tbuckley/cabot-search huggingface dataset:
PGC-1α Protects from Notch-Induced Kidney Fibrosis Development
Authors: Seung Hyeok Han, Mei-yan Wu, Bo Young Nam, Jung Tak Park, Tae-Hyun Yoo, Shin-Wook Kang, Jihwan Park, Frank Chinga, Szu-Yuan Li, Katalin Susztak
Journal: Journal of the American Society of Nephrology (2017)

Kidney fibrosis is the histologic manifestation of CKD. Sustained activation of developmental pathways, such as Notch, in tubule epithelial cells has been shown to have a key role in fibrosis development. The molecular mechanism of Notch-induced fibrosis, however, remains poorly understood. Here, we show that, that expression of peroxisomal proliferation g-coactivator (PGC-1α) and fatty acid oxidation-related genes are lower in mice expressing active Notch1 in tubular epithelial cells (Pax8-rtTA/ICN1) compared to littermate controls. Chromatin immunoprecipitation assays revealed that the Notch target gene Hes1 directly binds to the regulatory region of PGC-1α Compared with Pax8-rtTA/ICN1 transgenic animals, Pax8-rtTA/ICN1/Ppargc1a transgenic mice showed improvement of renal structural alterations (on histology) and molecular defect (expression of profibrotic genes). Overexpression of PGC-1α restored mitochondrial content and reversed the fatty acid oxidation defect induced by Notch overexpression in vitro in tubule cells. Furthermore, compared with Pax8-rtTA/ICN1 mice, Pax8-rtTA/ICN1/Ppargc1a mice exhibited improvement in renal fatty acid oxidation gene expression and apoptosis. Our results show that metabolic dysregulation has a key role in kidney fibrosis induced by sustained activation of the Notch developmental pathway and can be ameliorated by PGC-1α.
Abstract 5927: Eribulin modulates tumor microenvironment through vascular remodeling for antitumor effect in multiple mouse xenograft models
Authors: Ken Ito, Shusei Hamamichi, Takanori Abe, Tsuyoshi Akagi, Hiroshi Shirota, Satoshi Kawano, Makoto Asano, Osamu Asano, Akira Yokoi, Junji Matsui, Izumi O. Umeda, Hirofumi Fujii
Journal: Cancer Research (2017)

Abstract Eribulin mesilate (Eribulin), a first-in-class halichondrin B-based microtubule dynamics inhibitor, has been reported to remodel tumor vasculature (i.e., improvement of tumor vessels and perfusion) in human breast cancer xenograft models; however, the role of this vascular remodeling in anti-tumor effects is not fully understood. Here, we investigated the effects of eribulin-induced vascular remodeling on anti-tumor activities in multiple human cancer xenograft models. Microvessel densities (MVDs) were evaluated by immunohistochemistry (CD31 staining), and anti-tumor effects were examined in 10 human cancer xenograft models treated with eribulin. Eribulin treatment significantly increased MVDs compared to the corresponding control groups in 7 out of 10 models with a correlation between enhanced MVD levels and anti-tumor effects (R2=0.55). Because of observed increases in MVDs, we next utilized 111In-labeled PEGylated liposomes to examine if eribulin treatment would result in increased tumoral accumulation levels of such liposomes, and indeed, we found that eribulin, unlike vinorelbine another tubulin inhibitor, enhanced them. Since eribulin treatment increased accumulation of 111In-labeled PEGylated liposomes, we postulated that this treatment might enhance anti-tumor effect of Doxil (a liposomal anti-cancer agent). As expected, eribulin enhanced anti-tumor activity of Doxil in the PE-H1650 xenograft model. Then, we evaluated whether eribulin facilitated the recruitment of immune cells into the tumor. Infiltrating CD11b-positive immune cells were significantly increased in the multiple eribulin-treated xenografted tumors, and natural killer (NK) cell depletion reduced anti-tumor effects of eribulin. Collectively, these findings suggested a contribution of the immune cells for anti-tumor activities of eribulin. Taken together, our results obtained from multiple human cancer xenograft models suggested that vascular remodeling induced by eribulin therapy would act as a microenvironment modulator, and contributed to show anti-tumor effects of eribulin. Citation Format: Ken Ito, Shusei Hamamichi, Takanori Abe, Tsuyoshi Akagi, Hiroshi Shirota, Satoshi Kawano, Makoto Asano, Osamu Asano, Akira Yokoi, Junji Matsui, Izumi O. Umeda, Hirofumi Fujii. Eribulin modulates tumor microenvironment through vascular remodeling for antitumor effect in multiple mouse xenograft models [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 5927. doi:10.1158/1538-7445.AM2017-5927
Abstract SY33-02: Fueling T cells and antitumor immunity
Authors: Jeffrey C. Rathmell
Journal: Cancer Research (2017)

Abstract Lymphocyte activation leads to rapid proliferation and differentiation, and we have shown that T-cell subsets require distinct metabolic programs. The effector CD4 T-cell fates (Th1, Th2, Th17) activate a highly glycolytic program. Regulatory CD4 T cells (Treg), in contrast, utilize a more oxidative metabolism and utilize lipids as a major fuel. These metabolic distinctions may allow new understanding of T-cell function in tumors and approaches to manipulate immunity. We have now examined the metabolism of Treg in detail and found that FoxP3 itself can promote oxidative metabolism characteristic of Treg and that this is critical to maximize Treg suppressive capacity. Treg can be glycolytic and proliferative in vivo. We found, however, that glucose uptake and glycolysis impaired Treg stability. Thus, Treg regulate glycolytic and oxidative metabolism to balance proliferation and suppressive function. Conversely, the requirement of effector T cells for glucose uptake and glycolysis poses a barrier to inflammatory function in tumors. Understanding mechanisms that regulate T-cell metabolism may provide new tools to modulate immunity through the balance of T-cell effector and regulatory populations. Citation Format: Jeffrey C. Rathmell. Fueling T cells and antitumor immunity [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 SY33-02. doi:10.1158/1538-7445.AM2017-SY33-02
Abstract 2748: Liquid biopsy using extracellular vesicular DNA for EGFR mutation testing in the patients with NSCLC
Authors: Jae Young Hur, Hee Jung Kim, Chang-Min Choi, Jae Cheol Lee, Kye Young Lee
Journal: Cancer Research (2017)

Abstract Background Tumor-derived extracelluar vesicles (EV) have been proved to carry double-stranded DNA including oncogenic mutants and expected to be a novel biomarker in cancer detection. Liquid biopsy using cell-free (cf) DNA for EGFR mutation testing is being actively investigated. In this study, we investigated whether liquid biopsy using EV DNA is superior to cf DNA for EGFR mutation testing in the patients with NSCLC. Methods EV was isolated using ultracentrifugation and confirmed by transmission electron microscopy and zetasizer in 20 plasma samples (all tissue-proven EGFR mutated) and 32 bronchoalveolar lavage fluid (BALF) samples (23 EGFR-mutated including 14 TKI-naïve and 9 TKI resistant, and 9 wild-type). EV and cf DNA was separately extracted from each samples and EGFR mutation testing was performed by peptide nucleic acid (PNA)-clamping method. Results In 20 plasma samples, the concordance rate of EV DNA for tissue EGFR genotyping was 55% (11/20), while 30% (6/20) in cf DNA. In 32 BALF samples, however, the sensitivity, specificity and concordance rate of EV DNA for activating EGFR mutations was 100% (23/23), 100% (9/9), and 100% (32/32), while cf DNA showed 73.9% (17/23), 100% (9/9) and 81.3% (26/32), respectively. The kappa value (p-value) of EV DNA was 1.0 (&amp;lt;0.001), while it was 0.714 (p,0.001) in the case of cf DNA. As for 9 re-biopsy cases for T790M detection in which only 3 patients (33%) was proved as positive T790M, BALF EV DNA identified 2 more T790M patients (total 5 among 9 patients, 56%) without non-matching with tissue typing, while BALF cf DNA found 1 more T790M positive patient with missing 1 tissue proven case (total 3 among 9 patients, 33%) Conclusions Liquid biopsy using EV DNA is significantly superior to cf DNA in both plasma and BALF. A little low sensitivity in plasma EV DNA is supposed to be improved with much more sensitive method such as ddPCR or BEAMing. Liquid biopsy using BALF EV DNA showed almost 100% matching with tissue EGFR typing and seems to be highly promising for T790M detection. A large number of clinical trials should be prompted. Citation Format: Jae Young Hur, Hee Jung Kim, Chang-Min Choi, Jae Cheol Lee, Kye Young Lee. Liquid biopsy using extracellular vesicular DNA for EGFR mutation testing in the patients with NSCLC [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 2748. doi:10.1158/1538-7445.AM2017-2748
Abstract 57: Generation and characterization of novel anti-glycan monoclonal antibody against acute myeloid leukemia
Authors: Chong Kok Teo, Wee Joo Chng, Andre Boon Hwa Choo
Journal: Cancer Research (2017)

Abstract Hematological malignancies encompass a wide spectrum of cancers from hematopoietic and lymphoid tissues. Under this grouping, the various forms of leukemia, lymphoma and myeloma have been classified into more than 60 distinct disease types, each having particular clinical features and disease outcomes. Among these diseases, curative treatments with high long-term survival rate have been developed for some, e.g. Chronic Myeloid Leukemia, while such effective regimens are still unavailable for many others, e.g. Multiple Myeloma and Acute Myeloid Leukemia. In this study, a panel of antibodies was raised against SLAMF7, a cell surface marker that was associated to Multiple Myeloma. Among the antibodies, TAG-HC2 was surprisingly found to have preferential binding to SLAMF7 expressed on Acute Myeloid Leukemia (AML) cell lines instead. Characterization of TAG-HC2 revealed that the binding of TAG-HC2 to SLAMF7 requires the N-glycosylation of the antigen. Functionally, TAG-HC2 does not have non-specific binding to normal cell lines when tested via flow cytometry and immunohistochemistry. TAG-HC2, when complexed with saporin-conjugated secondary mAb, was able to internalize into and kill AML cell lines. These results suggest that TAG-HC2 has the potential to be developed into an Antibody Drug Conjugate against AML. Citation Format: Chong Kok Teo, Wee Joo Chng, Andre Boon Hwa Choo. Generation and characterization of novel anti-glycan monoclonal antibody against acute myeloid 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 57. doi:10.1158/1538-7445.AM2017-57
Abstract 4615: Development of an antibody-drug conjugate with broad anticancer activity
Authors: Siang-Yo Lin, Zoltan Szekely, Chen-Yong Lin, Joseph R. Bertino, Gulam Mohmad Rather
Journal: Cancer Research (2017)

Abstract Treatment for patients with advanced solid tumors that include triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and castrate resistant prostate cancer (CRPC), as well as Mantle Cell Lymphoma (MCL), while increasing survival is not curative. We have identified a membrane bound protease, “activated” matriptase, as an attractive target antigen for highly selective antibody delivery of cytotoxins as activated matriptase expression is restricted to epithelial tumors and some B-cell lymphomas. We generated a novel ADC by linking M69, a mouse antibody specific to activated matriptase, to monomethyl auristatin E (MMAE) via a PEGylated, releasable di-peptide linker as a proof-of-principle prototype. Both in cell lines and in human xenograft models of TNBC, NSCLC, CRPC and MCL, the conjugate was found to exhibit potent anticancer activity against all of these tumor types without toxicity. Encouraged by these results, we are also exploring the use of this ADC against gastric and pancreatic cancer, and in combination with chemotherapy and immunotherapy. As this is a mouse antibody, we are also generating a chimeric antibody for toxicity studies in primates. Citation Format: Siang-Yo Lin, Zoltan Szekely, Chen-Yong Lin, Joseph R. Bertino, Gulam Mohmad Rather. Development of an antibody-drug conjugate with broad anticancer activity [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 4615. doi:10.1158/1538-7445.AM2017-4615
Identification of a serum microRNA expression signature for detection of lung cancer, involving miR-23b and miR-423-3p.
Authors: Bo Zhu, Wenlei Zhuo
Journal: Journal of Clinical Oncology (2014)

e22134 Background: MircoRNAs (miRNAs) are small non-coding RNA molecules that regulate the gene expression and play important roles in the pathogenesis of lung cancer. Serum miRNAs, with their noticeable stability and unique expression pattern in patients with various diseases, are powerful novel non-invasive biomarkers for cancer detection. The objective of this study was to identify specific serum miRNAs as potential diagnostic markers for detection of lung cancer. Methods: The expression of serum miRNA from treatment-naive lung cancer patients (LC) Abenign pulmonary disease patients (PD) and healthy controls (HC) cases were examined by RT-qPCR. The study was divided into two phases: (I) Biomarker-screening phase: Serum samples were taken from 10 LC patients and 10 HC cases. (II) Biomarker-validation phase: Serum samples were taken from 40 LC patients, 40 PD patients and 40 HC cases. Logistic regression and receiver operating characteristics curve analyses were used to identify differentially expressed miRNA signatures that could distinguish LC from PD and HC. Results: Ten miRNAs (let-7f, miR-126-3p, miR-151-5p, miR-199a-3p, miR-221, miR-26a, miR-27b, miR-148b, miR-23b, and miR-423-3p) in LC were significantly increased compared to those in PD and HC in biomarker-validation phase (P < 0.05). Target prediction analysis showed that predicted targets of these miRNAs could be involved in phosphorylation processes and pathways involving in the formation and development of cancer. Furthermore, we have developed a panel including 2 miRNAs (miR-23b and miR-423-3p) that can be demonstrated as a signature for LC detection, yielding a receiver operating characteristic curve area of 0.883. Conclusions: Our findings define a distinct serum miRNA expression profile in lung cancer cases. The 2-miRNA signature (miR-23b and miR-423-3p) may be considered as a novel, non-invasive biomarker for lung cancer diagnosis.
Abstract 2254: Reactive oxygen species modulator 1 (Romo1) predicts unfavorable prognosis in colorectal cancer patients
Authors: Min Jee Jo, Hong Jun Kim, Suk-Young Lee, Dae-Hee Lee, Sang Cheul Oh
Journal: Cancer Research (2017)

Abstract Reactive oxygen species modulator 1 (Romo1) is a novel protein that has been reported to be crucial for cancer cell proliferation and invasion. However, its clinical implications in colorectal cancer (CRC) patients are not well-known. For the first time, we investigated the association between Romo1 and the clinical outcomes of CRC patients. We examined Romo1 expression in resected tumor tissues immunohistochemically and assessed it with histological scores. We conducted survival analyses for patients who had curative resection (n=190) in accordance with clinical parameters including level of Romo1 expression, and we examined the association between Romo1 expression and cell invasion using Matrigel invasion assay in CRC cell lines. We observed significantly longer mean disease-free survival (DFS) in the low Romo1 group compared with the high Romo1 group (161 vs 127.6 months, p=0.035), and the median overall survival (OS) of the low Romo1 group was significantly longer than that of the high Romo1 group (196.9 vs 171.3 months, p=0.036). Cell invasiveness decreased in the Romo1 knockdown CRC cells in contrast to the controlled cells. Romo1 overexpression in tumor tissue was associated with a high lymph node ratio (LNR) between the metastatic and examined lymph nodes (p=0.025). Romo1 overexpression in tumor tissue was significantly associated with survival in curatively resected CRC patients, suggesting Romo1 expression as a potential adverse prognostic marker. Increased Romo1 expression was found to be associated with high LNR. Cancer invasiveness appeared to be a key reason for the poor survival related to highly expressed Romo1. Citation Format: Min Jee Jo, Hong Jun Kim, Suk-Young Lee, Dae-Hee Lee, Sang Cheul Oh. Reactive oxygen species modulator 1 (Romo1) predicts unfavorable prognosis in colorectal cancer 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 2254. doi:10.1158/1538-7445.AM2017-2254
Abstract LB-206: Indicators of responsiveness to immune checkpoint inhibitors
Authors: Bradley D. Shields, Fade Mahmoud, Erin M. Taylor, Stephanie D. Byrum, Deepanwita Sengupta, Brian Koss, Giulia Baldini, Seth Ransom, Kyle Cline, Samuel Mackintosh, Ricky Edmondson, Sara C. Shalin, Alan J. Tackett
Journal: Cancer Research (2017)

Abstract Modulation of the immune system can produce anti-tumor responses in various cancer types, including melanoma. Recently, immune checkpoint inhibitors, in single agent and combination regimens, have produced durable and long-lasting clinical responses in a subset of metastatic melanoma patients. These monoclonal antibodies, developed against CTLA-4 and PD-1, block immune-inhibitory receptors on activated T-cells, amplifying the immune response. However, even when using anti-CTLA-4 and anti-PD-1 in combination, approximately half of patients exhibit innate resistance and suffer from disease progression. Currently, it is impossible to predict therapeutic response. Here, we report the first proteomic and histone epigenetic analysis of patient metastatic melanoma tumors taken prior to immune checkpoint inhibitor therapy, which revealed specific biological signatures that can stratify metastatic melanoma patients as responders or non-responders. Furthermore, our findings provide the first evidence of epigenetically-driven epithelial-mesenchymal transition, a known mechanism of immune-escape, in non-responding melanoma tumors. We identified elevated histone H3 lysine (27) trimethylation (H3K27me3), decreased E-cadherin, and other protein features indicating a more mesenchymal phenotype in non-responding tumors. Furthermore, we show E-cadherin is transcriptionally regulated by the EZH2-catalyzed H3K27me3 epigenetic mark in non-responding tumors. The repressive epigenetic mark H3K27me3, has known roles in melanoma pathogenesis and progression, but not in response to immunotherapies. Here, we provide the first report of an epigenetic program directly linking elevated levels of H3K27me3 to non-responding tumors. Our results have broad implications for immune checkpoint inhibitor therapy in a variety of carcinomas as patient specific responsiveness can be predicted through readily assayable proteins and histone epigenetic marks, and specific pathways activated in non-responders have been identified for therapeutic development to enhance responsiveness. Citation Format: Bradley D. Shields, Fade Mahmoud, Erin M. Taylor, Stephanie D. Byrum, Deepanwita Sengupta, Brian Koss, Giulia Baldini, Seth Ransom, Kyle Cline, Samuel Mackintosh, Ricky Edmondson, Sara C. Shalin, Alan J. Tackett. Indicators of responsiveness to immune checkpoint inhibitors [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-206. doi:10.1158/1538-7445.AM2017-LB-206
Abstract 4849: ELMO1 promotes metastasis in colorectal cancer cells via activation of MAPK/ERK signaling pathway
Authors: Xiao-bin Zheng, Chi Zhou, Hai-chun Cheng, Tuo Hu, Hua-shan Liu, Xuan-hui Liu, Xian-rui Wu, Feng-wei Wang, Yu-feng Chen, Jian-ping Wang, Xiao-sheng He, Ping Lan
Journal: Cancer Research (2017)

Abstract Background and Aim: Engulfment and cell motility 1 (ELMO1) has been linked to the invasive phenotype of various types of cancer cells such as glioma cells, rhabdomyosarcoma cells, ovarian cancer cells and so on. However, the biological functions of ELMO1 in colorectal cancer (CRC) cells remains unclear. The aim of this study is to evaluate the role of ELMO1 in the metastasis in CRC. Methods: The expression level of ELMO1 was detected using quantitative RT-PCR and western blot in 9 CRC cell lines and 1 human colon epithelial cell line NCM460. ELMO1 was overexpressed via lentiviral vector system and silenced using specific small interference RNA (si-ELMO1) in HCT116 and SW620. Then wound-healing, migration assay and invasion assay were carried out to investigate the function of ELMO1 in CRC cells. Western blot was performed to detect the change of signaling molecule extracellular signal-regulated kinase 1/2 (ERK1/2) following the down-regulated or up-regulated expression of ELMO1. Results: ELMO1 expression was inhibited by si-ELMO1 and was overexpressed by ELMO1-cDNA in HCT116 and SW620. Ectopic expression of ELMO1 in HCT116 and SW620 was shown to promote migration and invasion, while inhibited ELMO1 expression suppressed the capacity of cell migration and invasion. Furthermore, ELMO1 induced migration and invasion in CRC cells was found to be associated with the activation of MAPK/ERK pathway. Conclusions: High expression of ELMO1 was found to be associated with the metastasis via the activation of MAPK/ERK signaling pathway. This finding provides a molecular basis for the role of ELMO1 in the progression of CRC, which may suggest a novel target for the treatment of CRC. Citation Format: Xiao-bin Zheng, Chi Zhou, Hai-chun Cheng, Tuo Hu, Hua-shan Liu, Xuan-hui Liu, Xian-rui Wu, Feng-wei Wang, Yu-feng Chen, Jian-ping Wang, Xiao-sheng He, Ping Lan. ELMO1 promotes metastasis in colorectal cancer cells via activation of MAPK/ERK signaling pathway [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 4849. doi:10.1158/1538-7445.AM2017-4849
Anti‐MUC1 aptamer: A potential opportunity for cancer treatment
Authors: Maryam Sadat Nabavinia, Aida Gholoobi, Fahimeh Charbgoo, Mahboobeh Nabavinia, Mohammad Ramezani, Khalil Abnous
Journal: Medicinal Research Reviews (2017)

Abstract Mucin 1 (MUC1) is a protein usually found on the apical surface of most normal secretory epithelial cells. However, in most adenocarcinomas, MUC1 is overexpressed, so that it not only appears over the entire cell surface, but is also shed as MUC1 fragments into the blood stream. These phenomena pinpoint MUC1 as a potential target for the diagnosis and treatment of cancer; consequently, interest has increased in MUC1 as a molecular target for overcoming cancer therapy challenges. MUC1 currently ranks second among 75 antigen candidates for cancer vaccines, and different antibodies or aptamers against MUC1 protein are proving useful for tracing cancer cells in the emerging field of targeted delivery. The unique properties of MUC1 aptamers as novel targeting agents, and the revolutionary role that MUC1 now plays in cancer therapy, are the focus of this review. Recent advancements in MUC1‐targeted cancer therapy are also assessed.