Spore in lung cancer

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Project Title: Spore in lung cancer
Project Number: 5P50CA058184-17
Project web address: Follow on NIH
Project Description:
The Johns Hopkins Lung Cancer SPORE is in its fourteenth year and continues to have as its goals, the performance of highly translational research to provide new means for the prevention of, risk assessment for, early detection of, gauging prognosis of, and therapy for, lung cancers of all types. Our work encompasses collaboration with other Lung Cancer SPORE'S, extensive leveraging of foundation, institutional, and commercial partnering support, and interaction with other NCI initiatives. We use flexibility of the SPORE funding mechanism to extend projects that continually evolve higher and higher translational potential and curtail those that do not. We emphasize incorporation of new concepts and directions to facilitate development of areas that are headed for ultimate translational verification and even movement to common clinical practice. Two projects, Projects 1 and 2, the latter a collaborative venture with the Colorado SPORE, stress biomarker research at the highest translational level. Both involve highest translational level validation of gene DNA hypermethylation markers with high promise for: a) in assays of tumor and lymph node DNA, restaging stage 1 to stage 3 lung cancer and predicting patients with highest risk for rapid disease recurrence; and b) in assays of sputum DNA, predicting individuals at highest risk for imminent development of lung cancer and /or facilitating early diagnosis of the disease. In both projects, implications of the markers for developing epigenetic approaches to adjuvant therapy and prevention will be directly explored. This work also links participation of the Hopkins SPORE with the consortium lloprost chemoprevention trials (Lung Cancer Biomarker Chemoprevention Consortium-LCBCC) involving other Lung Cancer SPORES and, especially, the Colorado SPORE. In terms of developing novel lung cancer therapies, Project 4 is at a very high translational level with correlative science to be conducted in the setting of first in human clinical trials for the inhibition of the enzyme, fatty acid synthase. Project 3, will explore the correlation, in non-small cell lung cancer, of newly found frequent mutations in the NRF2 stress response pathway, that renders this protein constitutively active in the nucleus, with the presence of drug resistance to commonly employed treatment regimens and the possibilities for inhibiting this pathway to reverse chemoresistance.
Project Terms:
adjuvant therapy area biological adaptation to stress biological assay biological markers cancer etiology cancer therapy cell nucleus cessation of life chemoprevention clinical practice clinical trials collaborations colorado detection development disease dna drug resistance early diagnosis enzyme inhibition epigenetic process fatty-acid synthase flexibility foundations funding mechanisms genes goals head high risk human hypermethylation individual link lymph nodes malignant neoplasm of lung movement mutation non-small-cell lung carcinoma novel outcome forecast pathway interactions patients performance prevention proteins recurrence research risk assessment science sputum staging stress translational research treatment protocols tumor validation work
Project Title: Spore in lung cancer
Project Number: 5P50CA058184-17
Project web address: Follow on NIH
Organization: Johns Hopkins University, United States, Maryland, BALTIMORE
Principal Investigators (PI): Baylin Stephen B, US
Project Categories:
Natural Sciences > Aging Diseases and Pathology > Cancer & related diseases > Malignant neoplasms (including in situ)
Other Information:
Fiscal Year: 1997
Project Start Date: 5 September 1997
Project End Date: 30 November 2013
Project program: Specialized Center
Project Funding Information:
Funding Mechanism: Research Centers
Year Funding Organization Total Funding, $
2012 NIH - National Cancer Institute $2,300,000
Project Title: Spore in lung cancer
Project Number: 5P50CA058184-17
Project web address: Follow on NIH
Title Journal Year Country Rel
Early Detection of Lung Cancer Using DNA Promoter Hypermethylation in Plasma and Sputum. Clin Cancer Res 2017 united states
Combining Epigenetic and Immunotherapy to Combat Cancer. Cancer Res 2016 united states
Mutant p53 Together with TGF? Signaling Influence Organ-Specific Hematogenous Colonization Patterns of Pancreatic Cancer. Clin Cancer Res 2016 united states
Exposure to electronic cigarettes impairs pulmonary anti-bacterial and anti-viral defenses in a mouse model. PLoS One 2015 united states
Evaluation of azacitidine and entinostat as sensitization agents to cytotoxic chemotherapy in preclinical models of non-small cell lung cancer. Oncotarget 2015 united states
Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses. Cell 2015 united states
Unmasking the lung cancer epigenome. Annu Rev Physiol 2015 united states
Harnessing the potential of epigenetic therapy to target solid tumors. J Clin Invest 2014 united states
Rapamycin rescues ABT-737 efficacy in small cell lung cancer. Cancer Res 2014 united states
NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation. J Clin Invest 2014 united states
Functional identification of cancer-specific methylation of CDO1, HOXA9, and TAC1 for the diagnosis of lung cancer. Clin Cancer Res 2014 united states
The TGF?-miR200-MIG6 pathway orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors. Cancer Res 2014 united states
Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget 2014 united states
Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer. J Thorac Oncol 2013 united states
Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell 2013 united states
Inhibition of TWIST1 leads to activation of oncogene-induced senescence in oncogene-driven non-small cell lung cancer. Mol Cancer Res 2013 united states
Novel methylation biomarker panel for the early detection of pancreatic cancer. Clin Cancer Res 2013 united states
Hedgehog pathway inhibition radiosensitizes non-small cell lung cancers. Int J Radiat Oncol Biol Phys 2013 united states
Epigenetic therapy in non-small-cell lung cancer: targeting DNA methyltransferases and histone deacetylases. Expert Opin Biol Ther 2013 england
Loss of LSD1 (lysine-specific demethylase 1) suppresses growth and alters gene expression of human colon cancer cells in a p53- and DNMT1(DNA methyltransferase 1)-independent manner. Biochem J 2013 england
Invited commentary: the etiology of lung cancer in men compared with women. Am J Epidemiol 2013 united states
MicroRNA 4423 is a primate-specific regulator of airway epithelial cell differentiation and lung carcinogenesis. Proc Natl Acad Sci U S A 2013 united states
Differential epigenetic regulation of TOX subfamily high mobility group box genes in lung and breast cancers. PLoS One 2012 united states
Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 2012 united states
Defining a gene promoter methylation signature in sputum for lung cancer risk assessment. Clin Cancer Res 2012 united states
Novel therapeutic approaches for small cell lung cancer: the future has arrived. Curr Probl Cancer 2012 united states
Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012 united states
Prolonged sulforaphane treatment does not enhance tumorigenesis in oncogenic K-ras and xenograft mouse models of lung cancer. J Carcinog 2012 india
Oligoamine analogues in combination with 2-difluoromethylornithine synergistically induce re-expression of aberrantly silenced tumour-suppressor genes. Biochem J 2012 england
Micro Magnetic Gyromixer for Speeding up Reactions in Droplets. Microfluid Nanofluidics 2012
Human immunodeficiency virus infection as a prognostic factor in surgical patients with non-small cell lung cancer. Ann Thorac Surg 2012 netherlands
Vismodegib. Nat Rev Drug Discov 2012 england
Mapping DNA quantity into electrophoretic mobility through quantum dot nanotethers for high-resolution genetic and epigenetic analysis. ACS Nano 2012 united states
Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients. J Clin Invest 2011 united states
Itraconazole side chain analogues: structure-activity relationship studies for inhibition of endothelial cell proliferation, vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, and hedgehog signaling. J Med Chem 2011 united states
Single-molecule analysis enables free solution hydrodynamic separation using yoctomole levels of DNA. J Am Chem Soc 2011 united states
Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer. Cancer Res 2011 united states
Nuclear factor-kappaB (NF-kappaB) mediates a protective response in cancer cells treated with inhibitors of fatty acid synthase. J Biol Chem 2011 united states
The redox-sensitive transcription factor Nrf2 regulates murine hematopoietic stem cell survival independently of ROS levels. Blood 2011 united states
High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells. Proc Natl Acad Sci U S A 2011 united states
Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Am J Pathol 2011 united states
KEAP1 gene mutations and NRF2 activation are common in pulmonary papillary adenocarcinoma. J Hum Genet 2011 japan
Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov 2011 united states
Role of nuclear architecture in epigenetic alterations in cancer. Cold Spring Harb Symp Quant Biol 2010 united states
The detection of chromosomal aneusomy by fluorescence in situ hybridization in sputum predicts lung cancer incidence. Cancer Prev Res (Phila) 2010 united states
Transcriptional regulation of Wnt inhibitory factor-1 by Miz-1/c-Myc. Oncogene 2010 england
Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model. BMC Cancer 2010 england
Expression of ABCG2 (BCRP) is regulated by Nrf2 in cancer cells that confers side population and chemoresistance phenotype. Mol Cancer Ther 2010 united states
Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth. Mol Cancer Ther 2010 united states
Long-term survival outcomes by smoking status in surgical and nonsurgical patients with non-small cell lung cancer: comparing never smokers and current smokers. Chest 2010 united states
Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clin Cancer Res 2010 united states
Decoding circulating nucleic acids in human serum using microfluidic single molecule spectroscopy. J Am Chem Soc 2010 united states
Gain of Nrf2 function in non-small-cell lung cancer cells confers radioresistance. Antioxid Redox Signal 2010 united states
Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res 2010 england
Single-tube analysis of DNA methylation with silica superparamagnetic beads. Clin Chem 2010 united states
Re-expression of CXCL14, a common target for epigenetic silencing in lung cancer, induces tumor necrosis. Oncogene 2010 england
Enzymatic incorporation of multiple dyes for increased sensitivity in QD-FRET sensing for DNA methylation detection. Chembiochem 2010 germany
DNA methylation analysis on a droplet-in-oil PCR array. Lab Chip 2009 england
Progressive chromatin repression and promoter methylation of CTNNA1 associated with advanced myeloid malignancies. Cancer Res 2009 united states
A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro. Cancer Res 2009 united states
MS-qFRET: a quantum dot-based method for analysis of DNA methylation. Genome Res 2009 united states
Nrf2-dependent sulfiredoxin-1 expression protects against cigarette smoke-induced oxidative stress in lungs. Free Radic Biol Med 2009 united states
Profiling the expression pattern of GPI transamidase complex subunits in human cancer. Mod Pathol 2008 united states
Inhibiting fatty acid synthase for chemoprevention of chemically induced lung tumors. Clin Cancer Res 2008 united states
Cancer stem cells and the ontogeny of lung cancer. J Clin Oncol 2008 united states
DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med 2008 united states
Promoter hypermethylation of hallmark cancer genes in atypical adenomatous hyperplasia of the lung. Clin Cancer Res 2008 united states
RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy. Cancer Res 2008 united states
Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung. Carcinogenesis 2008 england
Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxid Redox Signal 2007 united states
Dual EGFR and mTOR targeting in squamous cell carcinoma models, and development of early markers of efficacy. Br J Cancer 2007 england
FDG-PET for pharmacodynamic assessment of the fatty acid synthase inhibitor C75 in an experimental model of lung cancer. Pharm Res 2007 united states
LOXL1 and LOXL4 are epigenetically silenced and can inhibit ras/extracellular signal-regulated kinase signaling pathway in human bladder cancer. Cancer Res 2007 united states
WNT10B functional dualism: beta-catenin/Tcf-dependent growth promotion or independent suppression with deregulated expression in cancer. Mol Biol Cell 2007 united states
Selective inhibition of fatty acid synthase for lung cancer treatment. Clin Cancer Res 2007 united states
Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci U S A 2007 united states
Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 2007 united states
Predicting gene promoter methylation in non-small-cell lung cancer by evaluating sputum and serum. Br J Cancer 2007 england
Role of lung maintenance program in the heterogeneity of lung destruction in emphysema. Proc Am Thorac Soc 2006 united states
Overexpression of glycosylphosphatidylinositol (GPI) transamidase subunits phosphatidylinositol glycan class T and/or GPI anchor attachment 1 induces tumorigenesis and contributes to invasion in human breast cancer. Cancer Res 2006 united states
C-fos assessment as a marker of anti-epidermal growth factor receptor effect. Cancer Res 2006 united states
Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide. Biochem Biophys Res Commun 2006 united states
Glutathione peroxidase 2, the major cigarette smoke-inducible isoform of GPX in lungs, is regulated by Nrf2. Am J Respir Cell Mol Biol 2006 united states
LKB1/STK11 suppresses cyclooxygenase-2 induction and cellular invasion through PEA3 in lung cancer. Cancer Res 2006 united states
Nested multigene MSP/DHPLC method for analyzing promoter hypermethylation status in clinical samples. Biotechniques 2006 united states
Promoter hypermethylation of multiple genes in sputum precedes lung cancer incidence in a high-risk cohort. Cancer Res 2006 united states
Delayed diagnosis and elevated mortality in an urban population with HIV and lung cancer: implications for patient care. J Acquir Immune Defic Syndr 2006 united states
Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med 2006 united states
Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest 2006 united states
Elevated incidence of lung cancer among HIV-infected individuals. J Clin Oncol 2006 united states
Hypermethylation of ASC/TMS1 is a sputum marker for late-stage lung cancer. Cancer Res 2006 united states
Ethanol sensitivity: a central role for CREB transcription regulation in the cerebellum. BMC Genomics 2006 england
Nrf2 regulates an adaptive response protecting against oxidative damage following diquat-mediated formation of superoxide anion. Arch Biochem Biophys 2006 united states
Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med 2005 united states
Silencing of genes by promoter hypermethylation: key event in rodent and human lung cancer. Carcinogenesis 2005 england
Can we improve the cytologic examination of malignant pleural effusions using molecular analysis? Ann Thorac Surg 2005 netherlands
DeltaNp63alpha up-regulates the Hsp70 gene in human cancer. Cancer Res 2005 united states
Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy. J Exp Med 2005 united states
Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res 2005 england
Surgical resection of limited disease small cell lung cancer in the new era of platinum chemotherapy: Its time has come. J Thorac Cardiovasc Surg 2005 united states
Project Title: Spore in lung cancer
Project Number: 5P50CA058184-17
Project web address: Follow on NIH
Title Phase Year
A Randomized Phase II Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients With Adenocarcinoma. Phase 2 1992
Broccoli Sprout Extract in Preventing Lung Cancer in Smokers N/A 1985