tbuckley/cabot-search huggingface dataset:
Abstract 1831: Mistletoe lectin induces apoptosis in MYC-driven cancers through post-translational downregulation of c-MYC protein
Authors: Gabrielle Kennelley, Eric Yuan, Mohammad Shatat, Betsy Gauthier, Peiying Yang, Analisa Difeo, Richard Lee
Journal: Cancer Research (2020)

Abstract c-Myc is part of the Myc family proteins associated with cellular proliferation, differentiation, and apoptosis. Dysregulated c-Myc expression is associated with tumorigenesis, and cancers with c-Myc overexpression are often associated with poor prognosis, partly due to difficulty in targeting c-Myc. Mistletoe lectin (ML), derived from the European mistletoe plant, has shown variable efficacy in cancer patients. One case series following 12 patients with advanced hepatocellular carcinoma (HCC) showed 2 patients with &amp;gt30% reduction in the tumor marker alpha-fetoprotein and 1 patient who had stable disease for 9 months. These cases indicate promising results. ML consists of a heteroprotein complex of an A- and B-chain connected by a disulfide bond. The A-chain was previously described to inhibit translation by 28s rRNA cleavage, while the B-chain binds cell surface glycoproteins to trigger internalization of the lectin. We found that purified mistletoe extract, consisting primarily of ML, downregulates c-Myc protein and induces apoptosis in in vitro and in vivo models of human-derived cancer, and that the efficacy of ML treatment is strongly correlated with MYC gene expression and c-Myc protein abundance in in vitro human models of HCC, ovarian cancer, small cell lung cancer, and lymphoma. MTS assay data demonstrated that exogenous MYC expression can sensitize low-MYC cell lines to ML treatment, suggesting that anti-cancer effects of ML are dependent on its ability to downregulate c-Myc. While ML may be able to downregulate many proteins via general translational inhibition, we found that of 296 proteins profiled by RPPA, c-Myc was one of 11 proteins decreased by ML with at least a 2-fold change (p&amp;lt0.01). We also found that ML promotes c-Myc ubiquitylation, suggesting that ML regulates c-Myc protein stability, rather than synthesis. In summary, here we describe a novel mechanism of action for ML in downregulating c-Myc and promoting apoptotic cell death in various models of MYC-driven cancer, and provide evidence for MYC gene expression as a predictive marker for response. This research supports the development of ML-based therapies that may provide a c-Myc-targeting treatment in multiple cancer types. Citation Format: Gabrielle Kennelley, Eric Yuan, Mohammad Shatat, Betsy Gauthier, Peiying Yang, Analisa Difeo, Richard Lee. Mistletoe lectin induces apoptosis in MYC-driven cancers through post-translational downregulation of c-MYC protein [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1831.
Abstract 2081: Intestinal estrogen receptor beta suppresses colon inflammation and tumorigenesis in both sexes
Authors: Linnea Hases, Rajitha Indukuri, Madeleine Birgersson, Trang Nguyen-Vu, Rodrigo Lozano, Ashish Saxena, Johan Hartman, Jonna Frasor, Jan-Åke Gustafsson, Pekka Katajisto, Amena Archer, Cecilia Williams
Journal: Cancer Research (2020)

Abstract Estrogen has been shown to protect women against colorectal cancer (CRC). In this study, using tissue-specific knockout mice, we characterize the role for intestinal estrogen receptor beta (ERβ) and, for the first time, demonstrate a direct preventive role against colitis-induced colon tumors in both sexes. By inducing colitis and CRC using azoxymethane and dextran sodium sulfate in intestine-specific ERβ knockout mice, we observe an increase in colon ulceration in addition to an enhanced development of neoplasms, with increased number of tumors in males and increased tumor size in females. We identify a local increase in TNFα expression and deregulation of NFκB targets. We note that males exhibit especially strong effects following intestinal ERβ knockout. The protection by intestinal ERβ against TNFα-induced damage is corroborated using ex vivo organoid culture, where we observe that activation of ERβ protects against TNFα-induced epithelial cell damage. Further, we characterize an underlying mechanism of action, using CRC cell lines with re-introduced ERβ, where ERβ binds to cis-regulatory chromatin areas of key NFκB regulators BCL3, BIRC3 and ATF3, and thereby modulates TNFα-induced signaling. With these results we define a clear role for intestinal ERβ and demonstrate an underlying mechanism, strongly supporting the notion that selective activation of intestinal ERβ has potential to prevent CRC in both sexes. Citation Format: Linnea Hases, Rajitha Indukuri, Madeleine Birgersson, Trang Nguyen-Vu, Rodrigo Lozano, Ashish Saxena, Johan Hartman, Jonna Frasor, Jan-Åke Gustafsson, Pekka Katajisto, Amena Archer, Cecilia Williams. Intestinal estrogen receptor beta suppresses colon inflammation and tumorigenesis in both sexes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2081.
Abstract 4979: Prevalence of proliferating CD8+cells in normal lymphatic tissues, inflammation and cancer
Authors: Maximilian Lennartz, Raed Abu-Hashem, Niclas Christian Blessin, Tim Mandelkow, Elena Bady, Ronald Simon, Claudia Hube-Magg, Guido Sauter, Christoph Fraune, Katharina Möller, Till S. Clauditz, Andreas M. Luebke, Franziska Büscheck
Journal: Cancer Research (2020)

Abstract Expansion of CD8+ cytotoxic T lymphocytes is a prerequisite for anti-cancer immune activity. In the era of immune checkpoint therapy, profound knowledge of the dynamics of CD8+ has regained considerable interest. However, systematically acquired data on CD8+ proliferation in large sets of normal and diseased tissues are sparse. Here, we applied multiplex fluorescence immunohistochemistry to conventional large sections and tissue microarrays in order to quantitate Ki67+CD8+ cells in &amp;gt;20 different compartments of normal lymphoid tissues, 7 types of inflammatory diseases and 785 cancers. In most normal lymphoid tissues (tonsil, lymph node, thymus, Peyer's patches, spleen, colon, appendix) the percentage of Ki67+CD8+ cells typically did not exceed 3%. The percentage of Ki67+CD8+ cells was markedly higher (45%) in the immune-active cortex of the thymus, however. In inflammatory conditions (including Hashimoto thyroiditis, Lichen sclerosus of the penis, sarcoidosis, sialadenitis, IgG4 pancreatitis, Crohn's disease and eczema), the percentage of Ki67+CD8+ cells was much more variable and often sharply higher than in normal tissues. It ranged from 0.5% in one patient with sialadenitis to 19% in the intraepithelial compartment of Crohn's disease. In 765 colorectal cancers, the fraction of Ki67 positive CD8+ cytotoxic T cells ranged from 0 to 100% (mean: 20.6%). A high fraction of Ki67+CD8+ cells was significantly associated with microsatellite instability (p&amp;lt;0.0001), low pT stage (p&amp;lt;0.0001) and absence of nodal metastases (p=0.0005). In summary, our data show a variable increase of the fraction of proliferating CD8+ T cells in cancers and in inflammatory diseases as compared to healthy secondary lymphoid organs. The striking link with microsatellite instability and unfavorable tumor features suggest a potential clinical utility of assessing Ki67+CD8+ in colorectal cancer. Citation Format: Maximilian Lennartz, Raed Abu-Hashem, Niclas Christian Blessin, Tim Mandelkow, Elena Bady, Ronald Simon, Claudia Hube-Magg, Guido Sauter, Christoph Fraune, Katharina Möller, Till S. Clauditz, Andreas M. Luebke, Franziska Büscheck. Prevalence of proliferating CD8+cells in normal lymphatic tissues, inflammation and cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4979.
Abstract 1231: Targeting JNK1/2 induces a potent cytostatic response in estrogen receptor expressing breast cancer cells, with induction of autophagy and senescence as measurable outcomes
Authors: Kyler Herrington, Carol Joseph, Samar Abdulmoneim, Allison Lewis, Jingwen Cai, Hannah Youngblood, Yutao Liu, Patricia Schoenlein
Journal: Cancer Research (2020)

Abstract The c-Jun N-terminal kinases, JNK1/2 are members of the mitogen activated protein kinase (MAPK) family that can mediate inflammatory responses, cell differentiation, cell proliferation, and/or cell death. In breast cancer, JNK signaling has been associated with increased proliferation, angiogenesis, and tumor metastasis. Also, inhibition of JNK has been shown to promote tumor cytostasis, but this inhibition also attenuates the cytotoxic effects of certain chemotherapeutics, calling into question the therapeutic potential of JNK inhibitors. In this study, we hypothesized that JNK1/2 inhibition induced autophagy, as a mechanism of protection against chemotherapy- and endocrine-induced apoptosis. Autophagy is a normal physiologic process required for the elimination of damaged mitochondria and misfolded proteins that can be induced in cancer cells under certain stresses such as hypoxia and drug insult to provide protection from death. To characterize the role of JNK1/2 in autophagy, we utilized two ERα expressing human breast cancer cell lines, T47-D and MCF-7. Autophagy flux experiments were performed in which the steady state levels of the autophagy protein LC3 II were analyzed in control cells versus cells undergoing JNK1/2 inhibition with the non-reversible JNK-IN8 inhibitor. JNK-IN8 was used as a single agent or in combination with estradiol and/or antiestrogen treatment. These studies reproducibly identified JNK1/2 inhibition as a mechanism of autophagy activation. The induction of autophagy correlated with sustained inhibition of proliferation as determined by cell counts, MTT, and clonogenic assays, and induction of senescence (in T47-D cells) as determined by the expression of β-galactosidase. In contrast, induction of apoptosis was not a major outcome of JNK1/2 inhibition. These pre-clinical studies provide strong evidence that JNK1/2 is an attractive molecular target to improve the treatment of endocrine responsive breast cancer, but they also emphasize that cells are surviving by autophagy and/or senescence. Because cell survival by autophagy and/or senescence could ultimately lead to breast cancer relapse, ongoing studies are addressing approaches to effectively kill these surviving cell populations. Citation Format: Kyler Herrington, Carol Joseph, Samar Abdulmoneim, Allison Lewis, Jingwen Cai, Hannah Youngblood, Yutao Liu, Patricia Schoenlein. Targeting JNK1/2 induces a potent cytostatic response in estrogen receptor expressing breast cancer cells, with induction of autophagy and senescence as measurable outcomes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1231.
Abstract 3533: Germline <i>POLE</i> and <i>POLD1</i> proofreading domain mutations in endometrial carcinoma from Middle Eastern region
Authors: Abdul K. Siraj, Sandeep K. Parvathareddy, Rong Bu, Kaleem Iqbal, Sarah Siraj, Tariq Masoodi, Laila Ghazwani, Yan Kong, Maria A. Sabido, Wafaa Albalawy, Ingrid F. Victoria, Mary J. Galvez, Khawla S. Al-Kuraya
Journal: Cancer Research (2020)

Abstract Endometrial carcinoma (EC) accounts for 5.8% of all cancers in Saudi females. Although most ECs are sporadic, 2%-5% tend to be familial, being associated with Lynch syndrome and Cowden syndrome. In this study, we attempted to uncover the frequency, spectrum and phenotype of germline mutations in the proofreading domain of POLE and POLD1 genes in a large cohort of ECs from Middle Eastern region. We performed Capture sequencing and Sanger sequencing to screen for proofreading domains of POLE and POLD1 genes in 432 EC cases, followed by evaluation of protein expression using immunohistochemistry. Variant interpretation was performed using PolyPhen-2, MutationAssessor, SIFT, CADD and Mutation Taster. In our cohort, four mutations (0.93%) were identified in 432 EC cases, two each in POLE and POLD1 proofreading domains. Furthermore, low expression of POLE and POLD1 was noted in 41.1% (170/1414) and 59.9% (251/419) of cases, respectively. Both the cases harboring POLE mutation showed high nuclear expression of POLE protein, whereas, of the two POLD1 mutant cases, one case showed high expression and another case showed low expression of POLD1 protein. Our study shows that germline mutations in POLE and POLD1 proofreading region are a rare cause of EC in Middle Eastern population. However, it is still feasible to screen multiple cancer related genes in EC patients from Middle Eastern region using multigene panels including POLE and POLD1. Keywords: POLE; POLD1; Endometrial carcinoma; Proof-reading domain mutations; Germline. Citation Format: Abdul K. Siraj, Sandeep K. Parvathareddy, Rong Bu, Kaleem Iqbal, Sarah Siraj, Tariq Masoodi, Laila Ghazwani, Yan Kong, Maria A. Sabido, Wafaa Albalawy, Ingrid F. Victoria, Mary J. Galvez, Khawla S. Al-Kuraya. Germline POLE and POLD1 proofreading domain mutations in endometrial carcinoma from Middle Eastern region [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3533.
Abstract 1956: In vitro and in vivo characterization of novel MAT2A allosteric inhibitors
Authors: Zhonghua Pei, Muzaffar Alam, Neil Bhola, Leah Cleary, Jake Drummond, Marcus Fisher, Melissa Fleury, Candy Garcia, Atieh Givmanesh, Xin Linghu, Ethan McSpadden, Zineb Mounir, Claire Neilan, Zach Newby, Senthil Perumal, Richard Steel, James Sutton, Kedar Vaidya, Marie-Claire Wagle, Jianhong Wang, Bing Yao, Mark Lackner, Michael P. Dillon
Journal: Cancer Research (2020)

Abstract Background: MAT2A (Methionine adenosyltransferase 2A) catalyzes the formation of S-adenosylmethionine (SAM) from methionine and ATP. PRMT5, a highly conserved protein arginine methyltransferase that is required for cell proliferation, uses SAM as its methyl donor. PRMT5 activity is inhibited by increased MTA levels in methylthioadenosine phosphorylase (MTAP)-deleted tumor cells. MTAP-deleted tumor cells are thus more vulnerable to MAT2A inhibition compared to MTAP-WT cells. This synthetic lethality between MTAP and MAT2A suggests that MAT2A inhibitors may be useful as anti-tumor agents in the MTAP-deleted cancers, which occurs in ~ 15% of all cancers. Results: We have designed, synthesized and evaluated a novel series of small-molecule MAT2A inhibitors that are very potent in biochemical assays. Co-crystal structures of inhibitor-MAT2A complexes were solved and shed light on binding mode and key interactions. Biochemical mechanistic studies suggested that these compounds are allosteric inhibitors of MAT2A and are non-competitive inhibitors of MAT2A with respect to both ATP and methionine. These compounds displayed potent cellular anti-proliferation activity as well as cellular SAM modulation along with desired DMPK properties. Optimized compounds, upon oral dosing, demonstrated significant PD marker modulation and tumor growth inhibition in HCT116 MTAP-null and several endogenous MTAP-null xenograft mouse models. These agents demonstrated an acceptable safety profile in 7-day oral repeat dose tolerability studies in the rat. Citation Format: Zhonghua Pei, Muzaffar Alam, Neil Bhola, Leah Cleary, Jake Drummond, Marcus Fisher, Melissa Fleury, Candy Garcia, Atieh Givmanesh, Xin Linghu, Ethan McSpadden, Zineb Mounir, Claire Neilan, Zach Newby, Senthil Perumal, Richard Steel, James Sutton, Kedar Vaidya, Marie-Claire Wagle, Jianhong Wang, Bing Yao, Mark Lackner, Michael P. Dillon. In vitro and in vivo characterization of novel MAT2A allosteric inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1956.
Abstract LB-210: Chemotherapy promotes metastasis through extracellular vesicle secretion
Authors: Carson A. Wills, Jeffrey Sundstrom, Hong-Gang Wang
Journal: Cancer Research (2020)

Abstract Neoadjuvant chemotherapy treatment is the gold standard for children and adults with intermediate- to high-risk tumors. However, a subset of patients develop distant metastases following treatment, and evidence suggests that chemotherapy itself may promote metastasis in some patients. Indeed, utilizing xenograft mouse model of human triple-negative breast cancer, we confirm that treatment with the chemotherapeutic agent Doxorubicin decreases primary tumor growth while promoting pulmonary metastasis. The purpose of this research is to understand how chemotherapy treatment regulates tumor-derived exosomes, extracellular vesicles that are secreted by all cells and that function in cellular communication through the horizontal transfer of biologically-active molecules. Specifically, our goal is to determine how exosomes derived from chemotherapy-treated tumor cells, or ‘chemoexosomes,' regulate tumor metastasis in order to develop more effective chemotherapeutic options for cancer patients. Utilizing models of both breast cancer and pediatric neuroblastoma, we demonstrate that sublethal doses of DNA-damaging chemotherapeutic agents significantly enhance exosome secretion compared to vehicle control. Xenografted mice treated with exosomes derived from chemotherapy-treated cells demonstrate a significant acceleration in metastasis with no increase in primary breast tumor growth compared to mice treated with exosomes derived from control-treated cells or saline. Although chemoexosomes do not enhance tumor cell migration or invasion in vitro, they demonstrate tumor type-specific preferential organotropic localization to the most common sites of tumor metastasis in vivo. Mice treated with chemoexosomes prior to tail-vein injection of either neuroblastoma or breast tumor cells demonstrate a significant increase in metastatic tumor burden compared to mice pre-treated with control exosomes or saline. Through proteomic analysis, we identified differentially-expressed exosomal proteins upregulated by chemotherapy treatment. Utilizing CRISPR-Cas9-mediated gene knockout, we identified a component of the complement pathway upregulated in chemoexosomes that is critically involved in exosome-mediated metastasis. Taken together, this research proposes a novel mechanism of chemotherapy-induced metastasis by which organ-specific uptake of exosomes derived from chemotherapy-treated cells primes the pre-metastatic niche in order to create a favorable environment for metastatic tumor growth. Citation Format: Carson A. Wills, Jeffrey Sundstrom, Hong-Gang Wang. Chemotherapy promotes metastasis through extracellular vesicle secretion [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-210.
TCTAP A-160 Association and Prognostic Implication of C-Reactive Protein with Risk of 1-Year Death or Disabling Stroke After Transcatheter Aortic Valve Replacement
Authors: Ungjeong Do, Tae-Oh Kim, Sangwoo Park, Sun Hack Lee, Yong-Hoon Yoon, Sang Yong Om, Minsoo Kim, Hanbit Park, Sang-Cheol Cho, Kyusup Lee, Osung Kwon, Do-Yoon Kang, Euihong Ko, Pil Hyung Lee, Jung-Min Ahn, Duk-Woo Park, Seung-Whan Lee, Seung-Jung Park
Journal: Journal of the American College of Cardiology (2018)
Abstract 4935: T-DM1-resistant cells gain high invasive activity via EGFR and integrin cooperated pathways
Authors: Yukinori Endo, Zachary Olson, Wen Jin Wu
Journal: Cancer Research (2020)

Abstract Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate developed to treat trastuzumab-resistant cancer. Despite initial favorable outcomes, most patients eventually cease to respond by developing acquired resistance to T-DM1. Currently, there is no targeted therapy to treat T-DM1-resistant cancer. To explore novel therapeutic targets to overcome T-DM1 resistance, we generated T-DM1-resistant cells using trastuzumab-resistant JIMT1 cells. We found that the loss of human epidermal growth factor receptor 2 (HER2) confers T-DM1 resistance, which in turn activates a compensatory mechanism that increases epidermal growth factor receptor (EGFR) expression. Upregulation of EGFR increases the protein levels of α5β1 integrin, resulting in enhanced motility and invasion of T-DM1-resistant cells. However, silencing β1 integrin expression by siRNA or β1 integrin blockage induced by an inhibitory antibody, MAB 13, significantly increases invasion of T-DM1-resistant cells. The discovery of functional cooperation between EGFR and integrin in regulating cell growth and invasion provides an opportunity to develop novel therapeutic strategy by dual-targeting EGFR and specific integrin to overcome T-DM1 resistance. We now try to identify downstream molecules involved in the increased invasion using next generation sequencing (NGS) technology in β1 integrin-deficient T-DM1 resistant cells. Citation Format: Yukinori Endo, Zachary Olson, Wen Jin Wu. T-DM1-resistant cells gain high invasive activity via EGFR and integrin cooperated pathways [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4935.
Abstract 3724: BMAL1 rewires mitochondrial metabolism and promotes tumor progress of triple negative breast cancer during insulin resistance
Authors: Cassandra A. Ramos, Ching Ouyang, Yue Qi, Yiyin Chung, Chun-Ting Cheng, Mark A. LaBarge, Victoria L. Seewasldt, David K. Ann
Journal: Cancer Research (2020)

Abstract Insulin resistance is a hallmark of metabolic diseases and negatively associated with breast cancer outcomes. While much work has dedicated to circadian dysregulation, metabolic diseases in breast cancer progression, the molecular mechanism connecting all these perspectives together has not yet established. To understand this underlying mechanism, we use in vitro and in vivo insulin-resistant triple-negative breast cancer (TNBC) models, illustrating that insulin resistance in TNBC reciprocally alters mitochondrial respiration and the expression of genes in the circadian rhythm pathway. Furthermore, genetic knockdown of BMAL1, an important circadian transcription factor, ablates key adaptations to insulin resistance, such as increased pyruvate flux, oxygen consumption, and lipid storage. Our in vivo study demonstrates that orthotopically transplanted E0771 mouse breast cancer cells with BMAL1 knocked down grow significantly faster than the parental counterpart in mice fed with the high-fat diet. This new understanding of BMAL1 expands our insights into circadian control of tumor metabolism and may lead to novel treatments for breast cancer. Citation Format: Cassandra A. Ramos, Ching Ouyang, Yue Qi, Yiyin Chung, Chun-Ting Cheng, Mark A. LaBarge, Victoria L. Seewasldt, David K. Ann. BMAL1 rewires mitochondrial metabolism and promotes tumor progress of triple negative breast cancer during insulin resistance [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3724.