ETS FAMILY OF TRANSCRIPTION FACTORS AS A THERAPEUTIC TARGET IN CANCER PDF Download
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Author: Tsion Zewdu Minas
Publisher:
ISBN:
Category : Oncology
Languages : en
Pages : 298
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Book Description
The ETS family of transcription factors share a conserved DNA binding domain that recognizes a purine rich consensus sequence with GGAA/T motif. ETS genes have been implicated in a wide array of malignancies including acute myeloid leukemia, Ewing sarcoma and prostate cancer. These genes are suppressed in most adult tissues, while in cancer; their expression is upregulated as a result of chromosomal rearrangements that leave the factors under a control of ubiquitously active promoters. In Ewing sarcoma (ES) patients, tumor specific chromosomal translocation involving FLI1 creates EWS-FLI1 protein. In previous studies, we identified a small molecule inhibitor, YK-4-279, that directly binds to EWS-FLI1 and inhibit its activities. Due to lack of an ES transgenic mouse model, we tested the in vivo therapeutic efficacy of YK-4-279 in the only available transgenic mouse model with EWS-FLI1 induced neoplasm. We showed that short-term YK-4-279 treatment led to correction of abnormal hematopoiesis and improved overall survival of EWS-FLI1+ leukemic mice. Thus far, a genetically engineered mouse model for EWS-FLI1 driven Ewing sarcoma has not been successfully generated. Here, we present data where we tried various approaches to conditionally express EWS-FLI1 using cre recombinase in order to generate a Ewing sarcoma transgenic mouse model. We used the Osx promoter to target Cre recombinase expression to the osteoblast lineage. Alternatively, we injected Cre expressing adenovirus to induce EWS-FLI1 expression locally. Most attempts resulted in embryonic lethality or developmental defects. Chromosomal translocations that involve members of the ETS transcription factor family are also present in a majority of prostate cancer patients. In order to understand how ETS transcription factors drive tumorigenicity in prostate cancer, we investigated their interacting protein partners. We identified and validated ezrin, RHA, and PARP as ERG interacting partners and show that YK-4-279 can inhibit these interactions. Overall, in this study, we demonstrate that direct targeting of ETS transcription factors with small molecules could be of significant therapeutic value in oncology.
Author: Tsion Zewdu Minas
Publisher:
ISBN:
Category : Oncology
Languages : en
Pages : 298
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Book Description
The ETS family of transcription factors share a conserved DNA binding domain that recognizes a purine rich consensus sequence with GGAA/T motif. ETS genes have been implicated in a wide array of malignancies including acute myeloid leukemia, Ewing sarcoma and prostate cancer. These genes are suppressed in most adult tissues, while in cancer; their expression is upregulated as a result of chromosomal rearrangements that leave the factors under a control of ubiquitously active promoters. In Ewing sarcoma (ES) patients, tumor specific chromosomal translocation involving FLI1 creates EWS-FLI1 protein. In previous studies, we identified a small molecule inhibitor, YK-4-279, that directly binds to EWS-FLI1 and inhibit its activities. Due to lack of an ES transgenic mouse model, we tested the in vivo therapeutic efficacy of YK-4-279 in the only available transgenic mouse model with EWS-FLI1 induced neoplasm. We showed that short-term YK-4-279 treatment led to correction of abnormal hematopoiesis and improved overall survival of EWS-FLI1+ leukemic mice. Thus far, a genetically engineered mouse model for EWS-FLI1 driven Ewing sarcoma has not been successfully generated. Here, we present data where we tried various approaches to conditionally express EWS-FLI1 using cre recombinase in order to generate a Ewing sarcoma transgenic mouse model. We used the Osx promoter to target Cre recombinase expression to the osteoblast lineage. Alternatively, we injected Cre expressing adenovirus to induce EWS-FLI1 expression locally. Most attempts resulted in embryonic lethality or developmental defects. Chromosomal translocations that involve members of the ETS transcription factor family are also present in a majority of prostate cancer patients. In order to understand how ETS transcription factors drive tumorigenicity in prostate cancer, we investigated their interacting protein partners. We identified and validated ezrin, RHA, and PARP as ERG interacting partners and show that YK-4-279 can inhibit these interactions. Overall, in this study, we demonstrate that direct targeting of ETS transcription factors with small molecules could be of significant therapeutic value in oncology.
Author: Nicholas B. La Thangue
Publisher: Springer Science & Business Media
ISBN: 1592591531
Category : Medical
Languages : en
Pages : 358
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Book Description
In Targets for Cancer Chemotherapy: Transcription Factors and Other Nuclear Proteins, a panel of leading basic researchers, pharmaceutical scientists, and clinical oncologists explain in detail the therapeutically-relevant protein targets that contribute to cancer pathology and spell out their implications for cancer drug discovery and clinical application. The authors identify and illuminate selected transcription factor oncoproteins and tumor suppressors, together with nuclear proteins that are central to the phenotype of the tumor cell involved in chromatin control. The emphasis is on new targets and approaches to cancer treatment derived from the cancer cell cycle, gene control targets, and angiogenesis.
Author: Andrew Clayton Haller
Publisher:
ISBN:
Category :
Languages : en
Pages : 135
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Book Description
One of the greatest problems in prostate cancer management today is accurate identification of patients who require treatment for aggressive disease versus those with indolent disease who are suitable for observational strategies. Histological appearance of the tumor, called Gleason score in the prostate cancer field, is the most predictive measure currently used. However, recent studies in multiple tumor types have shown that histological appearance does not always reflect the underlying molecular phenotype of the lesion. Therefore, in prostate cancer specifically, assessment of a molecular marker of androgen receptor driven epithelial differentiation may have clinical predicative capabilities. SAM pointed domain-containing Ets transcription factor (SPDEF) is a potential AR target gene that has shown to be necessary and sufficient for epithelial cell differentiation in many tissues. Although generally associated with good prognosis, SPDEF's role in cancer in unclear. This study demonstrates, through retrospective immunohistochemical analysis, the utility of SPDEF as a predictive biomarker for patients that have an extended benefit from androgen deprivation therapy (ADT). Furthermore, dual roles of SPDEF to inhibit the initiation and supporting the progression of castrate recurrent disease through novel androgen receptor expression regulation in castrate conditions are shown. In ADT naive patients, SPDEF did not associate with metastatic disease or an induction of epithelial to mesenchymal transition. However, aggressive tumors tended to be larger, have greater SPDEF variability, and lack vimentin expression; a phenotype that could be explained by a partial EMT. In conclusion, SPDEF may be clinically useful to assess the epithelial phenotype of tumors, and could have utility identifying patients that will respond well to androgen deprivation therapy.
Author: Ajit Varki
Publisher: CSHL Press
ISBN: 9780879696818
Category : Medical
Languages : en
Pages : 694
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Book Description
Sugar chains (glycans) are often attached to proteins and lipids and have multiple roles in the organization and function of all organisms. "Essentials of Glycobiology" describes their biogenesis and function and offers a useful gateway to the understanding of glycans.
Author: Mohit Kumar Jolly
Publisher: MDPI
ISBN: 3039367242
Category : Medical
Languages : en
Pages : 512
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Book Description
Recent studies have highlighted that epithelial-mesenchymal transition (EMT) is not only about cell migration and invasion, but it can also govern many other important elements such as immunosuppression, metabolic reprogramming, senescence-associated secretory phenotype (SASP), stem cell properties, therapy resistance, and tumor microenvironment interactions. With the on-going debate about the requirement of EMT for cancer metastasis, an emerging focus on intermediate states of EMT and its reverse process mesenchymal-epithelial transition (MET) offer new ideas for metastatic requirements and the dynamics of EMT/MET during the entire metastatic cascade. Therefore, we would like to initiate discussions on viewing EMT and its downstream signaling networks as a fulcrum of cellular plasticity, and a facilitator of the adaptive responses of cancer cells to distant organ microenvironments and various therapeutic assaults. We hereby invite scientists who have prominently contributed to this field, and whose valuable insights have led to the appreciation of epithelial-mesenchymal plasticity as a more comprehensive mediator of the adaptive response of cancer cells, with huge implications in metastasis, drug resistance, tumor relapse, and patient survival.
Author: Benjamin M. Greulich
Publisher:
ISBN:
Category : Cancer cells
Languages : en
Pages : 0
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Book Description
The ETS family of transcription factors is a large group of 28 proteins in humans, and its members regulate a wide variety of processes in both embryological and adult tissue. Four of these members, ERG, ETV1, ETV4, and ETV5, become expressed in prostate cancer cells following chromosomal rearrangements. By far, the most common ETS factor to become aberrantly expressed in prostate cancer is ERG, which occurs in approximately 50% of prostate cancers. Once expressed, ERG drives oncogenic phenotypes such as migration and invasion and cooperates with other mutations, such as activation of PI3K/AKT signaling, to drive tumorigenesis. Therefore, understanding molecular mechanisms that govern the regulation and activation of ERG is paramount for developing precision therapeutics for prostate cancer patients. As a transcription factor, ERG has three critical functions that enable it to transcriptionally regulate its target genes. ERG must bind DNA, ERG must gain an activating phosphorylation mark, and ERG must interact with its co-activator EWS. Disrupting any of these three processes has the potential to reduce ERG function, and thus be leveraged as a therapeutic approach. However, not all of these approaches have equal likelihoods of being therapeutically relevant. The ETS family of transcription factors is defined by the shared similarity between the DNA-binding domains of each of the ETS factors. Additionally, multiple non-oncogenic ETS factors are normally expressed in prostate cells, some of which have anti-tumor activities. Therefore, approaches aiming to disrupt the ETS-DNA interaction hold a distinct probability to produce side effects resulting from the disruption of non-oncogenic ETS, either in the prostate or elsewhere in the body. For this reason, the work here was focused on the mechanism of ERG's phosphorylation and interaction with EWS. Here, I detail a mechanism by which TLR4 signaling leads to the phosphorylation of ERG via the MAPK pathway. Activated ERG then transcriptionally activates its target gene program, including TLR4 and endogenous ligands for TLR4, resulting in a positive feedback loop. I also describe an indirect interaction between ERG and EWS, which is enabled by the RNA-binding protein, PABPC1.
Author: Jason Ellison
Publisher:
ISBN:
Category : Cancer
Languages : en
Pages : 438
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Book Description
Author: Zaki Shaikhibrahim
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
Author: Robert C. Bast, Jr.
Publisher: John Wiley & Sons
ISBN: 111900084X
Category : Medical
Languages : en
Pages : 2004
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Book Description
Holland-Frei Cancer Medicine, Ninth Edition, offers a balanced view of the most current knowledge of cancer science and clinical oncology practice. This all-new edition is the consummate reference source for medical oncologists, radiation oncologists, internists, surgical oncologists, and others who treat cancer patients. A translational perspective throughout, integrating cancer biology with cancer management providing an in depth understanding of the disease An emphasis on multidisciplinary, research-driven patient care to improve outcomes and optimal use of all appropriate therapies Cutting-edge coverage of personalized cancer care, including molecular diagnostics and therapeutics Concise, readable, clinically relevant text with algorithms, guidelines and insight into the use of both conventional and novel drugs Includes free access to the Wiley Digital Edition providing search across the book, the full reference list with web links, illustrations and photographs, and post-publication updates
Author:
Publisher:
ISBN:
Category :
Languages : en
Pages : 8
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Book Description
Recently, gene rearrangements involving ETS family transcription factors have been identified in>50% of prostate cancer cases. To address roles of these ETS factors, especially ERG, the most frequently rearranged ETS gene in prostate cancer, as well as in normal prostate development, we planned to, 1. Generate conditional knockin mouse models of prostate cancer based on the newly identified TMPRSS2- ERG (or ETV1) gene arrangements; 2 Explore roles of Erg during development as well as in normal prostate by disrupting its expression in mouse; 3. Identify downstream target genes of ERG or ETV1 in human prostate cancer cell lines carrying these gene arrangements using the ChIP-on-Chip approach. During the first year of this award, we have made significant progress in establishing systems and reagents for all three aims mentioned above. Specifically, we have successfully created conditional knockin mice expressing truncated human ERG and ETV1 (as found in patients) from the endogenous mouse Tmprss2 locus. We have generated an Erg knockdown allele in mice, which would allow us to study its roles during both embryonic development and postnatal prostate development. We have also made biotinylated ERG and ETV1 in prostate cell lines, which would allow us to identify the downstream targets of these factors in prostate epithelial cells. Further studies using these animal and cell culture models would allow us to develop preclinical animal models, and to identify and validate novel therapeutic targets, for treating prostate cancer.
