tbuckley/cabot-search huggingface dataset:
Abstract 5218: Breast cancer resistance protein (ABCG2) and P-glycoprotein (ABCB1) transport ibrutinib and may restrict its oral availability and brain accumulation, whereas CYP3A4 limits ibrutinib oral availability
Authors: Stephanie van Hoppe, Gert-Jan Rood, Els Wagenaar, Rolf Sparidans, Jos Beijnen, Alfred Schinkel
Journal: Cancer Research (2017)

Abstract Introduction: Ibrutinib (Imbruvica, PCI-32765) is an orally administered tyrosine kinase inhibitor (TKI) approved by the FDA in 2014 for treatment of B-cell malignancies. Ibrutinib is a confirmed irreversible inhibitor of Bruton tyrosine kinase (BTK) with promising clinical activity and tolerability in B-cell malignancies. Ibrutinib is converted into several metabolites, primarily by CYP3A4. Its main metabolite, PCI45227, has an inhibitory activity towards BTK approximately 10 times lower than its parent compound. We investigated whether ibrutinib is a substrate for the multidrug efflux transporters ABCG2 and ABCB1 and whether these transporters influence oral availability and brain and other tissue accumulation of ibrutinib. Materials: We used in vitro transport assays to assess human (h)ABCB1-, hABCG2- or murine (m)Abcg2-mediated transport of ibrutinib. To study the single and combined roles of Abcg2 and Abcb1a/1b in oral ibrutinib disposition, we used appropriate knockout mouse strains. To assess the role of Cyp3a in the bioavailability of ibrutinib we used knockout strains as well as humanized CYP3A4 strains and measured the ibrutinib and PCI45227 concentrations at various time points. Results: Ibrutinib was transported reasonably well by hABCB1 and mAbcg2, but not by hABCG2 in vitro. Upon oral administration of ibrutinib, Cyp3a-/-, Abcg2-/-, Abcb1a1b-/-, and Abcg2;Abcb1a1b-/- mice displayed an increase of 9.8-, 1.3-, 1.6- and 1.1 fold in ibrutinib plasma AUC0-20min compared to wild-type mice. At 20 min, preliminary data indicated that the relative brain accumulation of ibrutinib was not significantly altered for the Abcg2;Abcb1a/1b-/- mice compared to wild-type mice. Conclusion: Abcg2 and Abcb1a/1b possibly restrict oral availability of ibrutinib. Based on our (preliminary) data ibrutinib may not substantially cross the blood-brain barrier. Cyp3a restricts the oral availability of ibrutinib and therefore inhibition of this enzyme may be of clinical importance for patients undergoing ibrutinib therapy. Citation Format: Stephanie van Hoppe, Gert-Jan Rood, Els Wagenaar, Rolf Sparidans, Jos Beijnen, Alfred Schinkel. Breast cancer resistance protein (ABCG2) and P-glycoprotein (ABCB1) transport ibrutinib and may restrict its oral availability and brain accumulation, whereas CYP3A4 limits ibrutinib oral availability [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 5218. doi:10.1158/1538-7445.AM2017-5218
Abstract 1667: Identifying intrinsic regulators of PD-L1 expression in cancer cells: A genome-scale CRISPR knock-out approach
Authors: Jacqueline E. Mann, Megan L. Ludwig, Rebecca C. Hoesli, Aditi Kulkarni, Simmy Patel, Judy Kafelghazal, Alexey Nesvizhskii, J Chad Brenner
Journal: Cancer Research (2017)

Abstract Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer in the United States and affects 600,000 people each year worldwide. With a five-year survival rate of only 50% and a recent rise in HPV-associated HNSCCs, improved treatment protocols are urgently needed. Evidence of immunosuppression is often reported in HNSCC, making immunotherapy an attractive strategy for the management of this disease. The immune checkpoint inhibitor Pembrolizumab was recently approved for the treatment of metastatic and recurrent HNSCC, but only 18% of initial participants in a trial of Pembrolizumab responded, and it remains difficult to predict patients likely to experience benefit. To increase the number of patients that respond to immune checkpoint inhibition, we sought to identify targetable genetic factors modulating PD-L1, a molecule that serves to dampen the anti-tumor immune response. We show that several HNSCC models exhibit mild (2-4 fold) induction of PD-L1 expression following treatment with interferon-γ (adaptive expression), and recent reports suggest that common oncogenic pathways, including the EGFR and PI3K pathways, may provide a novel strategy to regulate PD-L1 expression. To this end, we developed a high throughput screen to identify targetable pathways that may be used to regulate PD-L1 expression in patients with specific genetic lesions. We have employed a Genome-scale CRISPR Knock-Out (GeCKO) screening technique in HNSCC cell lines and selected for genetic knockouts exhibiting altered PD-L1 expression. Stable knockout pools with representation of approximately 300 gRNAs per target gene (&amp;gt;20,000 target genes in the library) were expanded and serially sorted to create stable sub-populations with enhanced PD-L1 expression. These sub-populations were sequenced to identify gRNAs whose knockout causes a change in PD-L1 expression (e.g. genes that repress or enhance PD-L1 expression). We expect that these large-scale screens, when performed over multiple HNSCC cell lines with diverse genetic lesions, will identify patterns of targetable regulators that may ultimately be manipulated in combination with PD-1/PD-L1 inhibitors. Citation Format: Jacqueline E. Mann, Megan L. Ludwig, Rebecca C. Hoesli, Aditi Kulkarni, Simmy Patel, Judy Kafelghazal, Alexey Nesvizhskii, J Chad Brenner. Identifying intrinsic regulators of PD-L1 expression in cancer cells: A genome-scale CRISPR knock-out approach [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 1667. doi:10.1158/1538-7445.AM2017-1667
Abstract LB-057: The expression level and prognostic value of PD-L1 and PD-1 in cervical carcinoma patients
Authors: Yongxing Bao, Songan Zhang, Huerdidan Niyazi, Gulixian Tuluwengjiang, Lei Zhang, Yang Zhang, Weipeng Su
Journal: Cancer Research (2017)

Abstract Cervical cancer is one of the most common gynecologic malignant tumors that threaten the health of women. Recently some researches have found that radiotherapy combined with anti-PD-1/PD-L1 drugs might improve anti-tumor efficacy. But there is few report about this issue on cervical cancer field. In order to testify the possibility and feasibility in cervical cancer patients, we collected 70 tissue samples of cervical squamous cell carcinoma and 70 tissue samples of cervical benign lesion, of which 24 cases of the cervical squamous cell carcinoma had matched peripheral blood samples, compared to 30 cases with matched peripheral blood samples of benign lesions. We used immunohistochemistry to detect the expression of PD-L1 in the tissues and flow cytometry to detect the proportion of CD4+PD-1+ and CD8+PD-1+ subsets in peripheral blood. Then Log-rank and COX regression were used to analyze the relationship among survival time, expression of PD-L1 and proportion of PD-1+ T cells. The results indicated that the proportion of CD4+PD-1+ T cells and CD8+PD-1+ T cells in peripheral blood positively correlated with the expression of PD-L1 in tissue samples of cervical squamous cell carcinoma patients (R2=0.734, P=0.000; R2=0.66, P=0.000), while there were less correlation in cervical benign patients (R2=0.138, P=0.043; R2=0.174, P=0.022). There were significantly differences in the proportion of CD8+PD-1+T cells and PD-L1+ tissue cells between cervical cancer group and cervical benign disease group (P=0.000, P=0.002). With the increase of tumor stage, the percentage of CD4+PD-1+ T cells and CD8+PD-1+ T cells increased correspondingly. With the increase of tumor diameter and stage, the expression of PD-L1 in tumor tissue also increased. The patients with small proportion of CD4+PD-1+ T cells and low expression of PD-L1 seemed to have longer survival time. Multivariate analysis showed that the PFS time was affected by the expression of PD-L1(B=1.844, P=0.019). Taken together, the cervical squamous cell cancer patients had more CD4+PD-1+ T cells in peripheral blood and PD-L1+ cells in tissues, which correlated to the grading of tumor and associated with prognosis. Note: This abstract was not presented at the meeting. Citation Format: Yongxing Bao, Songan Zhang, Huerdidan Niyazi, Gulixian Tuluwengjiang, Lei Zhang, Yang Zhang, Weipeng Su. The expression level and prognostic value of PD-L1 and PD-1 in cervical carcinoma patients [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 LB-057. doi:10.1158/1538-7445.AM2017-LB-057
Abstract 4926: Gut microbiota regulates cisplatin mediated cachexia and systemic toxicity
Authors: Soumen Roy, Rodrigo Das Neves, Amiran Dzutsev, Carolyne Smith, Bathai Edwards, Miranda Dawson, Simone Difilippantonio, Loretta Smith, April Huang, Young Kim, Giorgio Trinchieri
Journal: Cancer Research (2017)

Abstract Chemotherapy induced toxicity severely affect the cancer survivors and lowers the quality of life. By 2020, there will be more than 18 million of cancer survivors all over the world. Majority of them might develop long term nephrotoxicity, ototoxicity and gut toxicity. In addition, chemotherapy may also facilitate the initiation and progression of cachexia. Recent studies have shown that gut microbiota modulates the efficacy of anti-cancer chemotherapy, however very limited knowledge is available regarding the role of gut microbiota in regulating systemic toxicity and cachexia. We hypothesized that gut microbiota modulates cisplatin induced systemic toxicity as well as cachexia. Four groups (n=10 in each group) of 6-8 weeks old C57B/6 mice were treated with cisplatin, cisplatin+antibiotics cocktails (ABX), ABX only and control. ABX cocktail contained primaxin, vancomycin and neomycin. This experiment was validated using C57B/6 germ free mice. We performed anti-p-γ-H2AX based toxicity assay for DNA damage. In addition, we performed immunohistochemistry for studying cachexia. H&amp;E staining and DNA damage were assessed by light and super resolution confocal microscopy (Zeiss 880) and quantified by 3-D reconstruction using IMARIS. We also performed high content imaging to evaluate DNA damage in bone marrow and spleen. Body weight and kidney blood content were also analyzed to determine the degree of toxicity. Depletion of gut microbiota significantly reduced nephrotoxicity and gut toxicity. In addition, we found that depletion of gut microbiota prevents muscle and adipose tissue loss by down-regulating UCP-1and PGC-1α in adipose tissue and MURF-1 and Atrogin-1 in muscle. Experiments are confirmed by using Germ free mice. Our data suggest that modulation of gut microbiota may be utilized to reduce chemotherapy associated cachexia and systemic toxicity. Citation Format: Soumen Roy, Rodrigo Das Neves, Amiran Dzutsev, Carolyne Smith, Bathai Edwards, Miranda Dawson, Simone Difilippantonio, Loretta Smith, April Huang, Young Kim, Giorgio Trinchieri. Gut microbiota regulates cisplatin mediated cachexia and systemic toxicity [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 4926. doi:10.1158/1538-7445.AM2017-4926
Iron Oxide Nanozyme: A Multifunctional Enzyme Mimetic for Biomedical Applications
Authors: Lizeng Gao, Kelong Fan, Xiyun Yan
Journal: Theranostics (2017)

Iron oxide nanoparticles have been widely used in many important fields due to their excellent nanoscale physical properties, such as magnetism/superparamagnetism. They are usually assumed to be biologically inert in biomedical applications. However, iron oxide nanoparticles were recently found to also possess intrinsic enzyme-like activities, and are now regarded as novel enzyme mimetics. A special term, "Nanozyme", has thus been coined to highlight the intrinsic enzymatic properties of such nanomaterials. Since then, iron oxide nanoparticles have been used as nanozymes to facilitate biomedical applications. In this review, we will introduce the enzymatic features of iron oxide nanozyme (IONzyme), and summarize its novel applications in biomedicine.
Abstract LB-084: Histone chaperone HIRA is required for Setd1a H3K4 methylation recruited by TAL1 oncoprotein in leukemogenesis
Authors: Ying Li
Journal: Cancer Research (2017)

Abstract TAL1/SCL is a hematopoietic specific member of the basic Helix-Loop-Helix (bHLH) family of transcription factors important for the development of all hematopoietic lineages and pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL), which plays a coordinating role in establishing the proper chromatin dynamics and gene regulation. We have previously demonstrated that TAL1 associated with H3K4 methyltransferase SETD1A, which mediated epigenetic regulation that regulates hematopoietic transcription and differentiation programs during hematopoiesis and leukemogenesis. We now find that a novel interaction between TAL1 and histone cell cycle regulation defective homolog A (HIRA) histone chaperone. TAL1 directly interacts with HIRA, which is not only essential for promoter H3K4 hypermethylation by Setd1a, but is also critical for the transcriptional activation of target genes mediated by TAL1 and Setd1a in T cell acute lymphoblast leukemia (T-ALL) Jurkat cells, such as CDK6 and NKX3.1. Our data revealed a collaborative role by which transcription factor-directed recruitment of histone chaperone and histone modification enzyme can lead to chromatin structure alterations at specific promoters in leukemogenesis. Citation Format: Ying Li. Histone chaperone HIRA is required for Setd1a H3K4 methylation recruited by TAL1 oncoprotein in leukemogenesis [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 LB-084. doi:10.1158/1538-7445.AM2017-LB-084
Abstract LB-082: Targeted inactivation of STAT3 inhibits proliferation and invasion of breast cancer cells and enhances antitumor activity of doxorubicin through reversion of EMT
Authors: Yi Ding, Yu Jiang, Wenqing Li, Shurong Liu, Zhong Lu, Lihong Shi, Xuejian Wang, Jian Zhang, Lihua Wang
Journal: Cancer Research (2017)

Abstract Breast cancer is one of the most common malignant diseases in women. Epithelial-mesenchymal transition (EMT) has been documented to play an important role in proliferation, invasion and metastasis of tumor cells as well as drug resistance. Even though the signal transducer and activator of transcription 3 (STAT3) is not a master transcription factor of EMT, STAT3 is involved in the regulation of EMT-related gene expression. However, it remains unclear whether targeted inhibitors of STAT3 affect EMT-mediated proliferation, migration, invasion and drug resistance of tumor cells. In this paper, we investigated the effects of STAT3 and its interaction with Twist, a master transcription factor, in EMT program and subsequent changes in proliferation, migration and invasion of breast cancer cells by interfering STAT3 signaling pathway with different strategies such as STAT3 inactivation and STAT3 silencing. Furthermore, we explored the role of inhibiting STAT3 phosphorylation in the EMT regulation of the sensitivity of tumor cells response to doxorubicin. The results showed that the expression and activation of STAT3 correlated with cell phenotype and invasive ability of breast cancer cells. IL-6 induced phosphorylation of STAT3 can promote the EMT of breast cancer cells. WP1066 completely inhibited STAT3 autophosphorylation and IL-6-induced phosphorylation in breast cancer cells. WP1066 reversed EMT to MET through inhibiting the phosphorylation of STAT3 in breast cancer cells and significantly inhibited the proliferation and invasion in breast cancer cells. Silence STAT3 with siRNA also reversed EMT to MET in breast cancer cells. The expression of EMT transcription factor Twist1 was positively correlated with the activation of STAT3 but not with the expression of STAT3. WP1066 increased doxorubicin antitumor activity through inhibiting the STAT3 phosphorylation. These data provide a proof of concept that targeted inactivation of STAT3 can inhibit proliferation and invasion of breast cancer cells and reduce the resistance of Doxorubicin through reversion of EMT. Support by Natural Science Foundation of China (No.81472489) and Science and Technology Development Plan of Shandong (No.2014GSF118040) Citation Format: Yi Ding, Yu Jiang, Wenqing Li, Shurong Liu, Zhong Lu, Lihong Shi, Xuejian Wang, Jian Zhang, Lihua Wang. Targeted inactivation of STAT3 inhibits proliferation and invasion of breast cancer cells and enhances antitumor activity of doxorubicin through reversion of EMT [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 LB-082. doi:10.1158/1538-7445.AM2017-LB-082
MLL4 prepares the enhancer landscape for Foxp3 induction via chromatin looping
Authors: Katarzyna Placek, Gangqing Hu, Kairong Cui, Dunfang Zhang, Yi Ding, Ji-Eun Lee, Younghoon Jang, Chaochen Wang, Joanne Elizabeth Konkel, Jiuzhou Song, Chengyu Liu, Kai Ge, Wanjun Chen, Keji Zhao
Journal: Nature Immunology (2017)
Abstract 1394: Bioorthogonal Profiling of Protein Methylation (BPPM) identified MCM5 as a new substrate for SETD8 in DNA replication
Authors: Fabio Pittella Silva, Gil Blum, Chamara Senevirathne, Luo Minkui
Journal: Cancer Research (2017)

Abstract SETD8 is the only member of the SET domain containing methyltransferase family, which catalyzes mono-methylation of K20 on histone H4 (H4K20me1). Lysine residues of non-histone proteins such as p53 and proliferating cell nuclear antigen (PCNA) are also monomethylated, while lysine residues in Numb were found to be dimethylated. As a consequence, SETD8 methyltransferase activity is implicated in several fundamental cellular processes such as transcriptional regulation and heterochromatin formation as well as processes that ensures genomic stability including DNA replication and the DNA damage response. Although it has been suggested that SETD8 is involved in DNA replication as a positive regulator of origin licensing through H4K20 methyation and by supporting Okazaki fragment processing through PCNA methylation, to date, there is no evidence whether other key protein in the replication fork is directly modified by SETD8. To address this question, we used Bioorthogonal Profiling of Protein Methylation (BPPM) with engineered enzyme and synthetic SAM analogues to profile new substrates for SETD8. We genetically engineered SETD8 and identified mutants amenable to accommodate non-native SAM analogues containing a terminal alkyne moiety for click chemistry. The engineered SETD8 can transfer this distinct chemical moiety into target proteins for subsequent pulldown and identification of the modified substrates. Among the new substrates discovered, we identified MCM5, a subunit of the hexameric minichromosome maintenance (MCM) DNA helicase complex. MCM5 directly interacts with MCM2 and 3 to form the MCM2-7 hexamer which associates with the origins of DNA replication to form part of the pre-replicative complex (preRC), playing a key role during replication initiation and elongation. We found that SETD8 can mono-methylate MCM5 directly affecting its binding affinity to MCM2 and 3. In addition, MCM5 mutations at the methylated lysine further evidenced a stronger binding to its interacting partners contributing to the formation of the MCM hexamer. Taken together our results indicate that MCM5 methylation contributes to the assembly of the MCM complex suggesting an important role for SETD8 in replication initiation. Our findings may bring new perspectives on the biological importance of SETD8 during DNA replication. Citation Format: Fabio Pittella Silva, Gil Blum, Chamara Senevirathne, Luo Minkui. Bioorthogonal Profiling of Protein Methylation (BPPM) identified MCM5 as a new substrate for SETD8 in DNA replication [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 1394. doi:10.1158/1538-7445.AM2017-1394
Abstract 2688: Multiplex IHC detection of immune checkpoint receptors in the tumor microenvironment
Authors: Jennifer E. Ziello, Sarah R. Klein, Emily Alonzo, Herbert Haack
Journal: Cancer Research (2017)

Abstract As immune checkpoint blockade has been shown to partially reverse the exhausted T cell phenotype and consequently lead to a decrease in tumor burden, there is a need for an understanding of this T cell type. Using recently developed, highly validated antibodies, we have developed a fluorescent multiplex, TSA-based assay in order to examine the interaction of PD-L1 with PD-1-expressing exhausted T cells in various tumor types. Here, we construct a seven-color multiplex panel in order to simultaneously visualize cytokeratin (the tumor mask), DAPI (nuclear counterstain), CD8 (cytotoxic T cell marker), the exhausted T cell markers PD-1, Tim-3 and Lag-3, and the ligand for PD-1, PD-L1. This technique not only enabled the concurrent detection of these markers, but also provided high-resolution visualization of interactions between PD-1-expressing CD8+ T cells and PD-L1-expressing CD68+ macrophages in the tumor microenvironment. The seven-plex panel was applied to FFPE tumor microarrays (TMAs) consisting of breast, lung and ovarian tumor tissue and each core was subsequently analyzed for the distribution, co-localization, frequency and proximity of these targets in relation to one another. While we often visualized co-expression of Lag-3 and PD-1 on T cells, Tim-3 was frequently observed on PD-L1+ macrophages in several tumor types. This data provides valuable insight into the co-expression profiles of these markers in multiple tumor types and has implications for the use of combination therapies that aim to target both the innate and adaptive immune systems. Citation Format: Jennifer E. Ziello, Sarah R. Klein, Emily Alonzo, Herbert Haack. Multiplex IHC detection of immune checkpoint receptors in the tumor microenvironment [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 2688. doi:10.1158/1538-7445.AM2017-2688