but both are immunoassays that lack current bioanalytical standards of selectivity and sensitivity. To provide an upgraded and more widely applicable assay, a UPLC-MS/MS method for quantitation of mithramycin in human plasma was developed. Solid-phase extraction allowed for excellent recoveries (>90%) necessary for high throughput analyses on sensitive instrumentation. However, a ∼55% reduction in analyte signal was observed as a result of plasma matrix effects. Mithramycin and the internal standard chromomycin were separated on a Waters Acquity BEH C18 column (2.1×50mm, 1.7μm) and detected using electrospray ionization operated in the negative mode at mass transitions m/z 1083.5→268.9 and 1181.5→269.0, respectively, on an AB Sciex QTrap 5500. The assay range was 0.5-500ng/mL and proved to be linear (r(2)>0.996), accurate (≤10% deviation), and precise (CV<15%). Mithramycin was stable in plasma at room temperature for 24h, as well as through three freeze-thaw cycles. This method was subsequently used to quantitate mithramycin plasma concentrations from patients enrolled on two clinical trials at the NCI.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 09/2014; 970C:95-101. · 2.78 Impact Factor
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    ABSTRACT: Purpose:This phase I/II study sought to determine the safety and maximum-tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor administered prior to and in combination with cisplatin (P), doxorubicin (A) and cyclophosphamide (C) in thymic epithelial tumors (TET). Anti-tumor activity, pharmacokinetics, and biomarkers of response were also assessed. Experimental Design:Patients with advanced, unresectable TET received increasing doses of belinostat as a continuous intravenous infusion over 48-hours with chemotherapy in 3-week cycles. In phase II, belinostat at the MTD was used. Results:26 patients were enrolled (thymoma: 12; thymic carcinoma: 14). Dose-limiting toxicities at 2000 mg/m2 belinostat were grade 3 nausea and diarrhea and grade 4 neutropenia and thrombocytopenia, respectively, in two patients. 24 patients were treated at the MTD of 1000 mg/m2 with chemotherapy (P 50 mg/m2 on day 2; A 25 mg/m2 on days 2, 3; C 500 mg/m2 on day 3). Objective response rates in thymoma and thymic carcinoma were 64% [95% confidence interval: 30.8%-89.1%] and 21% (4.7%-50.8%) respectively. Modulation of pharmacodynamic markers of HDAC-inhibition and declines in regulatory T cell (Tregs) and exhausted CD8+ T cell populations were observed. Decline in Tregs was associated with response (p=0.0041) and progression-free survival (p=0.021). Declines in TIM-3+ CD8+T cells were larger in responders than non-responders (p=0.049). Conclusions:This study identified the MTD of belinostat in combination with PAC and indicates that the combination is active and feasible in TETs. Immunomodulatory effects on regulatory T cells and TIM3+ CD8+ T cells warrant further study.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 09/2014;
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    ABSTRACT: BackgroundA prospective randomized trial was conducted to compare the impact of systemic chemotherapy versus multi-modality therapy (complete cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and systemic chemotherapy) on overall survival (OS) in patients with gastric carcinomatosis.Methods Patients with measurable metastatic gastric adenocarcinoma involving the peritoneum, and resectable to “no evidence of disease” were randomized to gastrectomy, metastasectomy, HIPEC, and systemic FOLFOXIRI (GYMS arm) or FOLFOXIRI alone (SA arm).ResultsSeventeen patients were enrolled (16 evaluable); 7 of 9 patients in the multi-modality GYMS arm achieved complete cytoreduction (CCR0). Median OS was 11.3 months in the GYMS arm and 4.3 months in the SA arm. Four patients in the GYMS arm survived >12 months, 2 patients close to 2 years at last follow-up, and 1 patient more than 4 years, with 2 of these patients still alive. No patient in the SA arm lived beyond 11 months. All patients surviving beyond 12 months in the surgery arm achieved complete cytoreduction and had an initial Peritoneal Cancer Index (PCI) of ≤15.Conclusion Maximal cytoreductive surgery combined with regional (HIPEC) and systemic chemotherapy in selected patients with gastric carcinomatosis and limited disease burden can achieve prolonged survival. J. Surg. Oncol. © 2014 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 07/2014; · 2.64 Impact Factor
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    ABSTRACT: Although implicated in the pathogenesis of several chronic inflammatory disorders and hematologic malignancies, telomerase mutations have not been thoroughly characterized in human cancers. The present study was performed to examine the frequency and potential clinical relevance of telomerase mutations in esophageal carcinomas.
    PLoS ONE 01/2014; 9(7):e101010. · 3.53 Impact Factor
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    ABSTRACT: Here, we report that kinase-dead IKKα knockin mice develop spontaneous lung squamous cell carcinomas (SCCs) associated with IKKα downregulation and marked pulmonary inflammation. IKKα reduction upregulated the expression of p63, Trim29, and keratin 5 (K5), which serve as diagnostic markers for human lung SCCs. IKKα(low)K5(+)p63(hi) cell expansion and SCC formation were accompanied by inflammation-associated deregulation of oncogenes, tumor suppressors, and stem cell regulators. Reintroducing transgenic K5.IKKα, depleting macrophages, and reconstituting irradiated mutant animals with wild-type bone marrow (BM) prevented SCC development, suggesting that BM-derived IKKα mutant macrophages promote the transition of IKKα(low)K5(+)p63(hi) cells to tumor cells. This mouse model resembles human lung SCCs, sheds light on the mechanisms underlying lung malignancy development, and identifies targets for therapy of lung SCCs.
    Cancer cell 04/2013; 23(4):527-540. · 25.29 Impact Factor
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    ABSTRACT: MicroRNAs are critical mediators of stem cell pluripotency, differentiation, and malignancy. Limited information exists regarding microRNA alterations that facilitate initiation and progression of human lung cancers. In this study, array techniques were used to evaluate microRNA expression in normal human respiratory epithelia and lung cancer cells cultured in the presence or absence of cigarette smoke condensate (CSC). Under relevant exposure conditions, CSC significantly repressed miR-487b. Subsequent experiments demonstrated that miR-487b directly targeted SUZ12, BMI1, WNT5A, MYC, and KRAS. Repression of miR-487b correlated with overexpression of these targets in primary lung cancers and coincided with DNA methylation, de novo nucleosome occupancy, and decreased H2AZ and TCF1 levels within the miR-487b genomic locus. Deoxy-azacytidine derepressed miR-487b and attenuated CSC-mediated silencing of miR-487b. Constitutive expression of miR-487b abrogated Wnt signaling, inhibited in vitro proliferation and invasion of lung cancer cells mediated by CSC or overexpression of miR-487b targets, and decreased growth and metastatic potential of lung cancer cells in vivo. Collectively, these findings indicate that miR-487b is a tumor suppressor microRNA silenced by epigenetic mechanisms during tobacco-induced pulmonary carcinogenesis and suggest that DNA demethylating agents may be useful for activating miR-487b for lung cancer therapy.
    The Journal of clinical investigation 03/2013; 123(3):1241-61. · 15.39 Impact Factor
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    ABSTRACT: INTRODUCTION:: Although thymic epithelial tumors (TETs) commonly infiltrate mediastinal structures, cardiac involvement is uncommon and has not been systematically studied. The purpose of this study was to describe our single-institution experience of the clinical presentation, treatment, and follow-up of cardiac involvement in patients with TETs. METHODS:: A single-institution retrospective review of cardiac involvement among patients with TETs from 2008 to 2012. RESULTS:: The frequency of cardiac involvement was 4%. All five patients with confirmed cardiac disease had left heart involvement. Only one patient was symptomatic. Myocardial invasion was the most common mode of involvement followed by transvenous spread. Surgical resection of the involved area was attempted in three patients: in one, surgery was aborted because of extensive myocardial involvement; in the other two patients, resection was incomplete. Surgery averted a potentially catastrophic hemodynamic complication in one patient. However, cardiac tumor recurred in both patients who underwent incomplete resection. One patient underwent radiation therapy resulting in complete regression of an aortic root mass. CONCLUSIONS:: This study represents the most comprehensive review of cardiac involvement in patients with TETs. In contrast to previous single-case reports, we found a preponderance of asymptomatic presentation, left heart involvement, and myocardial invasion. Dynamic cardiovascular magnetic resonance imaging should be considered in cases when cardiac involvement is suspected. Although immediate surgical resection is indicated for impending hemodynamic compromise, long-term palliation with surgery for myocardial involvement seems poor, especially when complete resection cannot be performed. Radiation therapy should be considered in selected patients.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2013; 8(2):246-249. · 4.55 Impact Factor
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    ABSTRACT: 3-Deazaneplanocin A (DZNep) has been shown to have anti-cancer activity in numerous cancer types and its continued preclinical, and eventual clinical, drug development will require rapid and sensitive bioanalytical methods in order to quantitate this drug for pharmacokinetic analyses. The ultra HPLC with positive thermospray tandem mass spectrometric (LC-MS/MS) detection affords the most sensitive (limit of quantitation 5ng/mL) and rapid (3min run time) bioanalytical method to date for DZNep. Due to the polar nature of this drug and the internal standard (tubercidin), a hydrophilic-interaction column (HILIC) was used. The method was accurate, with less than 10% deviation from nominal values, as well as precise, where both within-day and between-day precisions were less than 15%. A liquid-liquid extraction procedure was able to recover ∼90% of drug from a small volume (50μL) of mouse plasma. This method was successfully applied to a pharmacokinetic study in mice intravenously injected with DZNep.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 01/2013; · 2.78 Impact Factor
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    ABSTRACT: Epigenetic aberrations offer dynamic and reversible targets for cancer therapy; increasingly, alteration via overexpression, mutation, or rearrangement is found in genes that control the epigenome. Such alterations suggest a fundamental role in carcinogenesis. Here, we consider three epigenetic mechanisms: DNA methylation, histone tail modification and non-coding, microRNA regulation. Evidence for each of these in lung cancer origin or progression has been gathered, along with evidence that epigenetic alterations might be useful in early detection. DNA hypermethylation of tumor suppressor promoters has been observed, along with global hypomethylation and hypoacetylation, suggesting an important role for tumor suppressor gene silencing. These features have been linked as prognostic markers with poor outcome in lung cancer. Several lines of evidence have also suggested a role for miRNA in carcinogenesis and in outcome. Cigarette smoke downregulates miR-487b, which targets both RAS and MYC; RAS is also a target of miR-let-7, again downregulated in lung cancer. Together the evidence implicates epigenetic aberration in lung cancer and suggests that targeting these aberrations should be carefully explored. To date, DNA methyltransferase and histone deacetylase inhibitors have had minimal clinical activity. Explanations include the possibility that the agents are not sufficiently potent to invoke epigenetic reversion to a more normal state; that insufficient time elapses in most clinical trials to observe true epigenetic reversion; and that doses often used may provoke off-target effects such as DNA damage that prevent epigenetic reversion. Combinations of epigenetic therapies may address those problems. When epigenetic agents are used in combination with chemotherapy or targeted therapy it is hoped that downstream biological effects will provoke synergistic cytotoxicity. This review evaluates the challenges of exploiting the epigenome in the treatment of lung cancer.
    Frontiers in Oncology 01/2013; 3:261.
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    ABSTRACT: Cigarette smoke (CS) is a leading cause of death worldwide. The aryl hydrocarbon receptor (AHR) is partially responsible for tobacco-induced carcinogenesis although the underlying mechanisms involving early effector genes have yet to be determined. Here, we report that adrenomedullin (ADM) significantly contributes to the carcinogenicity of tobacco activated AHR. CS and AHR activating ligands induced ADM in vitro and in vivo but not in AHR-deficient fibroblasts and mice. Ectopic transfection of AHR rescued ADM expression in AHR-/- fibroblasts while AHR blockage with siRNA in wild type cells significantly decreased ADM expression. AHR regulates ADM expression through two intronic xenobiotic response elements located close to the start codon in the ADM gene. Using tissue microarrays we showed that ADM and AHR were coupregulated in lung tumor biopsies from smoker patients. Microarray metaanalysis of 304 independent microarray experiments showed that ADM is elevated in smokers and smokers with cancer. Additionally, ADM coassociated with a subset of AHR responsive genes and efficiently differentiated patients with lung cancer from non-smokers. In a novel preclinical model of CS-induced tumor progression, host exposure to CS extracts significantly elevated tumor ADM while systemic treatment with the ADM antagonist NSC16311 efficiently blocked tobacco-induced tumor growth. In conclusion, ADM significantly contributes the carcinogenic effect of AHR and tobacco combustion products. We suggest that therapeutics targeting the AHR/ADM axis may be of clinical relevance in the treatment of tobacco-induced pulmonary malignancies.
    Cancer Research 09/2012; · 9.28 Impact Factor
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    ABSTRACT: Cigarette smoking at diagnosis or during therapy correlates with poor outcome in patients with lung and esophageal cancers, yet the underlying mechanisms remain unknown. In this study, we observed that exposure of esophageal cancer cells to cigarette smoke condensate (CSC) led to upregulation of the xenobiotic pump ABCG2, which is expressed in cancer stem cells and confers treatment resistance in lung and esophageal carcinomas. Furthermore, CSC increased the side population of lung cancer cells containing cancer stem cells. Upregulation of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor, Sp1, and Nrf2 within the ABCG2 promoter, and deletion of xenobiotic response elements and/or Sp1 sites markedly attenuated ABCG2 induction. Under conditions potentially achievable in clinical settings, mithramycin diminished basal as well as CSC-mediated increases in AhR, Sp1, and Nrf2 levels within the ABCG2 promoter, markedly downregulated ABCG2, and inhibited proliferation and tumorigenicity of lung and esophageal cancer cells. Microarray analyses revealed that mithramycin targeted multiple stem cell-related pathways in vitro and in vivo. Collectively, our findings provide a potential mechanistic link between smoking status and outcome of patients with lung and esophageal cancers, and support clinical use of mithramycin for repressing ABCG2 and inhibiting stem cell signaling in thoracic malignancies.
    Cancer Research 07/2012; 72(16):4178-92. · 9.28 Impact Factor
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    ABSTRACT: CD4(+)FoxP3(+) regulatory T cells (Tregs) have been shown to suppress T cell-mediated host immune responses against self- and nonself-antigens; however, the impact of CD4(+) Tregs on human antitumor immune responses and their influence on cancer treatment are unknown. In the present study, we explored the factors that influence CD4(+) Treg reconstitution in patients receiving adoptive immunotherapy following conditioning regimens designed to enhance T-cell function and evaluated potential associations between CD4(+) Treg levels and clinical responses to therapy. The analysis of 4 trials employing nonmyeloablative chemotherapy with or without total body irradiation (TBI) before adoptive T-cell transfer revealed that the percentage and number of reconstituting CD4(+)FoxP3(+) Tregs observed in the peripheral blood was higher in nonresponders than in responders. The addition of TBI resulted in a further depletion of CD4(+) Tregs, and the degree of depletion was dependent on the TBI dose. The number of administered doses of IL-2 was found to be positively associated with peripheral Treg reconstitution. These observations provide strong evidence that endogenous CD4(+) Tregs have a negative impact on cancer therapy, and suggest that strategies reducing Treg levels may provide clinical benefit to cancer patients. All 5 clinical trials are registered at www.clinicaltrials.gov as NCT00001832, NCT00096382, NCT00335127, NCT00509496, and NCT00513604.
    Blood 05/2012; 119(24):5688-96. · 9.78 Impact Factor
  • David S Schrump
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    ABSTRACT: Lung and esophageal cancers and malignant pleural mesotheliomas are highly lethal neoplasms that are leading causes of cancer-related deaths worldwide. Presently, limited information is available pertaining to epigenetic mechanisms mediating initiation and progression of these neoplasms. The following presentation will focus on the potential clinical relevance of epigenomic alterations in thoracic malignancies mediated by DNA methylation, perturbations in the histone code, and polycomb group proteins, as well as ongoing translational efforts to target epigenetic regulators of gene expression for treatment of these neoplasms. This article is part of a Special Issue entitled: Chromatin in time and space.
    Biochimica et Biophysica Acta 04/2012; 1819(7):836-45. · 4.66 Impact Factor
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    ABSTRACT: Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of human cancers. This study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM). Microarray, quantitative reverse transcriptase PCR (qRT-PCR), immunoblot, and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral short hairpin RNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity, and tumorigenicity of MPM cells either exhibiting knockdown of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Microarray and qRT-PCR techniques were used to examine gene expression profiles mediated by knockdown of EZH2 or EED, or DZNep. EZH2 and EED, which encode components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM lines relative to normal mesothelial cells. EZH2 was overexpressed in approximately 85% of MPMs compared with normal pleura, correlating with diminished patient survival. Overexpression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knockdown of EZH2 orEED, or DZNep treatment, decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knockdown of PRC-2 members or DZNep treatment. Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy.
    Clinical Cancer Research 01/2012; 18(1):77-90. · 7.84 Impact Factor
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    ABSTRACT: A review of all resections for recurrent or metastatic ACC was performed to identify patients who might benefit from a surgical approach, and to identify factors that might aid in prognosis among patients with metastatic disease. Adrenocortical carcinoma (ACC) is a rare tumor, with frequent recurrences and metastases even after complete resection. Chemotherapy has limited efficacy, and surgical resection of metastatic ACC remains controversial. A retrospective review was performed of all patients who underwent surgical intervention for metastatic ACC in a single tertiary center from 1977 to 2009. All available clinicopathologic data were analyzed to determine potential factors associated with response to treatment and survival. Fifty-seven patients underwent 116 procedures for recurrent or metastatic disease. Twenty-three resections were for liver metastases, 48 for pulmonary metastases, 22 for abdominal disease including local recurrences, and 13 were for metastases at other sites. Median and 5-year survivals from time of first metastasectomy were 2.5 years, and 41%, respectively. The median survival of patients with DFI <12 months was 1.7 years, compared to 6.6 years for patients with DFI >12 months (P = 0.015). Median survival for right versus left-sided primaries was 1.9 years versus 3.8 years (P = 0.03). Liver metastases were more common with right-sided primaries (67% vs. 41%, P = 0.05). Chemotherapy had no impact on survival. Resection of recurrent or metastatic ACC is safe, and may result in prolongation of survival in selected patients with DFI greater than 1 year.
    Journal of Surgical Oncology 12/2011; 105(7):709-13. · 2.64 Impact Factor
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    ABSTRACT: The transcriptional repressor Blimp-1 promotes the differentiation of CD8(+) T cells into short-lived effector cells (SLECs) that express the lectin-like receptor KLRG-1, but how it operates remains poorly defined. Here we show that Blimp-1 bound to and repressed the promoter of the gene encoding the DNA-binding inhibitor Id3 in SLECs. Repression of Id3 by Blimp-1 was dispensable for SLEC development but limited the ability of SLECs to persist as memory cells. Enforced expression of Id3 was sufficient to restore SLEC survival and enhanced recall responses. Id3 function was mediated in part through inhibition of the transcriptional activity of E2A and induction of genes regulating genome stability. Our findings identify the Blimp-1-Id3-E2A axis as a key molecular switch that determines whether effector CD8(+) T cells are programmed to die or enter the memory pool.
    Nature Immunology 11/2011; 12(12):1230-7. · 26.20 Impact Factor
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    ABSTRACT: Adrenocortical carcinoma (ACC) is a rare neoplasm with a high propensity for locoregional recurrences and distant metastases for which there are no effective systemic therapies. This study was undertaken to determine outcomes of patients undergoing pulmonary metastasectomy for ACC. A single-institution retrospective review was performed of patients undergoing pulmonary metastasectomy for ACC from 1979 to 2010. Twenty-six patients underwent 60 pulmonary metastasectomies. Fifteen patients (58%) underwent unilateral thoracotomy, 6 (23%) had staged thoracotomies, and 5 (19%) underwent median sternotomy as the initial thoracic procedure. Median number and size of lesions were 6 and 2 cm, respectively. Twenty-three patients (88%) were rendered free of disease in the lung, and 14 (54%) were rendered completely free of disease. Median overall and 5-year actuarial survivals from initial pulmonary metastasectomy were 40 months and 41%, respectively, with a median potential follow-up of 120 months. Median recurrence-free survival (RFS) and 5-year RFS for ipsilateral thoracic recurrences were 6 months, and 25%, respectively. The median RFS in the contralateral thorax was 5 months. Time to first recurrence after adrenalectomy and T stage of the primary tumor, but not adjuvant or neoadjuvant chemotherapy, were associated with increased overall survival after pulmonary metastasectomy. This study represents the most comprehensive review of outcomes of patients undergoing pulmonary metastasectomy for ACC. Given the lack of effective systemic therapies, pulmonary metastasectomy may be beneficial in properly selected patients.
    The Annals of thoracic surgery 10/2011; 92(4):1195-200. · 3.45 Impact Factor
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    ABSTRACT: In vitro growth of alveolar soft part sarcoma (ASPS) and establishment of an ASPS cell line, ASPS-1, are described in this study. Using a recently developed xenograft model of ASPS derived from a lymph node metastasis, organoid nests consisting of 15 to 25 ASPS cells were isolated from ASPS xenograft tumors by capture on 70 μm filters and plated in vitro. After attachment to the substratum, these nests deposited small aggregates of ASPS cells. These cells grew slowly and were expanded over a period of 3 years and have maintained characteristics consistent with those of both the original ASPS tumor from the patient and the xenograft tumor including (1) presence of the alveolar soft part locus-transcription factor E3 type 1 fusion transcript and nuclear expression of the alveolar soft part locus-transcription factor E3 type 1 fusion protein; (2) maintenance of the t(X;17)(p11;q25) translocation characteristic of ASPS; and (3) expression of upregulated ASPS transcripts involved in angiogenesis (ANGPTL2, HIF-1-α, MDK, c-MET, VEGF, and TIMP-2), cell proliferation (PRL, PCSK1), metastasis (ADAM9), as well as the transcription factor BHLHB3 and the muscle-specific transcripts TRIM63 and ITGβ1BP3. This ASPS cell line forms colonies in soft agar and retains the ability to produce highly vascularized ASPS tumors in NOD.SCID/NCr mice. Immunohistochemistry of selected ASPS markers on these tumors indicated similarity to those of the original patient tumor as well as to the xenografted ASPS tumor. We anticipate that this ASPS cell line will accelerate investigations into the biology of ASPS including identification of new therapeutic approaches for treatment of this slow growing soft tissue sarcoma.
    Journal of Pediatric Hematology/Oncology 07/2011; 33(5):360-8. · 0.97 Impact Factor
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    ABSTRACT: Cancer-testis antigens (CTA), such as NY-ESO-1, MAGE-A1, and MAGE-A3, are immunogenic proteins encoded by genes, which are normally expressed only in male germ cells but are activated by ill-defined epigenetic mechanisms in human tumors, including lung cancers. Previously, we reported induction of these CTAs in cancer cells, but not normal cells, by DNA-demethylating agents and histone deacetylase inhibitors using clinically achievable exposure conditions. In the present study, we evaluated chromatin alterations associated with repression/activation of cancer-testis genes in lung cancer cells to further develop gene-induction regimens for cancer immunotherapy. Repression of NY-ESO-1, MAGE-A1, and MAGE-A3 coincided with DNA hypermethylation, recruitment, and binding of polycomb-group proteins, and histone heterochromatin modifications within the promoters of these genes. Derepression coincided with DNA demethylation, dissociation of polycomb proteins, and presence of euchromatin marks within the respective promoters. Short hairpin RNAs were used to inhibit several histone methyltransferases (KMT) and histone demethylases (KDM) that mediate histone methylation and repress gene expression. Knockdown of KMT6, KDM1, or KDM5B markedly enhanced deoxyazacytidine (DAC)-mediated activation of these cancer-testis genes in lung cancer cells. DZNep, a pharmacologic inhibitor of KMT6 expression, recapitulated the effects of KMT6 knockdown. Following DAC-DZNep exposure, lung cancer cells were specifically recognized and lysed by allogeneic lymphocytes expressing recombinant T-cell receptors recognizing NY-ESO-1 and MAGE-A3. Combining DNA-demethylating agents with compounds, such as DZNep, that modulate histone lysine methylation may provide a novel epigenetic strategy to augment cancer-testis gene expression as an adjunct to adoptive cancer immunotherapy.
    Cancer Research 06/2011; 71(12):4192-204. · 9.28 Impact Factor
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    ABSTRACT: The primary objective of this study was to determine the rate of pathological response after preoperative celecoxib and concurrent taxane-based chemotherapy in patients with cancer of the esophagus and gastroesophageal junction. Thirty-nine patients were enrolled in this single-arm, phase II clinical trial. Patients were administered daily celecoxib in combination with two to three cycles of carboplatin and paclitaxel with preoperative intent. Levels of cyclooxygenase (COX)-2 expression in resected tumors were analyzed by immunohistochemistry and correlated with clinical outcome measures. Postoperatively, patients were administered daily celecoxib for 1 year or until documented tumor recurrence. All patients received two to three cycles of chemotherapy plus celecoxib 800 mg/d. Toxicities were as expected. A major clinical response (complete response + partial response) was noted in 22 patients (56%); six patients (15%) had a complete clinical response. Thirty-seven patients underwent esophagectomy. Five patients had a major pathological response (12.8%). Four-year overall and disease-free survivals were 40.9% and 30.3%, respectively. Patients with tumors expressing COX-2 demonstrated a higher likelihood of a major clinical response response (62% versus 50%) and an improved overall survival, compared with patients with COX-2-negative tumors. Preoperative celecoxib with concurrent chemotherapy demonstrated sufficient effect on pathologic response to warrant further study. Patients with tumors expressing COX-2 demonstrated trends toward improved response to preoperative therapy and improved overall survival compared with nonexpressors.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2011; 6(6):1121-7. · 4.55 Impact Factor

Publication Stats

3k Citations
589.57 Total Impact Points

Institutions

  • 2006–2014
    • NCI-Frederick
      Maryland, United States
  • 1998–2014
    • National Cancer Institute (USA)
      • • Center for Cancer Research
      • • Developmental Therapeutics Program
      Maryland, United States
  • 2011
    • Weill Cornell Medical College
      • Department of Cardiothoracic Surgery
      New York City, New York, United States
  • 1999–2009
    • National Institutes of Health
      • • Branch of Surgery
      • • Center for Clinical Research
      • • Center for Cancer Research
      Bethesda, MD, United States
  • 2007
    • Wake Forest School of Medicine
      Winston-Salem, North Carolina, United States
  • 2001
    • National Eye Institute
      Maryland, United States
  • 1997–2000
    • University of Texas MD Anderson Cancer Center
      • Department of Thoracic Cardiovascular Surgery
      Houston, TX, United States