tbuckley/cabot-search huggingface dataset:
Abstract 955: Musashi-2 regulates EGFR expression in NSCLC, cell proliferation and survival, response to EGFR inhibitors in EGFR-mutant NSCLC
Authors: Alexander Kudinov, Petr Makhov, Bulat Faezov, Igor Bychkov, Alexander Deneka, Emmanuelle Nicolas, Kathy Q Q. Caid, Rohan Brebione, Eleanor Avrilf, Anna S. Nikonova, Ilya G. Serebriiskii, Hossein Borghaei, Erica A. Golemis, Yanis Boumber
Journal: Cancer Research (2019)

Abstract Musashi-2 (MSI2) is an RNA-binding protein that regulates mRNA translation. We recently established that MSI2 is elevated in a subset of non-small cell lung cancer (NSCLC) tumors upon progression and drives NSCLC metastasis, in part based on activity supporting a TGF-beta/SMAD3/claudin signaling cascade. Here, reverse phase protein array (RPPA) analysis of MSI2-depleted versus control KrasLA1/+;P53R172HΔG/+ murine NSCLC cell lines identified a significant upregulation of HER3 (ERBB3) upon MSI2 depletion. Negative MSI2-dependent regulation of ERBB3 protein was confirmed in multiple murine and human NSCLC models, based on analysis of MSI2 depletion or overexpression. Further, MSI2 positively regulated expression of the epidermal growth factor receptor (EGFR) protein in the same models. Comparing EGFR and KRAS driven models, we found that MSI2 depletion significantly impairs cell proliferation and clonogenicity only in EGFR-mutant NSCLC cell lines. Using RNA immunoprecipitation analysis coupled with qPCR, we show that MSI2 directly binds to EGFR and, to a lesser extent, to HER3 mRNA. MSI2 mRNA binding was correlating with the presence of predicted MSI2 binding sites in corresponding mRNAs. Taken together, this data suggest direct regulation of EGFR protein expression by MSI2 at post transcriptional level. NSCLC lung tissue microarray immunohistochemistry analysis revealed that MSI2 total positivity by H-score, 2+/3+ and 3+ positivity correlated with EGFR 3+ staining. Finally, EGFR inhibitors erlotinib and afatinib synergized with MSI2 depletion in EGFR mutant models, suggesting that therapeutic targeting of MSI2 could be of clinical value, especially in EGFR-mutant lung cancer. In vivo experiments of erlotinib treatments of wild type or MSI2 depleted tumors are ongoing and these results will be presented. Citation Format: Alexander Kudinov, Petr Makhov, Bulat Faezov, Igor Bychkov, Alexander Deneka, Emmanuelle Nicolas, Kathy Q Q. Caid, Rohan Brebione, Eleanor Avrilf, Anna S. Nikonova, Ilya G. Serebriiskii, Hossein Borghaei, Erica A. Golemis, Yanis Boumber. Musashi-2 regulates EGFR expression in NSCLC, cell proliferation and survival, response to EGFR inhibitors in EGFR-mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 955.
Abstract LB-316: Suppression of tumor angiogenesis and metastasis by targeting a novel p38-driven tumor-stromal crosstalk
Authors: Andrei V. Bakin, Justin Zonneville, Rebecca Walden, Sydney Grant, Sean Colligan, Alexandra Miller, Alexander M. Truskinovsky, Scott Abrams
Journal: Cancer Research (2019)

Abstract Triple-negative breast cancers (TNBCs, ER/PR/HER2-negative) pose significant clinical challenges largely due to a lack of targeted therapy. Our prior work revealed a novel tumor-stromal crosstalk that increases p38 kinase signaling in the breast tumor microenvironment (TME). Here, we examined the effects of systemic blockade of p38 signaling in the relevant TNBC models. Blockade of p38 with a selective p38 inhibitor Ralimetinib reduced tumor growth and metastasis to the lungs and liver. Histology revealed that p38 blockade greatly reduced tumor angiogenesis. Within the TME, we found a massive infiltration of myeloid cells i.e. polymorphonuclear (PMN) myeloid-derived suppressor-like cells (MDSC-like) to the lungs and liver of tumor-bearing (TB) mice. Further, TB-mice showed a significant rise in the numbers of granulocytes and monocytes in the circulation, and the accumulation of CD163+ macrophages in the TME. Blockade of p38 greatly reduced these responses. In contrast, p38 blockade increased abundance of cytotoxic CD8+ T-cells in the TME. Addressing the mechanism, we found that inactivation of p38 in tumor cells was sufficient to reduce the influx of macrophages to the tumor, suggesting a tumor-driven mechanism of mobilization or expansion of myeloid cell populations. Further, depletion of PMN-MDSC-like cells and neutrophils using anti-Ly6G antibody reduced metastases to the lungs and liver. Assessing the prognostic value of our results, we found an inverse correlation of CD163 levels with metastasis-free survival in patients with breast cancer. Together, these results demonstrate that p38 kinase promotes breast cancer growth and colonization to distant organs by regulating mobilization of pro-tumor myeloid cells. This p38-driven mechanism highlights a novel target for treatment of patients with TNBC or advanced disease. Citation Format: Andrei V. Bakin, Justin Zonneville, Rebecca Walden, Sydney Grant, Sean Colligan, Alexandra Miller, Alexander M. Truskinovsky, Scott Abrams. Suppression of tumor angiogenesis and metastasis by targeting a novel p38-driven tumor-stromal crosstalk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-316.
DNA mutation frequencies in metastatic small bowel adenocarcinoma (mSBA) in comparison to gastric (mGC), colon (mCC), and rectal cancer (mRC): Continuum or cutpoint?
Authors: Janet E. Murphy, Andrea Lyn Russo, Jackie Szymonifka, Eunice Lee Kwak, Jill N. Allen, Andrew X. Zhu, Lawrence Scott Blaszkowsky, Jeffrey W. Clark, David P. Ryan, Theodore S. Hong, Darrell R. Borger
Journal: Journal of Clinical Oncology (2013)

e14636 Background: The small intestine is in continuity with the stomach and colon/rectum. However mGC and mCC/mRC differ in oncogene profiles. No study has evaluated the oncogene profile of mSBA on the continuum of mGC and mCC/mRC. This may give insight into biology and have implications for treatment. Methods: Respective analysis was performed on GI cancer patients who underwent tumor mutational profiling since 2010. Genotyping was performed on formalin-fixed and paraffin-embedded tumor tissue using a multiplexed mutational profiling platform. Here we report results for APC, BRAF, EGFR, IDH1, KRAS, NRAS, PI3K, PTEN, and TP53. Results: We identified 12 patients with mSBA (11/12 with clinical data, 11/12 with genotype data). Median age at stage IV diagnosis was 61.1y (49.3-71.5y). Four patients had duodenal, 3 jejeunal, 2 ileal, and 2 multiple/unknown primary sites. All patients received 5FU and ox, while 8/11 received irino, 5/11 bev, 3/11 cetux, 1/11 regorafenib and 1/11 capecitabine. Two patients had adjuvant RT (both duodenal) while 4/11 received palliative RT. Survival was calculated from the date of stage IV diagnosis until death, with data censored on 2/1/2013. Median survival was 24.0 months (95% CI 6.4 – 60.0 mo). We compared genotype frequencies of mSBA patients (11) with mGC (41), mCC (161), and mRC (64) using Fisher’s exact test for pairwise comparisons. Conclusions: While the small bowel sample size was small, a significant difference in KRAS mutation frequency was found when compared to gastric cancer. No significant differences in mutation frequencies were found when compared with colon or rectal cancer. [Table: see text]
Expression of female sex hormone receptors, connective tissue growth factor, and HER2 in gallbladder cancer and adjacent normal tissue
Authors: B. Hryciuk, R. Pęksa, M. Bieńkowski, B. Szymanowski, B. Radecka, A. Perdyan, K. Winnik, J. Zok, N. Cichowska, M. Iliszko, R. Duchnowska
Journal: Annals of Oncology (2019)
Abstract 13063: Sex Specific Differences in Ventricular Function in Health and Disease
Authors: Hiroyuki Takahama, Selma F Mohammed, Veronique L Roger, Margaret M Redfield
Journal: Circulation (2013)

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is the predominant form of HF in women, while HF with reduced EF (HFrEF) is more common in men. Studies in healthy animals an...
Identification of Novel Causal Blood Biomarkers Linking Metabolically Favorable Adiposity With Type 2 Diabetes Risk
Authors: Marie Pigeyre, Jennifer Sjaarda, Shihong Mao, Michael Chong, Sibylle Hess, Salim Yusuf, Hertzel Gerstein, Guillaume Paré
Journal: Diabetes Care (2019)

OBJECTIVE Observations of a metabolically unhealthy normal weight phenotype suggest that a lack of favorable adiposity contributes to an increased risk of type 2 diabetes. We aimed to identify causal blood biomarkers linking favorable adiposity with type 2 diabetes risk for use in cardiometabolic risk assessments. RESEARCH DESIGN AND METHODS A weighted polygenic risk score (PRS) underpinning metabolically favorable adiposity was validated in the UK Biobank (n = 341,872) and the Outcome Reduction With Initial Glargine Intervention (ORIGIN Trial) (n = 8,197) and tested for association with 238 blood biomarkers. Associated biomarkers were investigated for causation with type 2 diabetes risk using Mendelian randomization and for its performance in predictive models for incident major adverse cardiovascular events (MACE). RESULTS Of the 238 biomarkers tested, only insulin-like growth factor–binding protein (IGFBP)-3 concentration was associated with the PRS, where a 1 unit increase in PRS predicted a 0.28-SD decrease in IGFBP-3 blood levels (P &amp;lt; 0.05/238). Higher IGFBP-3 levels causally increased type 2 diabetes risk (odds ratio 1.26 per 1 SD genetically determined IGFBP-3 level [95% CI 1.11–1.43]) and predicted a higher incidence of MACE (hazard ratio 1.13 per 1 SD IGFBP-3 concentration [95% CI 1.07–1.20]). Adding IGFBP-3 concentrations to the standard clinical assessment of metabolic health enhanced the prediction of incident MACE, with a net reclassification improvement of 11.5% in normal weight individuals (P = 0.004). CONCLUSIONS We identified IGFBP-3 as a novel biomarker linking a lack of favorable adiposity with type 2 diabetes risk and a predictive marker for incident cardiovascular events. Using IGFBP-3 blood concentrations may improve the risk assessment of cardiometabolic diseases.
Abstract MP077: Dietary Sodium Potassium Ratio as a Risk Factor for Stroke, Cardiovascular Diseases and All-cause Death Among Japanese: Nippondata80.
Authors: Akira Okayama, Katsuyuki Miura, Tomonori Okamura, Nagako Okuda, Shigeyuki Saitoh, Hirofumi Ohnishi, Hiroshi Akasaka, Naoyuki Takashima, Katsushi Yoshita, Yusuke Arai, Miho Nozue, Takehito Hayakawa, Yutaka Kiyohara, Hirotsugu Ueshima
Journal: Circulation (2012)

Objective Japanese have higher intake of sodium and lower intake potassium than Western countries. We evaluated the impact of Sodium potassium ratio on mortality from stroke, cardiovascular diseases (CVD) and all causes using 24 year follow-up data of population randomly selected from Japanese at National cardiovascular Survey in 1980. Method Participants with age 30 years old or more (n=10536) in the 1980 National Cardiovascular Survey was followed-up for 24 years with a follow-up rate of 92%. We combined individual National Nutrition Survey data conducted for the same participants. Participants without hypertensive treatment and without past histories of stroke and acute myocardial infarction (n = 8982) were divided into quintile according to sodium potassium ratio assessed by 3 day dietary record method at the baseline survey. Observed number of death during follow-up was 1938. Under line causes of death were identified by using Vital Statistics,Japan. Age adjusted and multi-adjusted hazard ratio was calculated using.Cox’s proportional hazard model. Results Mean intake of Sodium and potassium at the baseline was 242 and 208 mEq, and 77.7 and 70.8 mEq for men and women, respectively. Sodium potassium ratio was significantly related to mortality from stroke, cardio vascular diseases and all causes of death among men and for all adjusting other major risk factors. Multi-adjusted hazard ratio (95% confidence interval) of mortality from all causes, CVD and stroke for both sexes with one quintile of sodium potassium ratio was 1.04(1.01-1.08), 1.08(1.02-1.14) and 1.14 (1.05-1.24). Relationship was still significant after adjusting SBP levels. Conclusion Sodium potassium ratio was significant risk factor for death from all causes, CVD and stroke among Japanese.
Abstract 4426: Selective inhibition of CDK9 induces apoptosis of TNBC cells independent of Rb status
Authors: Hailey E. Brighton, Claire R. Hall, Kerry A. Dillon, John E. Bisi, Jay C. Strum
Journal: Cancer Research (2019)

Abstract The family of cyclin-dependent kinases (CDKs) are serine/threonine protein kinases important for cell cycle control and/or regulation of transcription. CDK9/CyclinT1 is a key regulator of transcription in eukaryotic cells and has been shown to be dysregulated at the level of protein and kinase activity in both hematologic and solid tumors. CDK9/CyclinT1 forms the active P-TEFb complex and phosphorylates Ser2 residues in the carboxy-terminal domain of RNA polymerase II (RNApol II) to initiate elongation of mRNA transcripts. CDK9 activity regulates transcription of a variety of short-lived transcripts that promote survival and directly suppress apoptosis in cancer cells, including MYC,XRN2, MCL-1,and XIAP. MYC-driven tumor types with Rb-loss or high expression levels of cyclin E, such as triple negative breast cancer (TNBC), are difficult to treat and are resistant to existing CDK4/6 inhibitors. Since CDK9 is upstream of these oncogenic drivers, inhibition of CDK9 could potentially bypass innate resistance mechanisms and induce cell death in TNBC through blocking expression of MYC and MCL-1, for example. To target CDK9 in TNBC, we used structure-based drug design and developed a library of novel, potent and selective CDK9 inhibitors (CDK9i). The lead CDK9i exhibit single digit nanomolar potency against CDK9/CyclinT1 complexes and good selectivity against other CDK family members in biochemical assays. In addition, they also display high selectivity over 502 other kinases. Lead CDK9 inhibitors were found to potently inhibit phosphorylation of RNApol II Ser2 in a time and dose dependent manner in TNBC cells and decrease MYC, MCL-1 and XIAP at both mRNA and protein levels. Additionally, treatment of TNBC cells led to a potent G2/M cell cycle arrest, inhibition of cell proliferation and induction of apoptosis within 24 hours, regardless of Rb status of the tumor cells. Primary human bone marrow and normal human fibroblast cells, however, did not undergo apoptosis within 72 hours of treatment with CDK9i, suggesting a potential therapeutic window for CDK9i treatment. Further studies are ongoing to assess the effect of dose and scheduling on tumor efficacy in mouse TNBC tumor models. Selective inhibition of CDK9 presents a novel treatment strategy for difficult-to-treat tumor types, including those resistant to existing targeted therapeutics. Citation Format: Hailey E. Brighton, Claire R. Hall, Kerry A. Dillon, John E. Bisi, Jay C. Strum. Selective inhibition of CDK9 induces apoptosis of TNBC cells independent of Rb status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4426.
Evaluation of ERCC1 and RRM1 as prognostic biomarkers in urothelial cancer (UC) treated with adjuvant platinum and gemcitabine chemotherapy.
Authors: Lauren Christine Harshman, Gerold Bepler, David I. Quinn, Jesse McKenney, Debra Hawes, Noah Simon, Sandy Srinivas, Tanya B. Dorff
Journal: Journal of Clinical Oncology (2012)

e15005 Background: Adjuvant (adj) treatment of UC generally entails platinum (plat)- and gemcitabine (gem)-based chemotherapy (chemo). Two candidate prognostic and predictive biomarkers are the excision repair cross-complementation group 1 gene (E1) and the regulatory subunit of ribonucleotide reductase (R1). Studies in advanced UC patients (pts) suggest that high E1 and R1 expression confers chemoresistance to cisplatin (cis) and gem respectively. We identified UC pts treated with adj chemo to assess for differences in time to recurrence (TTR) and overall survival (OS) based on tumoral E1/R1 expression and chemotherapy regimen. Methods: 184 pts, who received adj plat or gem for T2-4NxM0 UC from 1984-2009, were identified. Tissue microarrays were created from their primary bladder tumor and involved nodal tissue. E1 and R1 protein expression was assessed using AQUA (HistoRx). The median (med) values were established a priori as the cutoff for high and low expression. Medical records were retrospectively reviewed for pathology, treatment, and outcomes data. Results: 154 pts who had both clinical and gene expression data were eligible for analysis. Pts received cis (134), carboplatin (carbo, 20) and gem (62) based regimens. Med age was 65 yrs. The majority were male (79%) and had pT3 (48.7%) or nodal disease (53.2%). At med followup of 3.9 yrs, 53.4% have recurred. Med TTR and OS were 1.2 and 2.1 yrs. Primary tumor E1/R1 Spearman correlation was moderate at 0.49 but less between primary and nodal disease (E1 0.34, R1 0.23). Irrespective of chemo, E1 and R1 expression were not prognostic for TTR (E1 p=0.8, R1 p=0.3) or OS (E1 p=0.25, R1 p=0.83). Degree of E1 expression did not impact TTR or OS in plat-treated pts nor did R1 expression in gem-treated pts. Stage predicted increased TTR and OS (&lt;0.00001). Cis-treated pts had significantly longer TTR (p=0.02) than carbo-treated pts. Conclusions: Tumoral E1 and R1 expression were not prognostic biomarkers for UC pts treated with adj plat and gem chemotherapy in our cohort. Our data was limited by missing tissue in 22% of planned pts. Reproducibility by a second laboratory and heterogeneity analysis between primary and nodal tissue will be presented.
Abstract 20677: Deletion of PRAK Promotes Myocardial Ischemia and Reperfusion Injury in Mice
Authors: Yu T Zhao, Naohiro Yano, Hao Wang, Jianfeng Du, Ting C Zhao
Journal: Circulation (2017)

Background: p38 regulated/activated protein kinase (PRAK) plays an important role in modulating cellular survival and biological function. However, the specific function of PRAK in the regulation o...
Abstract P060: Serum 25-Hydroxyvitamin D, Parathyroid Hormone and Markers of Glucose Homeostasis in Middle-aged Adults
Authors: Patricia A Metcalf, Robert K Scragg
Journal: Circulation (2013)

Background: Epidemiological studies show that blood concentrations of 25-hydroxyvitamin D [25(OH)D] are inversely related to the prevalence of diabetes mellitus, glycemia, and insulin resistance. L...
Abstract LB-153: Therapeutic effect of MC-4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinaseM2 and mechanistic target of rapamycin complex 1 pathways
Authors: Hyung Sik Kim, Kyeong Seok Kim
Journal: Cancer Research (2019)

Abstract Current clinical trials of new anticancer therapies against metastatic renal cell carcinoma (RCC), including molecular-targeted therapies, have not shown promise. The purpose of this study was to preclinically assess the antitumor effects of MC-4, a partially purified material of Artemisia annua L., as a monotherapy or in combination with the known mechanistic target of rapamycin complex 1 (mTORC1) inhibitor, everolimus, against Caki-1 (Von Hippel-Lindau (VHL)+/+) and 786-O (VHL−/−) human RCC cells. MC-4 monotherapy significantly increased tumor growth inhibition and autophagic cell death in RCC cells in vitro and in vivo. Everolimus led to compensatory Akt activation by inhibiting only mTORC1 signaling pathway. In contrast to everolimus, MC-4 enhanced phosphatase and tensin homolog expression and reduced its downstream effector, Akt/pyruvate kinase muscle isozyme M2 (PKM2), leading to decreased expression of glucose transporter 1, which is associated with cancer cell metabolism. The synergistic antitumor and anti-metastatic effects induced by co-administration of MC-4 and everolimus involve cell growth inhibition and autophagic cell death via dual targeting of phosphatidylinositol 3-kinase (PI3K)/Akt/PKM2 and mTORC1. These findings suggest that MC-4 is a novel Akt/PKM2 inhibitor that can overcome the limitation of existing mTOR inhibitors and can be considered a novel strategy to treat patients with rapidly progressing advanced RCC. Citation Format: Hyung Sik Kim, Kyeong Seok Kim. Therapeutic effect of MC-4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinaseM2 and mechanistic target of rapamycin complex 1 pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-153.
Abstract 3062: PLK1: a new therapeutic target in mucinous ovarian carcinoma
Authors: Roberta Affatato, Rosaria Chilà, Monica Lupi, Valentina Restelli, Mark Erlander, Laura Carrassa, Giovanna Damia
Journal: Cancer Research (2019)

Abstract Epithelial ovarian cancer (EOC) is the most lethal gynaecological cancer. Amongst the five histotypes (high-grade serous, clear-cell, endometrioid, mucinous, and low-grade serous), mucinous epithelial ovarian cancer (mEOC) is a rare subset and represents approximately 3% of EOC. Beside these different histotypes are unique clinical entities with a different prognosis and response to therapy, they are still treated as a homogeneous group with a similar chemotherapeutic approach (platinum-paclitaxel combination), to which however mEOC is generally poor responsive. New specific and active therapeutic strategies are needed for mEOC. To find new therapeutic options for mEOC, we have performed a high-throughput screening using a siRNA library directed against 719 human protein kinases in the mEOC MCAS cell line. After two independent screenings and validation experiments with specific esiRNAs, Polo-like kinase1 (PLK1), a mitotic serine/threonine kinase, was identified as the most significant kinase whose downregulation interfered with both cell proliferation and survival. Both PLK1 siRNA and nanomolar concentrations of commercially available inhibitors against PLK1 (onvansertib (NMS-P937) and volasertib) inhibited cell growth in other two additional mEOC cell lines (EFO-27 and JHOM-1). In addition, in the mEOC cell lines PLK1 inhibition was able to induce apoptosis and to block cells in the G2-M phase of the cell cycle. We then evaluated in vitro combinations between the PLK1 inhibitors and different chemotherapeutic drugs used in mEOC, including cisplatin and paclitaxel used in front line therapy in all the available mEOC cell lines. No synergism could be found in any of the cell lines, when both PLK1 inhibitors were combined with cisplatin. On the contrary, strong synergism could be observed in two out the three mEOC cell lines investigated when onvansertib and volasertib were combined with both paclitaxel and eribulin. On the basis of the strong in vitro synergistic effect between onvansertib and paclitaxel, this combination was tested in vivo in nude mice transplanted with MCAS cells. Onvansertib as single agent was inactive, while paclitaxel at the dose used was active. Interestingly enough, the combination of the two drugs was well tolerated and was much more active than paclitaxel single agent, with both a stronger tumor regression and more sustained tumor growth inhibition that translated in a longer survival time. These data suggest that onvansertib and paclitaxel could represent a new active therapeutic option in mEOC. Citation Format: Roberta Affatato, Rosaria Chilà, Monica Lupi, Valentina Restelli, Mark Erlander, Laura Carrassa, Giovanna Damia. PLK1: a new therapeutic target in mucinous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3062.