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David S. Schrump, M.D.

Portait Photo of David Schrump
Thoracic and Gastrointestinal Oncology Branch
Head, Thoracic Oncology Section
Branch Co-Chief
Center for Cancer Research
National Cancer Institute
Building 10, Room 4-3942
Bethesda, MD 20892
Phone:  
301-496-2128
Fax:  
301-451-6934
E-Mail:  
David_Schrump@nih.gov

Biography

David S. Schrump graduated from the University of Connecticut School of Medicine and completed his general surgery residency at the University of Chicago as well as a 3-year research fellowship in Human Cancer Immunology at Memorial Sloan-Kettering Cancer Center. Following completion of his thoracic surgery residency at the University of Michigan in 1993, Dr. Schrump was appointed to the cardiothoracic surgery faculty at M.D. Anderson Cancer Center.In 1997, he was appointed Head of Thoracic Oncology, Surgery Branch, NCI. He received NIH tenure in 2006. He recieved an MBA in Health Services Management from the Carey School of Business, Johns Hopkins Univsersity in 2009. He is a member of the American Association for Thoracic Surgery, Society of Thoracic Surgeons, John Alexander Society, International Association for the Study of Lung Cancer, Society of Clinical Oncologists, and the American Association for Cancer Research.

Research

As Head of the Thoracic Oncology Section, Surgery Branch, NCI, I am responsible for overseeing thoracic surgery interventions in all patients enrolled on NIH protocols. In addition to these diverse consultative activities, our primary clinical efforts are devoted to care of patients with lung and esophageal cancers, and malignant pleural mesotheliomas referred to the NCI for standard multidisciplinary treatment, or investigational therapies.

Research endeavors in my laboratory focus on epigenetics of lung and esophageal cancers, and malignant pleural mesotheliomas (MPM). These efforts comprise four inter-related projects, which are briefly summarized below.

Project 1: Targeting the Epigenome for Lung Cancer Therapy

Identification of epigenetic alterations during malignant transformation provides impetus for utilization of chromatin remodeling agents for cancer therapy. The goals/objectives of this project include:
1. Analysis of clinical and molecular responses in lung cancer patients receiving chromatin remodeling agents
2. Targeting cancer-testis (CT) gene expression for lung cancer therapy

To date, nearly 150 patients with thoracic malignancies (mostly lung cancers) have received deoxyazacytidine (DAC), Depsipeptide (DP), sequential DAC/DP, or sequential DP/Flavopiridol infusions on protocols initiated in the Thoracic Oncology Section. Treatment regimens have been designed to recapitulate drug exposures used in our preclinical experiments. Quantitative RT-PCR (qRT-PCR), methylation-specific-PCR, immunohistochemistry, micro-array, and ELISA techniques have been used to assess a variety of molecular endpoints in pre-and post-treatment tumor biopsies and sera. Whereas no objective clinical responses have been observed, approximately 10% of patients have exhibited prolonged stabilization of disease following epigenetic therapy. Manuscripts summarizing several of these clinical protocols have been published in peer reviewed journals.

Additional recent protocol efforts have focused on evaluation of cell-based vaccines as a means to broadly immunize patients to CT antigens that potentially can be up-regulated in their cancers by systemic gene induction regimens. One strategy involves the use of autologous epigenetically-modified tumors cells, whereas another pertains to the use of allogeneic tumor cell lines, which express high levels of multiple, relevant CT antigens without pharmacologic manipulation. The vaccines are administered in conjunction with novel adjuvants, which have been shown to potentiate immune responses to purified protein vaccines, as well as metronomic oral cyclophosphamide and celecoxib to deplete/inhibit immunosuppressive T regulatory cells.

Project 2: Epigenetic Mechanisms of Gene Expression in Thoracic Malignancies

Thoracic malignancies exhibit profound alterations in chromatin structure secondary to aberrant expression/function of epigenetic regulators of gene expression. Numerous tumor suppressor genes are silenced in these malignancies via polycomb-mediated DNA hypermethylation mechanisms. Genome-wide DNA demethylation facilitates loss of imprinting, and de-repression of endogeneous retroviruses, and CT genes. The specific goals/objectives of this project include:
1. Evaluation of epigenetic events mediating de-repression of CT genes in lung cancer cells
2. Identification of novel epigenomic targets for intervention in thoracic malignancies

Elucidation of mechanisms regulating de-repression of CT genes in thoracic malignancies may provide insight into fundamental epigenetic alterations, which promote malignant transformation, and enable development of novel strategies to augment CT antigen expression for cancer therapy. In recent studies, qRT-PCR, pyrosequencing and chromatin immunoprecipitation (ChIP) techniques were used to comprehensively examine chromatin alterations associated with repression/activation of NY-ESO-1, MAGE-A1, and MAGE-A3 CT genes in lung cancer cells. Repression of CT genes in lung cancer cells as well as cultured normal respiratory epithelia coincided with CpG hypermethylation, recruitment of DNA methyltransferases (DNMTs), histone methyltransferases (HMT) such as EZH2, histone demethylases (HDM) including LSD1, JARID1B and JARID1D, deacetylation of histones H3/H4, and increased levels of H3K9Me3 and H3K27Me3 within the NY-ESO-1 MAGE-A1 and MAGE-A3 promoters. In contrast, spontaneous or pharmacologic activation of these CT genes in lung cancer cells coincided with marked DNA demethylation, reduced levels of DNMTs, HMTs and HDMs, hyperacetylated core histones, and increased levels of H3K4Me2, H3K4Me3, and H3K9Ac within the respective promoters. Repression of CT genes in lung cancer cells appeared related to persistence of normal chromatin structure within the respective promoters, rather than aberrant silencing mechanisms. Additional studies revealed that knock-down of HMTs, or HDMs including EZH2, LSD1, JARID1B, and JARID1D, but not the Class III HDAC SIRT1 markedly enhanced DAC-mediated activation of NY-ESO-1, MAGE-A1 and MAGE-A3 in lung cancer cells. Subsequent experiments revealed that at doses one log lower than the IC-50, 3-deaza-neplanocin A (DZNep) depleted EZH2, and enhanced DAC-mediated activation of CT genes in lung cancer cells, but not normal respiratory epithelia. Consistent with these observations, DZNep markedly enhanced recognition and lysis of lung cancer cells by allogeneic T cells expressing receptors for NY-ESO-1 and MAGE-A3. In addition, DZNep potentiated apoptosis mediated by DNA demethylating agents and HDAC inhibitors in lung cancer cells. These experiments, which were the first to demonstrate that inhibition of histone methyltransferases may be a novel strategy to augment CT gene expression for lung cancer immunotherapy have been published recently in Cancer Reseach.

Additional experiments have been performed to identify novel epigenetic targets for therapy of MPM. Briefly, a panel of pleural mesothelioma lines and normal mesothelial cell cultures either initiated in our laboratory or obtained from commercial sources were processed for micro-array analysis. These experiments revealed aberrant expression of a variety of genes encoding DNA methyltransferases, histone acetyltransferases and histone deacetylases in MPM cells relative to normal mesothelia. Micro-array, qRT-PCR, and western blot experiments revealed that relative to normal pleura, MPM cell lines exhibit significant up-regulation of EZH2, which encodes a key component of polycomb repressive complex-2 (PRC-2), which has been implicated in mediating stem cell pluripotency, as well as aberrant silencing of tumor suppressor genes. Additional experiments utilizing primary pleural mesothelioma specimens and commercial tissue microarrays demonstrated over-expression of EZH2 in 85% of mesotheliomas. No EZH2 expression was detected in normal pleura or peritoneum. Subsequent micro-array experiments revealed that EZH2 expression correlated with decreased survival of patients with pleural mesothelioma. Knockdown of EZH2 decreased global H3K27Me3 levels, and significantly diminished proliferation, migration, clonogenicity, and tumorigenicity of cultured MPM cells. DZNep mediated dose-dependent depletion of EZH2, and H3K27Me3, and significantly inhibited proliferation, migration, and clonogenicity of MPM cells; furthermore, DZNep significantly inhibited growth of established mesothelioma xenografts in nude mice. These experiments, which were the first to demonstrate that aberrant expression of PRC-2 contributes to the malignant phenotype of pleural mesotheliomas, suggest that PRC-2 is a novel target for mesothelioma therapy. A manuscript pertaining to these experiments has been published recently in Clinical Cancer Research.

Project 3: Epigenetic Alterations Induced by Cigarette Smoke in Thoracic Malignancies

The vast majority of lung cancers are directly attributable to cigarette smoke. Elucidation of epigenomic mechanisms associated with initiation and progression of lung cancers may hasten the development of novel epigenetic strategies for treatment and possible prevention of these malignancies. The specific aims of this project include:
1. Utilization of a novel in-vitro model to characterize epigenetic alterations in normal human respiratory epithelia mediated by cigarette smoke
2. Examination of the effects of cigarette smoke on the lung cancer epigenome

We have established an in-vitro system to examine sequential epigenetic effects of cigarette smoke in respiratory epithelia. Briefly, normal human small airway epithelial cells (SAEC) and cdk4/hTERT-immortalized human bronchial epithelial cells (HBEC) have been cultured in normal media (NM) with or without cigarette smoke condensate (CSC) for up to 24 months under relevant exposure conditions. Western blot analysis demonstrated that CSC mediated dose- and time-dependent diminution of H4K16Ac and H4K20Me3, while increasing relative levels of H3K27Me3; these histone alterations coincided with decreased DNMT1 and increased DNMT3b expression. Pyrosequencing, qRT-PCR, ChIP and microarray experiments revealed time-dependent genomic hypomethylation and locoregional DNA hypermethylation induced by CSC, which coincided with a dramatic increase in soft agar clonogenicity but not tumorigenicity of HBEC. A manuscript pertaining to results of the initial analysis of the model (9 months of CSC exposure) has been published in Oncogene. Comprehensive analyses of global DNA methylation and gene expression are underway using samples pertaining to baseline, as well as 6, 12, 18 and 24 months of continuous CSC exposure.

Additional studies have been performed to examine epigenetic mechanisms by which cigarette smoke enhances the malignant phenotype of lung cancer cells. Under conditions mimicking 1 pack per day (ppd) exposures in humans, short-term CSC treatment did not alter in-vitro proliferation rates, yet dramatically enhanced tumorigenicity of lung cancer cells in nude mice. Subsequent qRT-PCR, ChIP and pyrosequencing experiments demonstrated that CSC induced polycomb-mediated repression of Dickkopf-1 (Dkk-1), encoding a secreted Wnt antagonist and putative tumor suppressor, in lung cancer cells and normal respiratory epithelia. CSC exposure or knock-down of Dkk-1 in lung cancer cells dramatically up-regulated expression of Wnt5a, a non-canonical Wnt ligand implicated in cancer stem cell signaling. Knock-down of Dkk-1 recapitulated the pro-tumorigenic effects of CSC in lung cancer cells. Results of these studies have been published in Cancer Research.

Project 4: Modulating Cancer Stem Cell Signaling in Thoracic Malignancies

Relatively limited information is available regarding mechanisms by which miRNA alterations contribute to initiation and early progression of these malignancies. The goals/objectives of this project include:
1. Utilization of an in-vitro model to examine miRNA alterations mediated by cigarette smoke in normal human respiratory epithelia and lung cancer cells
2. Identification of novel mechanisms by which cigarette smoke activates stem cell signaling during human pulmonary carcinogenesis

Array techniques were used to examine miRNA expression profiles in lung cancer lines established from smokers and non-smokers, as well as normal respiratory epithelia cultured in the presence or absence of cigarette smoke condensate (CSC). Under relevant exposure conditions, CSC significantly up-regulated miR-31 in lung cancer cells and normal respiratory epithelia; miR-31 levels remained elevated following removal of CSC from culture media, suggestive of reprogramming. Subsequent studies demonstrated that miR-31 targeted Dkk-1, as well as transcripts encoding several other Wnt antagonists. MiR-31 expression levels were significantly lower in lung cancers (particularly those from smokers) relative to adjacent normal lung tissues. Constitutive over-expression of miR-31 significantly increased Wnt signaling, and enhanced proliferation and tumorigenicity of lung cancer cells. Results of these studies have been published in PloS One.

In additional experiments, we observed that CSC significantly up-regulates ABCG2 in lung and esophageal cancer cells. ABCG2 encodes a xenobiotic pump protein highly expressed in cancer stem cells. Consistent with these observations, CSC increased the side population (SP) of lung cancer cells. Subsequent promoter-reporter, immunoblot and ChIP experiments demonstrated that CSC-mediated induction of ABCG2 coincided with increased occupancy of aryl hydrocarbon receptor (AhR), Sp1, and Nrf2, as well as increased levels of RNA pol II and H3K9Ac within the ABCG2 promoter. 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 down-regulated ABCG2 expression, decreased SP, dramatically inhibited in-vitro proliferation of lung and esophageal cancer cells, and arrested growth of established lung cancer xenografts. Micro-array analysis revealed that mithramycin mediated profound dose-dependent repression of numerous canonical pathways mediating stem cell signaling, cell cycle progression and chromosomal replication in-vitro and in-vivo. A manuscript pertaining to these studies has been tentatively accepted for publication in Cancer Research, and a clinical protocol utilizing mithramycin to inhibit cancer stem cell signaling in patients with thoracic malignancies is under IRB review, and will be initiated in the next several months.






This page was last updated on 2/28/2014.