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  • American Association for Cancer Research (AACR)  (12)
  • 2015-2019  (12)
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  • American Association for Cancer Research (AACR)  (12)
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  • 2015-2019  (12)
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  • 1
    Online Resource
    Online Resource
    Abstract 2867: Inhibition of BET bromodomain proteins as a therapeutic approach in small cell lung cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2867-2867
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2867-2867
    Abstract: BET (bromodomain and extra-terminal) family proteins are epigenetic readers that regulate expression of genes involved in cell growth and oncogenesis. Selective small molecule BET inhibitors, such as the GSK I-BETs (I-BET762, I-BET151), abrogate binding of BET proteins to acetylated histones and inhibit transcriptional activation of BET target genes. BET inhibitors attenuate proliferation and survival in a number of hematologic cancer models, partially through down-regulation of the critical oncogene, MYC. We and others have previously shown activity for BET inhibitors in solid tumor models such as neuroblastoma and prostate cancer, with concomitant down-regulation of MYC family gene expression. However, MYC or MYCN silencing only partially accounts for the activity of BET inhibitors in these models, suggesting that transcriptional regulation of multiple pathways promotes I-BET induced phenotypes. Here we describe the activity of the selective BET inhibitor, I-BET762, in small cell lung cancer (SCLC), a highly aggressive malignancy with few treatment options. We observe potent growth inhibition and apoptosis in a subset of cell lines and patient-derived SCLC models in vitro, as well as significant tumor growth inhibition in cell line and primary mouse xenografts. These anti-proliferative effects are likely mediated by inhibition of BRD2, BRD3, and BRD4, as siRNAs individually targeting all three proteins result in partial inhibition of SCLC cell line growth. Similar to our observations in neuroblastoma and prostate cancer, I-BET762 treatment in SCLC cell lines results in transcriptional changes affecting MYC and other pathways. We explore the contribution of these changes to the anti-proliferative effects observed in SCLC models, and identify potential combination strategies to enhance the activity of I-BET762. Taken together, our data highlight the potential of BET inhibitors as novel therapeutic agents to treat small cell lung cancer driven by various oncogenic pathways. All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed by the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed. Citation Format: Anastasia Wyce, BaoChau Le, Yuchen Bai, David Soong, Xi-Ping Zhang, Jeanne J. Matteo, Susan Korenchuk, Michael F. Butticello, Ramona Plant, Maureen R. Bleam, Yan Degenhardt, Charles F. McHugh, Christopher Carpenter, Peter J. Tummino, Olena Barbash. Inhibition of BET bromodomain proteins as a therapeutic approach in small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2867. doi:10.1158/1538-7445.AM2015-2867
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-2867
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 2
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    Online Resource
    HNF1B Loss Exacerbates the Development of Chromophobe Renal Cell Carcinomas
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 19 ( 2017-10-01), p. 5313-5326
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 19 ( 2017-10-01), p. 5313-5326
    Abstract: Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here, we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of HNF1B loss is unique to ChRCC. We also observed a strong correlation between reduced HNF1B expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, HNF1B deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell-cycle checkpoint proteins RB1 and p27. Furthermore, it altered the chromatin accessibility of Mad2l1, Bub1b, and Rb1 genes and triggered aneuploidy development. Analysis of The Cancer Genome Atlas database revealed TP53 mutations in 33% of ChRCC where HNF1B expression was repressed. In clinical specimens, combining HNF1B loss with TP53 mutation produced an association with poor patient prognosis. In cells, combining HNF1B loss and TP53 mutation increased cell proliferation and aneuploidy. Our results show how HNF1B loss leads to abnormal mitotic protein regulation and induction of aneuploidy. We propose that coordinate loss of HNF1B and TP53 may enhance cellular survival and confer an aggressive phenotype in ChRCC. Cancer Res; 77(19); 5313–26. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-17-0986
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 3
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    Abstract P2-08-01: Loss of function of Brca1 or Gata3 induces basal-like breast cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 4_Supplement ( 2018-02-15), p. P2-08-01-P2-08-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 4_Supplement ( 2018-02-15), p. P2-08-01-P2-08-01
    Abstract: BACKGROUND: Breast cancer is mainly divided into estrogen receptor (ER)-positive luminal and ER-negative basal-like tumors. Luminal-type tumors are associated with better survival and respond to hormone therapies whereas basal-like tumors are more aggressive and associated with a poor prognosis. Mammary epithelia are mainly composed of luminal and basal cells that are maintained by luminal and basal progenitors, respectively. The maintenance of luminal cell fate is orchestrated by networks of transcription factors, including BRCA1 and GATA3. Functional loss of BRCA1 by germline or somatic mutation or by promoter methylation is associated with more than one third of basal-like breast cancers. GATA3 expression is reduced in basal-like breast cancers and cancers that metastasize. Overexpression of GATA3 in cancer cells inhibits tumor formation. Deletion of Brca1 or Gata3 in mice results in early lethality or growth defects. How BRCA1 and GATA3 suppress breast cancer remains elusive. METHODS: We generated mice lacking Brca1 or Gata3 in mammary epithelia. Due to the proliferative defects and induction of p18Ink4c (p18), an inhibitor of CDK4/6, in mammary epithelial cells of these mice, we then generated mice lacking Brca1 or Gata3 in p18 deficient mammary epithelia. We determined spontaneous mammary tumor development in mutant mice and the mechanisms underlying the role of Brca1 and Gata3 in suppressing tumorigenesis and progression. RESULTS: Depletion of Brca1 or Gata3 led to growth defects of mammary epithelial cells, which was rescued by loss of p18. Depletion of Brca1 or Gata3 in a p18 null background induced heterogeneous mammary tumors with less luminal and more basal-like features and accelerated metastasis. Deletion of Brca1 eliminated Gata3 expression in human and mouse mammary tissues and cells. How Brca1 interacts with Gata3 to control mammary tumor development and progression is currently under investigation. CONCLUSION: Our results suggest that loss of function of either Brca1 or Gata3 induces basal-like mammary tumors in p18 deficient background. Citation Format: Pei X-H, Chan HL, Zhang L, Wang C, Robbins DJ, Capobianco T, Bai F. Loss of function of Brca1 or Gata3 induces basal-like breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-08-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS17-P2-08-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 4
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    A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody–Drug Conjugates (ADCs)
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 3 ( 2018-03-01), p. 650-660
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 3 ( 2018-03-01), p. 650-660
    Abstract: Tumor-selective delivery of cytotoxic agents in the form of antibody–drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA–cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here, we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar in vitro potency, but improved bystander killing and in vivo efficacy, compared with those of the cross-linker. Thus, the improved in vivo tolerability and antitumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment. Mol Cancer Ther; 17(3); 650–60. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-17-0940
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 5
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    Abstract 5083: A novel and highly efficacious small-molecule degrader of BET-BRD proteins for the treatment of acute leukemia
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5083-5083
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5083-5083
    Abstract: The bromodomain and extra-terminal domain (BET-BRD) family of lysine acetylation readers comprises BRD2, BRD3, BRD4, and BRDT that contain two conserved N-terminal bromodomains (BD1 and BD2) and a long C-terminal region containing the extraterminal (ET) protein-protein interaction domain. These proteins have key roles in the assembly of transcriptional regulatory complexes containing RNA polymerase II. BET-BRDs are new therapeutic targets for cancer treatment and several small-molecule BET-BRD inhibitors are currently in clinical development for a diverse set of cancers including leukemia. Based on the proteolysis targeting chimera (PROTAC) concept, we have developed novel and highly potent BET degraders, ZBC246 and ZBC260, with exceptional selectivity based upon a new class of BET inhibitor, ZBC11. ZBC260 effectively degrades all BET-BRD proteins at concentrations as low as 30 pM within a few hours of treatment in the RS4;11 leukemia cell line and achieves IC50 values of 50 pM in inhibition of RS4;11 cell growth. ZBC260 was tested in a panel of 10 acute leukemia cell lines generating IC50s ranging from 20 pM to 1 nM in 4-days cell growth inhibition assays. In contrast to the cytostatic effect observed with BET-BRD inhibition, degradation of BET-BRDs by ZBC246 and ZBC260 induced robust apoptosis demonstrating a differential biology between BET-BRD inhibitors and BET-BRD degraders. Significantly, ZBC260 induces rapid regression of RS4;11 xenograft tumors without overt signs of toxicity in mice. More importantly, treatment of leukemia cells obtained from 10 patients with ZBC260 demonstrated efficient degradation of BET-BRDs within 5 h at 0.3 nM, while treatment with the inhibitor (300 nM) induced up-regulation of BET-BRDs. Treatment of patients’ peripheral blasts with ZBC260 at 1 to 10 nM induced remarkable levels of apoptosis within 24 h, even in relapsed and refractory patient samples. In conclusion, ZBC260 represents a highly potent and efficacious BET-BRD degrader undergoing extensive preclinical evaluation for the treatment of acute leukemias. Citation Format: Ester Fernandez-Salas, Zhuo Chen, Mei Lin, Bing Zhou, Donna McEachern, Sally Przybranowski, Karson Kump, Luke F. Peterson, Malathi Kandarpa, Jiantao Hu, Fuming Xu, Liu Liu, Longchuan Bai, Bo Wen, Duxin Sun, Moshe Talpaz, Shaomeng Wang. A novel and highly efficacious small-molecule degrader of BET-BRD proteins for the treatment of acute leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5083. doi:10.1158/1538-7445.AM2017-5083
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-5083
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 6
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    Abstract 5599: Noninvasive genomic profiling of cerebral spinal fluid in breast cancer patient with leptomeningeal disease
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5599-5599
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5599-5599
    Abstract: Leptomeningeal disease (LMD) involves the dissemination of tumor cells from the primary breast tumors into the membranes surrounding the central nervous system and spinal cords. LMD occurs in about 5% of breast cancer patients and is associated with very poor survival. The genomic evolution of LMD in breast cancer patients has remained difficult to study, in part due to technical challenges in collecting longitudinal biopsy samples from the central nervous system. Liquid biopsies of the cerebral spinal fluid (CSF) may provide a unique opportunity to profile circulating tumor DNA (ctDNA) and has not been compared directly to non-invasive monitoring of ctDNA in blood samples. Furthermore, most non-invasive ctDNA profiling methods are limited to a targeted set of genes and have not allowed unbiased whole-genome profiling. To address these limitations, we developed an unbiased method for ctDNA analysis called PEGASUS (Plasma Exome and Genome Analysis by Size-selection and Unbiased Sequencing) that enables whole-genome sequencing of copy number aberrations and somatic mutations from ctDNA. We applied PEGASUS to sequence matched blood samples and CSF from 10 breast cancer patients with LMD. Quantitation of ctDNA levels showed that ctDNA was detected in CSF samples from 9/10 patients, while blood ctDNA was detected in only 1 LMD patient with extensive metastatic disease. Whole-genome copy number profiling at 220kb resolution and mutational profiling of a 2000 cancer gene panel of the matched CSF and blood samples was performed in 10 LMD patients using PEGASUS. Our data identified aneuploid copy number aberrations and somatic mutations (range: 11-25) in the CSF of 7 patients, including mutations in known driver genes such as BRAF, RB1, TP53 and amplifications of MYC and ERBB2. In contrast the matched blood samples showed only diploid copy number profiles and no detectable somatic mutations in 9/10 LMD patients. In one patient with extensive cranial metastatic disease with matched CSF and blood ctDNA, we found a high concordance in copy number profiles (R= 0.75) and modest concordance of somatic mutations (59.5%), but also additional CNAs and mutations that were specific to the CSF. Collectively, these data show that genomic profiling of ctDNA in CSF is technically feasible for patients with LMD, and provides a major advantage over blood ctDNA which cannot be detected in mostcases. Citation Format: Masahiro Oikawa, Naveen Ramesh, Emi Sei, Shanshan Bai, Min Hu, de Groot F. John, Murthy Rshmi, Barbara O'Brien, Nicholas Navin. Noninvasive genomic profiling of cerebral spinal fluid in breast cancer patient with leptomeningeal disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5599.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-5599
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Abstract P6-08-08: GATA3 inhibits breast basal-like tumorigenesis
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 4_Supplement ( 2017-02-15), p. P6-08-08-P6-08-08
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 4_Supplement ( 2017-02-15), p. P6-08-08-P6-08-08
    Abstract: BACKGROUND: Breast cancer can be broadly categorized into two groups depending on the cell type affected. Luminal-type tumors are typically estrogen receptor (ER) positive that are associated with better survival and respond to hormone therapies whereas basal-like tumors are ER negative, more aggressive, and associated with a poor prognosis. GATA3 is a transcription factor well studied for its role as a master regulator of cellular differentiation and stem cell self renewal. Loss of Gata3 in mouse mammary glands blocks luminal cell differentiation and induces growth defects, and low levels of GATA3 are associated with basal-like and metastatic human breast cancers with epithelial-to-mesenchymal transition (EMT). Importantly, luminal cells have been shown to be the origin of some basal-like breast cancers. Due to the proliferation defects caused by GATA3 deficiency, it remains elusive how loss of function of GATA3 contributes to breast cancers development and progression. METHODS: We previously demonstrated that p18Ink4c (p18), a cell cycle inhibitor, is a downstream target of GATA3 in regulating mammary luminal cell proliferation and loss of p18 leads to luminal type tumorigenesis. To test the role of Gata3 deficiency in tumorigenesis, we generated p18-/-;Gata3+/- mice. Mammary gland development and tumorigenesis were characterized in vivo using a panel of cellular and molecular assays. Results were further confirmed in vitro with well established cell lines. RESULTS: Loss of p18 rescued mammary growth defects caused by Gata3 heterozygosity. Gata3 heterozygosity impaired luminal, but promoted basal gene expression in mammary epithelial cells. Gata3 heterozygosity in p18 null mice accelerated spontaneous mammary tumorigenesis, reducing the average latency of tumor onset. More importantly, Gata3 heterozygosity transformed the luminal type tumors of p18 null mice into heterogeneous basal-like breast cancers with activated EMT. Conversely, reintroduction of GATA3 inhibited tumor growth and reduced expression of EMT markers in basal-like tumor xenografts. We discovered that expression of GATA3 and Vimentin, an EMT marker, is inversely related in human breast cancers. CONCLUSION: Our data indicates that GATA3 promotes luminal but suppresses basal cell differentiation in the mammary gland and in tumor development. Mechanisms underlying the role of GATA3 in suppressing basal-like tumor development are under investigation.BACKGROUND: Breast cancer can be broadly categorized into two groups depending on the cell type affected. Luminal-type tumors are typically estrogen receptor (ER) positive that are associated with better survival and respond to hormone therapies whereas basal-like tumors are ER negative, more aggressive, and associated with a poor prognosis. GATA3 is a transcription factor well studied for its role as a master regulator of cellular differentiation and stem cell self renewal. Loss of Gata3 in mouse mammary glands blocks luminal cell differentiation and induces growth defects, and low levels of GATA3 are associated with basal-like and metastatic human breast cancers with epithelial-to-mesenchymal transition (EMT). Importantly, luminal cells have been shown to be the origin of some basal-like breast cancers. Due to the proliferation defects caused by GATA3 deficiency, it remains elusive how loss of function of GATA3 contributes to breast cancers development and progression. METHODS: We previously demonstrated that p18Ink4c (p18), a cell cycle inhibitor, is a downstream target of GATA3 in regulating mammary luminal cell proliferation and loss of p18 leads to luminal type tumorigenesis. To test the role of Gata3 deficiency in tumorigenesis, we generated p18-/-;Gata3+/- mice. Mammary gland development and tumorigenesis were characterized in vivo using a panel of cellular and molecular assays. Results were further confirmed in vitro with well established cell lines. RESULTS: Loss of p18 rescued mammary growth defects caused by Gata3 heterozygosity. Gata3 heterozygosity impaired luminal, but promoted basal gene expression in mammary epithelial cells. Gata3 heterozygosity in p18 null mice accelerated spontaneous mammary tumorigenesis, reducing the average latency of tumor onset. More importantly, Gata3 heterozygosity transformed the luminal type tumors of p18 null mice into heterogeneous basal-like breast cancers with activated EMT. Conversely, reintroduction of GATA3 inhibited tumor growth and reduced expression of EMT markers in basal-like tumor xenografts. We discovered that expression of GATA3 and Vimentin, an EMT marker, is inversely related in human breast cancers. CONCLUSION: Our data indicates that GATA3 promotes luminal but suppresses basal cell differentiation in the mammary gland and in tumor development. Mechanisms underlying the role of GATA3 in suppressing basal-like tumor development are under investigation. Citation Format: Pei X-H, Chan HL, Liu S, Scott A, Pimentel E, Slingerland J, Robbins D, Capobianco A, Bai F. GATA3 inhibits breast basal-like tumorigenesis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-08-08.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS16-P6-08-08
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 8
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    Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 9 ( 2017-05-01), p. 2476-2487
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 9 ( 2017-05-01), p. 2476-2487
    Abstract: Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In this study, we report the development of a second-generation BET protein degrader, BETd-246, which exhibits superior selectivity, potency, and antitumor activity. In human TNBC cells, BETd-246 induced degradation of BET proteins at low nanomolar concentrations within 1 hour of exposure, resulting in robust growth inhibition and apoptosis. BETd-246 was more potent and effective in TNBC cells than its parental BET inhibitor compound BETi-211. RNA-seq analysis revealed predominant downregulation of a large number of genes involved in proliferation and apoptosis in cells treated with BETd-246, as compared with BETi-211 treatment that upregulated and downregulated a similar number of genes. Functional investigations identified the MCL1 gene as a critical downstream effector for BET degraders, which synergized with small-molecule inhibitors of BCL-xL in triggering apoptosis. In multiple murine xenograft models of human breast cancer, BETd-246 and a further optimized analogue BETd-260 effectively depleted BET proteins in tumors and exhibited strong antitumor activities at well-tolerated dosing schedules. Overall, our findings show that targeting BET proteins for degradation represents an effective therapeutic strategy for TNBC treatment. Cancer Res; 77(9); 2476–87. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-16-2622
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 9
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    Abstract P4-08-13: Prognostic significance of CD8+ tumor-infiltrating lymphocytes (TILs) in patients with early breast cancer (EBC) treated with dose-dense sequential adjuvant chemotherapy (dds-CT). An observational study (ACTRN12616001043426)
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. P4-08-13-P4-08-13
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. P4-08-13-P4-08-13
    Abstract: Background - aim: Information on the prognostic role of cytotoxic CD8+ T cells in the era of modern adjuvant CT is limited. The primary objective of the present report is to assess the prognostic impact of CD8+ cells in patients with intermediate or high-risk EBC (T1-3N1-2M0) treated with dds-CT. Secondary endpoints are safety, disease-free survival (DFS) and overall survival (OS). Patients and Methods: Patients (N=1,000) were treated with 4 cycles of Epirubicin, 75mg/m2, and Cyclophophamide, 600mg/m2 every 2 weeks followed by 4 cycles of Docetaxel (D), 100mg/m2 every 3 weeks with G-CSF support in all cycles. Trastuzumab was initiated concurrently with D and continued for a total of 1 year. Hormonal and radiation therapy were given post CT, as indicated. Formalin-fixed paraffin-embedded tumors were available for 642 patients (64.2%) and were centrally assessed for immunohistochemical subtypes (IHC4; N=526), stromal TILs density by morphology (N=636), as well as stromal and intratumoral cytotoxic CD8+ T cell numbers (N=554). TILs and CD8+ were assessed as continuous variables for associations and as 10% increments for outcome. Results: In total, 901/1,000 pts (90.1%) completed 8 cycles of CT. Severe (gradeIII-IV) toxicitiesincludedneutropenia (5.6%), leucopenia (3.6%), lymphopenia (2.1%), hand-footsyndrome (2.1%), and hepatotoxicity (1.8%). Febrileneutropenia occurred in 1.6% of the patients. The 5-year DFS and OS rates were 89.5% and 93.1%, respectively. Luminal A tumors were classified in 26.2%, Luminal B in 35.2%, luminal HER2 in 9.5%; HER2-enriched in 7.2%; and, triple-negative (TNBC) in 21.9% of informative patients. Among subtypes, stromal TILs density was higher in HER2-enriched and TNBC (p & lt;0.001); intratumoral CD8+ values were higher in TNBC (p & lt;0.001); and, stromal CD8+ were higher in HER2-enriched (p=0.034). In all patients, TILs density and intratumoral CD8+ cell numbers were not associated with DFS and OS, while increased stromal CD8+ were marginally associated with prolonged DFS (HR=0.98, 95%CI 0.96-1.00, p=0.066).Adjusted for histological grade, menopausal, ER/PgR and nodal status, higher stromal CD8+ were associated with prolonged DFS (HR=0.98, 95% CI 0.96-1.00, p=0.043). In TNBC, higher stromal TILs density conferred prolonged DFS (HR=0.97, 95%CI 0.94-0.99, p=0.029), which retained its prognostic significance in multivariate analysis (HR=0.97, 95% CI 0.94-1.00, p=0.049). Conclusions: In this study, dds-CT was well tolerated and active in patients with EBC. We confirm the presence of morphologically assessed higher TILs density, and of higher cytotoxic CD8+ T cell numbers in hormone receptor negative EBC, as well as the favorable prognostic impact of higher stromal TILs density in TNBC. In comparison to stromal TILs density, higher stromal CD8+ may confer favorable prognosis irrespectively of EBC subtype. Stromal CD8+ seems to be a marker worth further standardizing for reporting on immune cell infiltrates in EBC. Citation Format: Kourea HP, Koletsa T, Kotoula V, Koliou G-A, Batistatou A, Pentheroudakis G, Arapantoni-Dadioti P, Zagouri F, Bobos M, Sotiropoulou M, Papoudou-Bai A, Chrisafi S, Efstratiou I, Aravantinos G, Nicolaou I, Gogas H, Visvikis A, Christodoulou C, Petraki C, Koutras A, Psyrri A, Pectasides D, Fountzilas G. Prognostic significance of CD8+ tumor-infiltrating lymphocytes (TILs) in patients with early breast cancer (EBC) treated with dose-dense sequential adjuvant chemotherapy (dds-CT). An observational study (ACTRN12616001043426) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-13.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-P4-08-13
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 10
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    Identification of Glycopeptides as Posttranslationally Modified Neoantigens in Leukemia
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Immunology Research Vol. 5, No. 5 ( 2017-05-01), p. 376-384
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 5, No. 5 ( 2017-05-01), p. 376-384
    Abstract: Leukemias are highly immunogenic, but they have a low mutational load, providing few mutated peptide targets. Thus, the identification of alternative neoantigens is a pressing need. Here, we identify 36 MHC class I–associated peptide antigens with O-linked β-N-acetylglucosamine (O-GlcNAc) modifications as candidate neoantigens, using three experimental approaches. Thirteen of these peptides were also detected with disaccharide units on the same residues and two contain either mono- and/or di-methylated arginine residues. A subset were linked with key cancer pathways, and these peptides were shared across all of the leukemia patient samples tested (5/5). Seven of the O-GlcNAc peptides were synthesized and five (71%) were shown to be associated with multifunctional memory T-cell responses in healthy donors. An O-GlcNAc-specific T-cell line specifically killed autologous cells pulsed with the modified peptide, but not the equivalent unmodified peptide. Therefore, these posttranslationally modified neoantigens provide logical targets for cancer immunotherapy. Cancer Immunol Res; 5(5); 376–84. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-16-0280
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2732517-9
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