tbuckley/cabot-search huggingface dataset:
Abstract 4360: Altering the regulation of KRAS GTPase cycle via Src and SHP2 creates a potential therapeutic vulnerability for pancreatic cancer
Authors: Teklab Gebregiworgis, Christopher B. Marshall, Yoshihito Kano, Nikolina Radulovich, Ming-Sound Tsao, Michael Ohh, Mitsuhiko Ikura
Journal: Cancer Research (2018)

Abstract More than 30% of all human cancers have Ras mutations and more than 95% of pancreatic cancers harbor KRAS mutations. However, therapeutically targeting cancers driven by oncogenic Ras mutations is still an ongoing investigation. KRas is a small GTPase found in either a GDP-bound inactive form or a GTP-loaded activated form. The activated form of KRas localizes on the membrane where it binds and activates downstream effector proteins such as Raf kinases. GDP-bound Ras can be activated by nucleotide exchange of GTP for GDP, a reaction that is catalyzed by guanine nucleotide exchange factors (GEFs). Ras is inactivated by hydrolysis of GTP, which is assisted by GTPase activating proteins (GAPs). It was recently reported that Ras can be tyrosyl phosphorylated by Src and dephosphorylated by SHP2 (PNAS 2014;111(36):E3785-94; Nat Commun 2015;6:8859). Here we have characterized the structural and functional alterations of Src-phosphorylated KRas to mechanistically explain the impact of tyrosyl phosphorylation on the GTPase cycle. Our NMR and MS analyses show that Src phosphorylates KRas at Tyr32 and Tyr64, which perturbs the chemical shifts of several residues in each of the two "switch" regions that mediate interactions with effectors and regulators. Using real-time NMR and biolayer interferometry (Octet) assays, we demonstrated the negative impact of KRas phosphorylation on the GTPase cycle as well as BRAF binding. Conversely, the SH2 domain containing inositol 5-phosphatase 2 (SHP2) dephosphorylates KRAS and reverses Src-induced phosphorylation. In vivo, either the pharmacologic inhibition or genetic ablation of SHP2 promotes cell death in several KRAS mutant cancers. Our findings reveal that altering the KRas GTPase cycle regulation via the balance of Src and SHIP2 activities may create a therapeutic vulnerability for pancreatic cancer. Citation Format: Teklab Gebregiworgis, Christopher B. Marshall, Yoshihito Kano, Nikolina Radulovich, Ming-Sound Tsao, Michael Ohh, Mitsuhiko Ikura. Altering the regulation of KRAS GTPase cycle via Src and SHP2 creates a potential therapeutic vulnerability for pancreatic cancer [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 4360.
Abstract 4405: Pharmacologic profile of INT-1B3: A novel synthetic microRNA 193a-3p mimic for therapeutic intervention in oncology
Authors: Sanaz Yahyanejad, Thijs de Gunst, Iman Schultz, Harm den Boer, Monica Raimo, Bryony Telford, Rogier Vos, Laurens van Pinxteren, Roel Schaapveld, Michel Janicot
Journal: Cancer Research (2018)

Abstract MicroRNAs (miRNAs) are a family of small, non-coding RNAs and serve as small snippets of genetic material that regulate gene expression. As a result, miRNAs modulate a wide range of biological processes including; cell cycle control and apoptosis, cell signaling and differentiation, cell adhesion and motility. Thus, it is not surprising that their misregulation is linked to cancer initiation, treatment response, and metastasis. Due to the inherent ability of miRNAs to concurrently target multiple pathways, their therapeutic potential to be used as anti-cancer drugs is attractive. In this study, we are investigating the mode of action and development of a novel synthetic miRNA mimic (INT-1B3) as a therapeutic candidate for substitution and functional restoration of a depleted miRNA in variety of cancers. To identify miRNAs that control the survival of cancer cells, we performed a functional miRNA screening in which a wide range of relevant miRNAs were selected and miR-193a-3p was chosen as the potential candidate for further preclinical characterization. Compelling evidence demonstrate a tumor suppressor function for miR-193a-3p in many cancer types and link its reduced expression with cancer, metastasis and therapy resistance. Consistent with the described role for miR-193a-3p in literature, our cell-based assays conducted in various experimental tumor cell systems demonstrated efficient target engagement leading to reduced cell proliferation/survival, cell cycle arrest and induction of apoptosis, inhibition of cell motility as well as a potential immune-modulatory role (via adenosine-mediated tumor immune evasion). Furthermore, development of a novel lipid nanoparticle-based formulation as an efficient delivery system demonstrated a marked anti-tumor activity of INT-1B3 as single agent following systemic administration in tumor-bearing mice. Robust tumor growth inhibition in these experimental tumor models is correlated and consistent with efficient target engagement in tumor cells and relevant organs. We are currently investigating the in vitro and in vivo effect of INT-1B3 in variety of cancer types including hepatocellular carcinoma, melanoma and triple negative breast cancer. Our data thus far supports an anti-tumor role for INT-1B3 and encourages further preclinical and clinical investigation. Citation Format: Sanaz Yahyanejad, Thijs de Gunst, Iman Schultz, Harm den Boer, Monica Raimo, Bryony Telford, Rogier Vos, Laurens van Pinxteren, Roel Schaapveld, Michel Janicot. Pharmacologic profile of INT-1B3: A novel synthetic microRNA 193a-3p mimic for therapeutic intervention in oncology [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 4405.
Abstract 1553: Carcinoembryonic antigen (CEA) expression is regulated by mutant KAS in mucinous colon cancers
Authors: Murali Kuracha, Venkatesh Govindarajan, Brian W. Loggie, Peter Thomas
Journal: Cancer Research (2018)

Abstract Purpose: Carcinoembryonic antigen (CEA/CEACAM5) is a marker and prognostic indicator for colorectal cancers (CRCs). CEA overexpression is also a major causative factor in the development of liver metastasis from a significant fraction of colorectal cancers (CRC) including mucinous adenocarcinomas (MCAs). Very little is known about the molecular mechanisms that regulate the expression of CEA in cancers in general and in CRCs in particular. This study tests the hypothesis that mutant KRAS, a frequently mutated gene in CRCs, regulates CEA expression in CRCs. Methods: Mutant KRAS expression was reduced in two high CEA-expressing mucinous CRC cell lines, LS174T (KRAS G12D) and RW7213 (KRAS G12C), by short hairpin RNA (shRNA)-mediated knockdown using a lentiviral vector. Inducible and reversible knockdown of KRAS was achieved by addition or withdrawal of doxycycline. Alterations in activation of ERK-and PI3K-pathway effectors downstream of KRAS were assessed by Western blots. Two small-molecule inhibitors, pictilisib (GDC0941) and cobimetinib (GDC0973), were used to inhibit PI3K and MEK respectively. Results: Knockdown of mutant KRAS in CRC cell lines reduced CEA expression. However, knockdown of wild-type RAS did not change CEA expression. Restoration of mutant KRAS reestablished CEA expression in both cell lines. This recovery of CEA expression was blocked by addition of the MEK inhibitor, cobimetinib or the PI3K inhibitor, picstilisib. Combined treatment with both inhibitors was more effective in reducing CEA expression than single-agent treatment. Conclusions: Our results suggest that mutant KRAS, through engagement of MEK-ERK and PI3K-AKT signaling pathways, regulates CEA expression in CRCs. CEA has been implicated in the development of lung and liver metastasis from CRCs, by reacting with stromal cells and altering the tumor microenvironment. Our results therefore, suggest a potential vulnerability that could be exploited for antimetastatic therapy. Citation Format: Murali Kuracha, Venkatesh Govindarajan, Brian W. Loggie, Peter Thomas. Carcinoembryonic antigen (CEA) expression is regulated by mutant KAS in mucinous colon cancers [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 1553.
Troponin I as a Predictor of Coronary Heart Disease and Mortality in 70-Year-Old Men
Authors: BjörnZethelius, NinaJohnston, PerVenge
Journal: Circulation (2006)

Background— Cardiac troponin I (cTnI), a standard for detection of myocardial damage, has recently been reported to predict acute myocardial infarction or death in patients with unstable coronary heart disease (CHD). Cardiac TnI concentrations increase with age in subjects free from clinical signs of CHD, suggesting silent myocardial damage. We investigated the association between cTnI and future CHD and mortality in a community-based cohort of men. Methods and Results— A community-based study was conducted from August 1991 to May 1995 among 1203 men in Uppsala, Sweden, aged 70 years at baseline with a follow-up of up to 10.4 years with the use of registry data (National Board of Health and Welfare, Sweden). CHD was defined with the use of data taken from the Cause of Death Registry or from first-time hospitalization for CHD as recorded in the Hospital Discharge Registry. Cardiac TnI concentrations were measured blinded for outcome, in frozen baseline plasma samples, with the use of the AccuTnI from Beckm...
Abstract P360: Framingham Risk Score Predicts Mortality in White and African American Adults
Authors: Amanda E Staiano, Peter T Katzmarzyk
Journal: Circulation (2013)

Introduction: Coronary heart disease (CHD) remains the number one cause of death in U.S. adults. Identifying clinical tools to predict mortality risk based on CHD risk factors is important for the prevention of CHD-related deaths. Hypothesis: We tested the hypothesis that the Framingham Risk Score (FRS), which estimates 10-year CHD risk, significantly predicted all-cause mortality in white and African American adults. Methods: The sample included 6,464 white and African American participants aged 18 to 80 years from the Pennington Center Longitudinal Study. Baseline measurements occurred between 1996 and 2009, and mortality status through 2009 was determined via the National Death Index. Age and smoking status were self-reported. Systolic blood pressure was measured with a sphygmomanometer or validated Omron device. Serum total cholesterol and HDL-C were assayed from a 12-hour fasting blood draw. FRS was calculated based on age- and sex-specific levels of risk (age, smoking, blood pressure, cholesterol, a...
Abstract 4738: IL-17 induces myeloid-related stimulating factors by stromal cells
Authors: Gianluca Mucciolo, Roberta Curto, Claudia Curcio, Cecilia Roux, Luca Vannucci, Francesco Novelli, Paola Cappello
Journal: Cancer Research (2018)

Abstract Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive cancer with a 5-year survival rate of ∼ 8%. An hallmark of PDA is the massive desmoplasia and the complex stromal-tumor interaction, regulated by a pletory of secreted factors. The role of IL-17 and T-helper 17 in cancer progression or anti-tumour immunity remain controversial. To assess the role of this molecule, we crossed genetically engineered mice (GEM) characterized by a spontaneous PDA development, with IL-17 knockout mice (GEM/IL-17 KO). The absence of IL-17 correlated with an increased pancreatic fibrosis, evaluated by second harmonic generation approach. The transcripts and secretome of Cancer Associated Fibroblasts (CAFs), obtained from tumors arose in both WT and IL-17 KO GEM, have been evaluated. More than 60 genes were differently modulated in the CAFs from GEM/IL-17 KO mice. Among them, GM-CSF, G-CSF, M-CSF, CXCL1 and 2 where strongly up-regulated in GEM/WT compared to GEM/IL-17 KO mice and significantly inhibited by the addition of the recombinant cytokine. The absence of those factors paralleled an increased Th1-skewed cytokine pattern released by CAF that affected T cell infiltration and response. Taken together, these results suggest that IL-17 does affect the tumor progression by promoting a CAFs-mediated release of cytokines involved in myeloid cells recruitment and suppression of an anti-tumoral immune response. This feature defines IL-17 as a potential target to shape the tumor microenvironment and favour immunotherapy success. Citation Format: Gianluca Mucciolo, Roberta Curto, Claudia Curcio, Cecilia Roux, Luca Vannucci, Francesco Novelli, Paola Cappello. IL-17 induces myeloid-related stimulating factors by stromal cells [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 4738.
LncRNA PTAR promotes EMT and invasion-metastasis in serous ovarian cancer by competitively binding miR-101-3p to regulate ZEB1 expression
Authors: Haihai Liang, Tong Yu, Yue Han, Hua Jiang, Chengyu Wang, Tianyi You, Xiaoguang Zhao, Huitong Shan, Rui Yang, Lida Yang, Hongli Shan, Yunyan Gu
Journal: Molecular Cancer (2018)

Abstract Background Ovarian cancer (OvCa) is one of the most common malignant diseases of the female reproductive system in the world. The majority of OvCa is diagnosed with metastasis in the abdominal cavity. Epithelial-to-mesenchymal transition (EMT) plays a key role in tumor cell metastasis. However, it is still unclear whether long non-coding RNA (lncRNA) is implicated in EMT and influences cell invasion and metastasis in OvCa. Results In this study, using bioinformatcis analysis, we constructed a lncRNA-mediated competing endogenous RNA (ceRNA) network for mesenchymal OvCa and identified lncRNA AP000695.4, which we named pro-transition associated RNA (PTAR). PTAR was significantly up-regulated in the mesenchymal subtype samples compared with the epithelial subtype samples from the TCGA OvCa data sets. In addition, our study showed that PTAR expression was positively correlated with the expression level of ZEB1 in the mesenchymal OvCa samples. Meanwhile, we found that silencing miR-101 promoted cell migration, whereas the overexpression of miR-101 suppressed EMT and cell migration in OvCa cell lines through the regulation of ZEB1. Further analysis showed that enhanced expression of PTAR promoted EMT and metastasis through the regulation of miR-101, whereas silencing PTAR led to the attenuation of TGF-β1-induced tumorigenicity in ovarian cancer cells. Mechanistically, we found that PTAR acted as a ceRNA of miR-101, as forced expression of PTAR reduced the expression and activity of miR-101. More importantly, the knockdown of PTAR reduced tumorigenicity and metastasis in vivo. Conclusions Taken together, the results from our study highlight a role for the PTAR-miR-101-ZEB1 axis in OvCa, which offers novel strategies for the prevention of metastasis in OvCa.
Abstract 4580: Changes in the efficacy of anti-EGFR antibody drugs by exosomes derived from colorectal cancer patients
Authors: Rii Morimura, Kei Tsukamoto, Shinji Irie, Shiro Kitano, Eiji Shinozaki, Kensei Yamaguchi
Journal: Cancer Research (2018)

Abstract Background: One of the biggest hurdles in cancer treatment is drug resistance. Exosomes are small membrane vesicles of endocytic origin, which contain mRNAs, DNA fragments, and proteins, and are released by many different cell types, including cancer cells. Several studies have shown exosome-mediated drug resistance mechanisms: drug export via the exosome pathway, neutralization of antibody-based drugs and exosome-mediated transfer of miRNAs. Here, we demonstrated the effect of exosomes derived from colorectal cancer (CRC) patients on the efficacy of anti-EGFR agent by in vitro cell-based assay. Method: Exosomes were purified by ultracentrifugation from culture media of HCT116 cell line and the sera of CRC patients with stage IV pre- and post-treatment with cetuximab (Cmab). As a control, sera from healthy volunteers were used. The number of exosomes and amount of protein were determined by NanoSight and Qubit fluorometer, respectively. The isolated exosomes and 0.01 mg/mL and 0.1 mg/mL of Cmab were added to HT29 and NCI-H508, which stained with PKH dye previously. NCI-H508 is a Cmab super sensitive cell line. After culturing for 3 days, the cells were collected, stained with trypan blue, and the number of the remaining viable cancer cells was calculated with a cell counter. Cmab in the exosome fraction was quantified by ELISA. Result: HT29 became drug ineffective depending on the number of exosomes produced by Cmab-insensitive HCT-116 harboring KRAS G13D mutation. In addition, exosomes in 9 of 18 cases of colorectal cancer patients changed NCI-H508 into a drug-ineffective state and also correlated with clinical information. In contrast, NCI-H508 was not converted into a drug-ineffective state by exosomes of healthy volunteers and Cmab responder patients. However, on the other hand, quantitative results by ELISA showed that Cmab in sera of some patients remained in the exosome fraction and inhibited the growth of NCI-H508. As a remarkable point, exosomes derived from healthy volunteers significantly promoted the efficacy of Cmab. Conclusion: In this feasibility study, Cmab resistance in CRC patients may be reproducible by cell-based assay using exosomes. We believe that understanding this mechanism of action will contribute to drug discovery and personalized medicine in the future. Now, we are searching for biomarkers in these exosomes that change the efficacy of Cmab. Citation Format: Rii Morimura, Kei Tsukamoto, Shinji Irie, Shiro Kitano, Eiji Shinozaki, Kensei Yamaguchi. Changes in the efficacy of anti-EGFR antibody drugs by exosomes derived from colorectal cancer patients [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 4580.
Abstract 5290: My crown or my health: Black women's knowledge of breast cancer and hair product-related risk
Authors: Dede Teteh, Phyllis Clark, Lenna Dawkins-Moultin, Rick Kittles, Susanne Montgomery
Journal: Cancer Research (2018)

Abstract Introduction/Purpose: Black women now have higher breast cancer (BC) incidence and mortality than White women. They also use more hair products containing hormonally-active chemicals. Studies are beginning to link chemical ingredients in these products to BC risk. Little is known about community knowledge of BC and the potential association with hair product-related risk. The purpose of this study was to evaluate the hazard level of hair products used by Black women, and assess their knowledge about BC and hair product-related risks. Methodology: We employed principles of community-based participatory research and conducted the study through partnership between community advocates and university scientists. We collected hair products from locations frequented by Black women and hair stylists and used the Environmental Working Group's Skindeep© database to evaluate ingredient toxicity. We then explored knowledge of BC and hair product-related risk using a 41-item survey. Survey data were analyzed using SPSS. Results: All 54 products evaluated contained hazardous ingredients. Fourteen of the ingredients had an overall high hazard rating between 7-10, with 10 indicating very high levels of toxicity. The potential harmful effects of these chemicals include cancer, endocrine disruption and reproductive system toxicant. Survey data showed most women (62%) in the sample had a college or graduate degree. Participants (n=211) were more knowledgeable about the diagnosis and treatment of BC (46.3%), lifestyle-related risk factors (59.6%), and genetic risk factors (54.9%) than about hair product risk (40.8%). Conclusion: Several hair products frequently used by black women contained ingredients that have potential links to BC. Though the women in this study were highly educated, they had limited knowledge about the association between BC and toxins found in hair products. Research should further clarify the link between hair products and BC risk. As knowledge is evolving, given our emerging risk understanding, health educators and community advocates can promote efforts for women to learn more about exposure reduction to help them make informed decisions about the risk beauty product chemicals may hold regarding cancer. There is also a need for policies on personal care products that aim to protect the health of our communities. Citation Format: Dede Teteh, Phyllis Clark, Lenna Dawkins-Moultin, Rick Kittles, Susanne Montgomery. My crown or my health: Black women's knowledge of breast cancer and hair product-related risk [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 5290.
Abstract A35: Ovarian cancer stem cells subvert tumor-specific T cells by disrupting T cells’ metabolic fitness
Authors: Feng Qian, Jianqun Liao, Anthony J. Miliotto, Katherine A. Collins, Kunle Odunsi
Journal: Clinical Cancer Research (2018)

Abstract Cancer stem cells (CSCs) are defined by their unlimited self-renewal ability and their capacity to initiate and maintain malignancy, traits that are not found in most cells that compose the tumor. These stem cells have been shown to be relatively resistant to conventional chemotherapeutic regimens and radiation. Previously, we have reported that spheroid cells derived from 3D epithelial ovarian cancer cells are enriched with cancer stem cells by in vitro and in vivo experiments. In addition, we have demonstrated that CSCs adopt unique metabolic pathways by routing glucose predominantly to anaerobic glycolysis and pentose cycle to the detriment of rerouting glucose for anabolic purposes. In the current study, we hypothesized that CSCs may contribute to the immunosuppressive microenvironment of ovarian cancer by disrupting the metabolic fitness of infiltrating T cells. We isolated fresh spheroid cells from ovarian cancer patients’ ascites and examined their effect on T-cell responses ex vivo. In addition, other than ovarian cancer, we generated more spheroid cells from pancreatic cancer and breast cancer cells. Compared to nonspheroid cells, these spheroid cells have upregulated stem cell gene expression, higher ALDH activity, and more tumor-initiating capacities in SCID mice, indicating CSCs enrichment in spheroid cells. Seahorse XF analysis revealed a glycolytic metabolic phenotype of spheroid cells with increased extracellular acidification rate (ECAR) compared to nonspheroid cells. Spheroid cells suppress the response of cocultured T cells to TCR stimulation by inhibiting T-cell activation, growth, proliferation, and function independent of cell-cell contact determined by transwell assay and supernatant incubation. After spheroid cells treatment, activated T cells metabolically shifted from energetic to quiescence phenotype, which is reversely correlated with increased glycolysis in spheroid cells, indicating that highly glycolytic spheroid cells suppress T-cell response through reprogramming T-cell metabolic status. Furthermore, we found that spheroid cells dampen T cells’ response by inhibiting Erk-AKT-mTor signaling and by activating the integrated stress response pathway. This study provides novel insights into the relationship between cancer stem cells and T cells’ response and has clinical implications for cancer therapy. Citation Format: Feng Qian, Jianqun Liao, Anthony J. Miliotto, Katherine A. Collins, Kunle Odunsi. Ovarian cancer stem cells subvert tumor-specific T cells by disrupting T cells’ metabolic fitness. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A35.