George Blanck

Moffitt Cancer Center, Tampa, Florida, United States

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Publications (53)194.12 Total impact

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    ABSTRACT: Successful use of anticancer designer drugs is likely to depend on simultaneous combinations of these drugs to minimize the development of resistant cancer cells. Considering the knowledge base of cancer signaling pathways, mechanisms of designer drug resistance should be anticipated, and early clinical trials could be designed to include arms that combine new drugs specifically with currently US Food and Drug Administration (FDA)-approved drugs expected to blunt alternative signaling pathways. In this review, we indicate examples of alternative signal pathways for recent anticancer drugs, and the use of original, Python-based software to identify systematically signaling pathways that could facilitate resistance to drugs targeting a particular protein. Pathway alternatives can be assessed at http://www.alternativesignalingpathways.com, developed with this review article. Copyright © 2015. Published by Elsevier Ltd.
    Drug Discovery Today 02/2015; DOI:10.1016/j.drudis.2015.02.005 · 5.96 Impact Factor
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    ABSTRACT: Melanoma cells express high levels of HLA class II, cell surface antigen-presenting proteins, which is an anomalous phenotype among solid tumors. There has never been a satisfying explanation for how this HLA class II-positive phenotype is related to tumor development. Lugini and colleagues demonstrated that melanoma cells have the capacity to engulf T-cells. We considered the possibility that this capacity could be dependent on HLA class II expression. We co-cultured melanoma and CD4-positive, labeled, Jurkat-C T-cells. The melanoma cells were transformed with an expression vector for CIITA, the obligate HLA class II gene transactivator. We then assayed for the transfer of label to the melanoma cells. CIITA expression facilitated engulfment of the T-cell material but not material from B-cells. The results suggest a possible mechanism for HLA class II-positive melanoma cells in blunting an anti-tumor response and suggest a possible target for melanoma therapy. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
    Anticancer research 01/2015; 35(1):25-9. · 1.87 Impact Factor
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    ABSTRACT: A continuing conundrum of cancer biology is the dichotomous function of transcription factors that regulate both proliferation and apoptosis, seemingly opposite results. Previous results have indicated that regulated entry into the S-phase of the cell cycle can be anti-apoptotic. Indeed, tumor suppressor genes can be amplified in tumors and certain, slow growing cancers can represent a relatively poor prognosis, both phenomena likely related to reduced cancer cell apoptosis, in turn due to reduced, unproductive entry into S-phase. In this report, we demonstrate that the Oct-1 transcription factor, commonly considered pro-proliferative, indeed facilitates IFN-γ induced apoptosis in 5637 bladder carcinoma cells, consistent with the role of the retinoblastoma protein in down-regulating Oct-1 DNA binding activity and in suppressing IFN-γ induced apoptosis. More importantly, despite the commonly appreciated process of IFN-γ induced apoptosis, IFN-γ at low concentrations stimulated cell bladder cancer cell proliferation, consistent with apoptosis being dependent on an overstimulation of what is otherwise a pro-proliferative pathway. This observation is in turn consistent with a feed forward mechanism of apoptosis, whereby transcription factors activate proliferation-effector genes at relatively low levels, then apoptosis-effector genes when the transcription factors over-accumulate. Finally, Oct-1 mediated apoptosis is inhibited by co-culture with Raji B-cells, raising the question of whether the normal lymph node environment, or other microenvironments with high concentrations of B-cells, is protective against Oct-1 facilitated apoptosis.
    Experimental and Molecular Pathology 12/2014; 97(3). DOI:10.1016/j.yexmp.2014.09.010 · 2.88 Impact Factor
  • Shea A Ford, George Blanck
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    ABSTRACT: Research in cancer biology has been largely driven by experimental approaches whereby discreet inputs are used to assess discreet outputs, for example, gene-knockouts to assess cancer occurrence. However, cancer hallmarks are only rarely, if ever, exclusively dependent on discreet regulatory processes. Rather, cancer-related regulatory factors affect multiple cancer hallmarks. Thus, novel approaches and paradigms are needed for further advances. Signal pathway persistence and amplification, rather than signal pathway activation resulting from an on/off switch, represent emerging paradigms for cancer research, closely related to developmental regulatory paradigms. In this review, we address both mechanisms and effects of signal pathway persistence and amplification in cancer settings; and address the possibility that hyper-activation of pro-proliferative signal pathways in certain cancer settings could be exploited for therapy. Copyright © 2014. Published by Elsevier B.V.
    Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 11/2014; 1855(1):18-23. DOI:10.1016/j.bbcan.2014.11.001 · 7.58 Impact Factor
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    ABSTRACT: We determined the most commonly mutated genes in five cancer genome atlas (TCGA) datasets. Many of these genes were extraordinarily large, as are many cancer fusion gene partners. And many of these genes had cytoskeletal related functions. We further determined that these genes were distributed into high and low frequency mutation groups largely according to overall rate of gene-occurrence in the high and low mutation frequency groups, as was also the case with common metastasis and tumor suppressor genes. Oncoproteins were selectively mutated in the low mutation frequency groups in colon and lung datasets. Thus, genes that have very large coding regions and may impact the cytoskeleton are more commonly mutated than are common metastasis and tumor suppressor genes in both high and low frequency mutation groups. These analyses raise questions related to cell shape: (i) Are cancer cells often spherical because cytoskeletal-related proteins are large mutagen targets? (ii) Is drug-resistance facilitated by relatively common mutant proteins that lead to round cells, with altered cell physiology or reduced surface to volume ratios that could reduce intra-cellular drug concentrations? Copyright © 2014. Published by Elsevier Ireland Ltd.
    Cancer Letters 10/2014; DOI:10.1016/j.canlet.2014.09.044 · 5.02 Impact Factor
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    ABSTRACT: Cancer cells undergo a variety of DNA copy number gains and losses (CNV), raising two important questions related to cancer development: (i) Which genes are affected? (ii) And how do CNVs, that do not represent complete deletions but do represent gene-dosage alterations, impact cancer cell functions? Recent studies have indicated that CNVs in cancer can impact genes for regulatory proteins long known to be associated with cancer development, but less is understood about CNVs affecting effector genes. Also, we have recently indicated the likely importance of transcription factor binding site (TFBS) copies in effector genes, in regulating the transition from a proliferative to an apoptotic state. Here we report data-mining analyses that indicate that copies of apoptosis-effector genes are commonly lost in cancer development, in comparison to proliferation-effector genes, and when not, apoptosis effector genes have silenced chromatin structures.
    Gene 10/2014; DOI:10.1016/j.gene.2014.10.021 · 2.08 Impact Factor
  • George Blanck
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    ABSTRACT: Background: U.S. medical colleges commonly administer both M.D. and Ph.D. programs, but the value and application of these degrees are being challenged by economic developments. Summary: In medicine, the country faces a long-term period of cost cutting and new models for efficient healthcare delivery. In research, the outlook for the independently creative career is bleak, owing to the failure of the National Institutes of Health to engineer a sustainable program of scientists' training and subsequent funding of the trained scientists' research. However, an educational bright spot for medical colleges has been the biomedical science master's program. Conclusions: These programs have been highly popular with students and have the potential of reinvigorating the pool of student researchers, educating professionals in allied fields who are competent advocates for biomedical research, and providing professionals who can enter the healthcare delivery system with reduced expense, for example, as genetic or personalized medicine counselors.
    Teaching and Learning in Medicine 10/2014; 26(4):409-411. DOI:10.1080/10401334.2014.910122 · 1.12 Impact Factor
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    ABSTRACT: The objective of this study was to investigate and quantify the morphological and molecular changes in the thymus for common causes of human infant death. Thymic architecture and molecular changes apparent in human infant head trauma victims were assessed by microscopy and quantified by image analysis of digital whole slide images. Thymuses from victims of SIDS and suffocated infants displaying normal thymus architecture were used for comparison. Molecular expression of proliferation and serotonin receptor and transporter protein markers was evaluated. Duplicate morphological and molecular studies of rodent thymuses were completed with both mouse and rat models. Quantification of novel parameters of digital images of thymuses from human infants suffering mortal head trauma revealed a disruption of the corticomedullary organization of the thymus, particularly involving dissolution of the corticomedullary border. A similar result was obtained for related mouse and rat models. The human thymuses from head trauma cases also displayed a higher percentage of Ki-67-positive thymocytes. Finally, we determined that thymus expression of the human serotonin receptor, and the serotonin transporter, occur almost exclusively in the thymic medulla. Head trauma leads to a disruption of the thymic, corticomedullary border, and molecular expression patterns in a robust and quantifiable manner.
    06/2014; 16(1). DOI:10.3727/194982414X13971392823398
  • George Blanck
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    ABSTRACT: New cancer research strategies have developed very rapidly over the past five years, including extensive DNA sequencing of tumor and normal cells; use of highly sensitive cancer cell detection methods; vaccine development and tumor-specific (designer) drugs. These developments have raised questions about where to concentrate efforts in the near future when establishing clinical trials, particularly important in an age of diminishing resources and during a period when competing strategies for cancer control are likely to overwhelm the opportunities for establishing large, effective clinical trials. In particular, it behooves the research community to be mindful of the inevitable, challenging obligation to responsibly choose between clinical trials that offer the credible hope of incremental advances vs. trials that are less traditional but may have revolutionary outcomes.
    Human Vaccines & Immunotherapeutics 12/2013; 10(3). DOI:10.4161/hv.27458 · 3.64 Impact Factor
  • James A Mauro, George Blanck
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    ABSTRACT: In cancer biology, most molecular regulatory mechanisms are casually treated as on/off switches for specific cancer hallmarks, despite the lack of compelling evidence that cancer hallmarks can be exclusively attributed to specific regulatory proteins. To consider a novel paradigm for the basis of regulating a set of effector genes for proliferation, versus apoptosis-effector genes, we used a bioinformatics approach to ascertain differences between the transcription factor binding site occurrences in the two sets of genes. Results indicated that there are more binding sites per gene, for transcription factors that regulate both proliferation and apoptosis, among the proliferation-effector genes than among the apoptosis-effector genes. Proliferation-effector genes also had more open chromatin regions. We also applied this paradigm to the question of why p53 and interferon regulatory factor-1 (IRF-1) first activate cell cycle arrest genes followed by apoptosis genes, with results indicating the cycle arrest genes are bigger p53 and IRF-1 traps. These data support the idea that, as a set of transcription factors becomes active, there is a stochastic component leading to the accumulation of these transcription factors on genes that effect an initial phenotype before their accumulation on genes that effect a subsequent phenotype.
    Gene 11/2013; DOI:10.1016/j.gene.2013.11.013 · 2.08 Impact Factor
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    ABSTRACT: Numerous molecular eff ects have been attributed to histone deacetylase inhibitors (HDACI’s), including the induction of major histocompatibility (MHC) genes. Here we report that one FDA approved HDACI, Vorinostat, and a second HDACI currently in clinical trials, Entinostat, reduce the ratio of class II associated invariant peptide (CLIP) to the MHC class II molecule, HLA-DR, indicating an increase in the non-CLIP peptides bound to HLA-DR. The HDACI eff ects are apparent with immortalized B-cells, HLA-DR constitutive melanoma cells and with melanoma cells expressing HLA-DR due to transformation with an expression vector for the HLA-DR gene co-activator, CIITA. Entinostat treatment leads to upregulation of Cathepsin L1, and the HLA-DR peptidome of the Entinostat treated cells is consistent with increased Cathepsin L1 mediated proteolysis. These results indicate that HDACI treatments may alter the HLA-DR peptidome of cells in patients and provide a way to identify novel immunogens for vaccinations and the study of autoantigens.
    Human vaccines 04/2013; 9(4):1-6. DOI:10.4161/hv.23085 · 3.64 Impact Factor
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    ABSTRACT: Numerous molecular effects have been attributed to histone deacetylase inhibitors (HDACI's), including the induction of major histocompatibility (MHC) genes. Here we report that one FDA approved HDACI, Vorinostat, and a second HDACI currently in clinical trials, Entinostat, reduce the ratio of class II associated invariant peptide (CLIP) to the MHC class II molecule, HLA-DR, indicating an increase in the non-CLIP peptides bound to HLA-DR. The HDACI effects are apparent with immortalized B-cells, HLA-DR constitutive melanoma cells and with melanoma cells expressing HLA-DR due to transformation with an expression vector for the HLA-DR gene co-activator, CIITA. Entinostat treatment leads to upregulation of Cathepsin L1, and the HLA-DR peptidome of the Entinostat treated cells is consistent with increased Cathepsin L1 mediated proteolysis. These results indicate that HDACI treatments may alter the HLA-DR peptidome of cells in patients and provide a way to identify novel immunogens for vaccinations and the study of autoantigens.
    Human Vaccines & Immunotherapeutics 01/2013; 9(4). · 3.64 Impact Factor
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    ABSTRACT: Genes that fuse to cause cancer have been studied to determine molecular bases for proliferation, to develop diagnostic tools, and as targets for drugs. To facilitate identification of additional, cancer fusion genes, following observation of a chromosomal translocation, we have characterized the genomic features of the fusion gene partners. Previous work indicated that cancer fusion gene partners, are either large or evolutionarily conserved in comparison to the neighboring genes in the region of a chromosomal translocation. These results raised the question of whether large cancer fusion gene partners were also evolutionarily conserved. Methods and We developed two methods for quantifying evolutionary conservation values, allowing the conclusion that both large and small cancer fusion gene partners are more evolutionarily conserved than their neighbors. Additionally, we determined that cancer fusion gene partners have more 3' untranslated region secondary structures than do their neighbors. Coupled with previous algorithms, with or without transcriptome approaches, we expect these results to assist in the rapid and efficient use of chromosomal translocations to identify cancer fusion genes. The above parameters for any gene of interest can be accessed at www.cancerfusiongenes.com.
    11/2012; 9(6):389-95.
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    ABSTRACT: The induction of the major histocompatibility (MHC), antigen-presenting class II molecules by interferon-gamma, in solid tumor cells, requires the retinoblastoma tumor suppressor protein (Rb). In the absence of Rb, a repressosome blocks the access of positive-acting, promoter binding proteins to the MHC class II promoter. However, a complete molecular linkage between Rb expression and the disassembly of the MHC class II repressosome has been lacking. By treating A549 lung carcinoma cells with a novel small molecule that prevents phosphorylation-mediated, Rb inactivation, we demonstrate that Rb represses the synthesis of an MHC class II repressosome component, YY1. The reduction in YY1 synthesis correlates with the advent of MHC class II inducibility; with loss of YY1 binding to the promoter of the HLA-DRA gene, the canonical human MHC class II gene; and with increased Rb binding to the YY1 promoter.. These results support the concept that the Rb gene regulatory network (GRN) subcircuit that regulates cell proliferation is linked to a GRN subcircuit regulating a tumor cell immune function.
    Gene 10/2012; DOI:10.1016/j.gene.2012.09.092 · 2.08 Impact Factor
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    ABSTRACT: We tallied the number of possible mutant amino acids in proteins thought to be inactivated early in tumorigenesis and in proteins thought to be inactivated late in tumorigenesis, respectively. Proteins thought to be inactivated early in tumorigenesis, on average, have a greater number of alternative, mutant possibilities, which raises the possibility that the sequential order of mutations associated with cancer development reflects the random chance, throughout life, of a mutagen inactivating a larger versus a smaller target. The hypothesis that the temporal order of genetic changes in cancer reflects mutagen target sizes leads to novel considerations of 1) the mechanisms of the acquisition of cancer hallmarks and 2) cancer screening strategies.
    Genes & cancer 10/2011; 2(10):927-31. DOI:10.1177/1947601911436200
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    ABSTRACT: Numerous cancer fusion genes have been identified and studied, and in some cases, therapy or diagnostic techniques have been designed that are specific to the fusion protein encoded by the fusion gene. There has been little progress, however, in understanding the general features of cancer fusion genes in a way that could provide the foundation for an algorithm for predicting the occurrence of a fusion gene once the chromosomal translocation points have been identified by karyotype analyses. In this study, we used publicly available data sets to characterize 59 cancer fusion genes. The results indicate that all but 17% of the genes involved in fusion events are either relatively large, compared to neighboring genes, or are highly conserved in evolution. These results support a basis for designing algorithms that could have a high degree of predictive value in identifying fusion genes once conventional microscopic analyses have identified the chromosomal breakpoints.
    Cancer genetics and cytogenetics 07/2009; 191(2):78-84. DOI:10.1016/j.cancergencyto.2009.02.004 · 1.93 Impact Factor
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    ABSTRACT: Protein inhibitors of activated STATs (PIAS) regulate the interferon-gamma (IFN-gamma) signaling pathway, which has numerous effects on tumor development and tumor cell biology. PIAS's also regulate STAT family members not directly involved in IFN-gamma signaling. This project was designed to assess PIAS1 expression in colon cancer. To determine whether PIAS1, one of the PIAS family members, or IFN-gamma signaling pathway components could be used to stratify colon tumors, we stained tissue microarrays for PIAS1, interferon regulatory factor-1 (IRF-1) and STAT1alpha. PIAS1 staining of the colon cancer tissue microarrays indicated a strong correlation of normal colon cells, and adenomas, with high expression of both PIAS1 and IRF-1. The PIAS1 results in particular may represent a basis for new approaches for efficiently distinguishing adenomas from colon cancer.
    Journal of Cancer Research and Clinical Oncology 04/2009; 135(9):1287-91. DOI:10.1007/s00432-009-0570-z · 3.01 Impact Factor
  • Melissa Ihla Niesen, George Blanck
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    ABSTRACT: Major histocompatibility (MHC) class II expression is ordinarily inducible by interferon-gamma (IFN-gamma), but the induction is repressed in retinoblastoma protein (Rb)-defective cells. The repression can be rescued by histone deacetylase (HDAC) inhibitor treatment, but this has never been shown for an HDAC inhibitor that is suitable for clinical trials and eventual patient therapy. Here we demonstrate that the HDAC inhibitor, MS-275, can rescue the IFN-gamma inducibility of human leukocyte antigen (HLA)-DR in non-small cell lung cancer cells. This HDAC inhibitor is currently being tested in phase I/II clinical trials for non-small cell lung cancer. We further verified that the MS-275 effect is related to an HDAC tethered to the HLA-DRA promoter by the transcription factor, YY1. HDAC inhibitors that can be used to treat patients may augment the expression of tumor cell MHC class II, and the results suggest an opportunity to determine the immunological consequences of HDAC inhibitor treatment in tumor therapy.
    Biological & Pharmaceutical Bulletin 04/2009; 32(3):480-2. DOI:10.1248/bpb.32.480 · 1.78 Impact Factor
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    ABSTRACT: Several advances were established in examining the interaction of transcriptional factors with the HLA-DRA promoter. First, hydrodynamic injection was used to demonstrate the activation of the promoter by class II transactivator in a live mouse. Second, the Oct-1 DNA-binding site in the HLA-DRA promoter is a negative element in many cells, but here we show that Oct-1 activates the promoter independently of the Oct-1-binding site. Third, the retinoblastoma (Rb) protein is required for the induction of the endogenous HLA-DRA gene, due to a poorly understood, pleiotropic effect on the Oct-1 and YY1 repressive functions at the HLA-DRA promoter. There has never been an indication that direct promoter activation, by Rb, is possible. Here, we report that the first HLA-DRA intron has an Rb-responsive element, as indicated by a transient transfection/promoter reporter assay. Finally, RFX activates a methylated version of an HLA-DRA promoter reporter construct, consistent with the role of RFX in rescuing the expression of the methylated, endogenous HLA-DRA gene. Here, we report that this RFX function is not limited to a specific RFX-binding sequence or to the HLA-DRA promoter. These advances provide bases for novel investigations into the function of the major histocompatibility class II promoter.
    Acta Biochimica et Biophysica Sinica 04/2009; 41(3):198-205. DOI:10.1093/abbs/gmp002 · 2.09 Impact Factor
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    ABSTRACT: Neutrophil infiltrates into tumors have been reported in certain circumstances to reduce tumor growth and in other circumstances to augment tumor growth, particularly by facilitating metastasis. Neutrophil chemotaxis can be facilitated by both interleukin-8 (IL-8) and transforming growth factor-beta (TGF-beta). However, the combined effects of these two cytokines on neutrophil tumor infiltrates is unknown, and we considered the possibility that studying the combined effects might resolve apparent contradictions with regard to neutrophil effects on tumor development. First, we determined that a simultaneous IL-8 and TGF-beta blockade is far more efficient at eliminating the neutrophil infiltrate from an A549 derived tumor than is blockade of either cytokine alone. Blockade of IL-8 alone, led to smaller tumors, consistent with the known inhibitory role of TGF-beta on A549 cell proliferation. Blockade of TGF-beta alone rescued the tumor growth but led to reduced metastasis volume. Surprisingly, blockade of both cytokines rescued both tumor volume and metastasis, underscoring the difficulty of understanding the effects of complete tumor cytokine elaboration profiles by isolating the effects of only one cytokine.
    Immunology letters 01/2009; 122(1):26-9. DOI:10.1016/j.imlet.2008.10.010 · 2.37 Impact Factor

Publication Stats

478 Citations
194.12 Total Impact Points

Institutions

  • 2014
    • Moffitt Cancer Center
      Tampa, Florida, United States
  • 1998–2014
    • University of South Florida
      • • Division of Molecular Medicine
      • • Morsani College of Medicine
      • • Moffitt Cancer Center
      Tampa, Florida, United States
  • 1997
    • The American Society for Biochemistry and Molecular Biology
      Tampa, Florida, United States
  • 1995
    • Emory University
      Atlanta, Georgia, United States