bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2726: Functional multiomic profiling identifies Aurora kinase inhibition as a therapeutic strategy in RIT1-mutant lung adenocarcinoma
Authors: Vichas Athea , Nkinsi Naomi T. , Berger Alice 
Published: August 2019

Abstract
Treatment of lung cancer is evolving from standard cytotoxic to personalized treatment based on the molecular alterations unique to each patient’s tumor. In our recent work with TCGA and others, we identified somatic mutations in the gene encoding the RAS-related small GTPase, RIT1, in lung adenocarcinomas. In addition, somatic RIT1 mutations have also been identified in myeloid malignancies and germline RIT1 mutations are found in the developmental “RAS-opathy,” Noonan syndrome. In all these diseases, RIT1 mutations are mutually-exclusive with other RAS/MAPK pathway mutations, including mutations in EGFR, KRAS, and ALK. While our previous work demonstrated that gain-of-function RIT1 mutations induce activation of PI3K and MEK signaling, the specific effectors used by RIT1 to promote tumorigenesis are unknown. To genetically dissect the signaling pathways downstream of RIT1, KRAS, EGFR, and PIK3CA, we performed genome-wide CRISPR/Cas9 screens in four isogenic lung adenocarcinoma cell lines in which cell survival is dependent on the expression of the oncogene. Through integrative analysis of essential genes across the four cell lines, we identified synthetic lethal relationships unique and shared in each isogenic background. Among the dependencies identified was the requirement of aurora kinase pathway genes for survival of RIT1-mutant cells, raising the possibility of therapeutic aurora kinase inhibition in RIT1-positive tumors. To evaluate whether the dependence on Aurora kinases extended to small molecule inhibition, we performed a screen of 160 small molecules in clinical development or approved by the FDA. Consistent with our CRISPR/Cas9 results, we find that RIT1-mutant cells depend on Aurora kinase activity for survival. Interestingly, global phosphoproteomic profiling identified RIT1 regulation of an Aurora kinase-Haspin axis. Taken together these results identify a new arm of RIT1 signaling and nominate Aurora kinase inhibition as a potential therapeutic strategy in RIT1-mutated tumors.
Citation Format: Athea Vichas, Naomi T. Nkinsi, Alice Berger. Functional multiomic profiling identifies Aurora kinase inhibition as a therapeutic strategy in RIT1-mutant lung adenocarcinoma [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 2726.
Abstract 2732: Frameshift neoantigen vaccination prevent Lynch syndrome mouse model intestinal cancer
Authors: Gelincik Ozkan , Ibrahim Hamza , Ozkan Mine , Ahadova Aysel , Sei Shizuko , Shoemaker Robert , Kloor Mattias , Doeberitz Magnus Von Knebel , Lipkin Steven M. 
Published: August 2019

Abstract
Microsatellite-unstable (MSI) cancers occurring in the context of Lynch syndrome elicit pronounced tumor-specific immune responses directed against frameshift peptide (FSP) neoantigens, which result from mismatch repair (MMR) deficiency-induced insertion/deletion mutations in coding microsatellites (cMS). We have recently completed a clinical phase I/IIa trial that successfully demonstrated safety and immunogenicity of an FSP neoantigen-based vaccine in MSI colorectal cancer patients (Clinical trial number: NCT01461148). The vaccine was safe and induced robust cellular and humoral immune responses in all vaccinated patients. To further develop a cancer preventive vaccine against MSI cancers in Lynch syndrome, we aimed to establish a preclinical mouse model. A systematic database search was performed to identify cMS sequences in the murine genome. Subsequently, intestinal tumors obtained from Lynch syndrome mice (Msh2flox/flox VpC+/+) were evaluated for mutations affecting these candidate microsatellites. Thirteen candidate cMS were detected that presented with a mutation frequency of 15% or higher. Epitope prediction using the netMHC4.0 algorithm was performed, and ten most promising FSP neoantigens were synthesized. Immunogenicity was evaluated after vaccination of C57BL/6 mice using IFN-gamma ELISpot. Four FSP neoantigens derived from cMS mutations in the genes Nacad, Maz, Xirp1, and Senp6 elicited strong antigen-specific cellular immune responses. CD4-specific T cell responses were detected for Maz, Nacad, and Senp6 and CD8-positive T cells were detected for Xirp1 and Nacad. Vaccination with peptides encoding these four intestinal cancer FSP neoantigens promoted anti-neoantigen immunity, reduced intestinal tumorigenicity and prolonged overall survival (P&lt;0.01). Additionally, NSAIDs, which have chemopreventive efficacy for Lynch syndrome, increase T cell immunity against neoantigens. Mechanistic tumor mutation burden and adaptive immune response studies will be shown. In summary, these data support the further development of vaccination strategies for preventing cancers associated with Lynch syndrome.
Citation Format: Ozkan Gelincik, Hamza Ibrahim, Mine Ozkan, Aysel Ahadova, Shizuko Sei, Robert Shoemaker, Mattias Kloor, Magnus Von Knebel Doeberitz, Steven M. Lipkin. Frameshift neoantigen vaccination prevent Lynch syndrome mouse model intestinal cancer [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 2732.
Abstract 2759: Chemoproteomic profiling of the oncometabolite fumarate
Authors: Bergholtz Sarah E. , Briney Chloe A. , Kulkarni Rhushikesh A. , Wei David , Bak Daniel W. , Shrimp Jonathan H. , Weerapana Eranthie , Linehan W. Marston , Meier Jordan L. 
Published: August 2019

Abstract
Dysregulated metabolism is a feature of many diseases, including cancer. In addition to providing energy and building blocks to growing cells, altered metabolism can assist in tumor growth by producing “oncometabolites”. For example, in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) inactivating mutations in fumarate hydratase (FH) leads to accumulation of millimolar levels of an oncometabolite, fumarate. At such high concentrations, fumarate can spontaneously react with protein cysteine residues leading to a post-translational modification (PTM) called cysteine succination. This PTM can directly stimulate tumorigenic signaling, however, current methods to study this PTM are limited. Our lab has developed chemical proteomic methods to investigate proteome-wide targets of cysteine succination. Using these methods, we have identified hundreds of targets of fumarate in normal kidney cells as well as HLRCC cells. One interesting target identified that has implications in cancer progression is SMARCC1, a core subunit of a nucleosome remodeling complex known as the SWI/SNF complex. The SWI/SNF complex is a well-known tumor suppressor and mutation of this complex leads to cancer development. We have demonstrated that excess fumarate levels result in hyper-modification of SMARCC1 and decrease in SWI/SNF complex stability. This instability also results in an increase in EZH2 expression as well as activity, and an increase in H3K27Me3. Our current efforts are aimed at understanding how fumarate affects the function of this complex in vivo and exploring the potential of using EZH2 inhibitors in the treatment of HLRCC.
Citation Format: Sarah E. Bergholtz, Chloe A. Briney, Rhushikesh A. Kulkarni, David Wei, Daniel W. Bak, Jonathan H. Shrimp, Eranthie Weerapana, W. Marston Linehan, Jordan L. Meier. Chemoproteomic profiling of the oncometabolite fumarate [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 2759.
Abstract 2764A: Elucidating the pharmacological effects of covalent microtubule stabilizing taccalonolides through functional tagging
Authors: Yee Samantha S. , Du Lin , Risinger April L. 
Published: August 2019

Abstract
Microtubule stabilizing taxanes are highly effective in the treatment of solid tumors and continue to be used as single agents and in combination with targeted therapies and immunotherapies. However, limitations of taxane therapy include acquired and inherent drug resistance. The taccalonolides are a novel class of microtubule stabilizers that circumvent clinically relevant forms of drug resistance to the taxanes in vitro and in vivo. The taccalonolides are efficacious in taxane-resistant models due to their distinct mechanism of microtubule stabilization that involves covalent binding to β-tubulin. Pharmacological studies of the taccalonolides have been complicated by their irreversible binding to tubulin. A functional tagged taccalonolide would facilitate a greater understanding of the pharmacological, cellular, and physiological effects of this novel drug class. We have generated and characterized a series of fluorescently tagged taccalonolides that retain microtubule binding and stabilizing activities to serve as functional pharmacological taccalonolide probes. Biochemical tubulin polymerization, live cell fluorescence, immunofluorescence imaging, and the sulforhodamine B cytotoxicity assay were conducted to evaluate the microtubule binding and stabilizing effects of these taccalonolide probes. We identified stable taccalonolide probes that retain the biological activities of untagged taccalonolides and facilitate their detection in live cells and in cell lysates. The rates of taccalonolide uptake and tubulin binding in cells, tumors, and normal tissues were determined. These studies have also allowed for an evaluation of the anatomical distribution of the taccalonolides in vivo, which can inform on their potential for antitumor efficacy in distinct tumor sites. Furthermore, we have generated a cellular model to evaluate the kinetics of taccalonolide binding to β-tubulin mutants that are predicted to influence drug binding based on the crystal structure. These studies have confirmed the covalent interaction between the taccalonolides and D224 on β-tubulin and informed on other residues critical for drug binding. The generation of a functional tagged taccalonolide will continue to be a valuable tool in evaluating the pharmacokinetics of these agents and inform on drug targeting strategies that will facilitate their clinical development.
Citation Format: Samantha S. Yee, Lin Du, April L. Risinger. Elucidating the pharmacological effects of covalent microtubule stabilizing taccalonolides through functional tagging [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 2764A.
Abstract 2769: A squalene epoxidase-cholesterolaxis drives colorectal cancer progression and metastatic dissemination
Authors: Jun Soo Young , Brown Andrew J. , Yoon Ji-Yong , Lee Jeong-Ju , Chua Ngee Kiat , Yang Jin OK , Min Ju-Sik , Jang Insu , Jeon Su-Jin , Choi Min-Hyuk , Choi Tae-Ik , Kim Cheol-Hee , Kim Nam-Soon 
Published: August 2019

Abstract
Links between cholesterol and cancer are well-documented, but the mechanisms remain unclear. Squalene epoxidase (SQLE), a key enzyme in cholesterol biosynthesis degraded by excess cholesterol, is suggested as a proto-oncogene. Paradoxically, we found reduced SQLE in aggressive colorectal cancer (CRC); low SQLE being associated with a shortened survival of CRC patients. This was confirmed in a spontaneous CRC metastasis mouse model where SL-15 reduction, by either a high-cholesterol regimen or genetic knockdown, strikingly promotes CRC aggressiveness through the production of migratory cancer stem cells. Experiments in CRC cell-lines demonstrated that SQLE reduction helps overcome constraints for malignant transformation. Specifically, we uncovered a surprising interaction of SQLE with GSK3β and p53. Depletion of SQLE disrupted the GSK3β/p53 complex, resulting in a metastatic phenotype. Our findings provide mechanistic insights into the link between cholesterol and CRC, identifying SQLE as a key regulator in CRC progression and potentially a biomarker for risk assessment.
Citation Format: Soo Young Jun, Andrew J. Brown, Ji-Yong Yoon, Jeong-Ju Lee, Ngee Kiat Chua, Jin OK Yang, Ju-Sik Min, Insu Jang, Su-Jin Jeon, Min-Hyuk Choi, Tae-Ik Choi, Cheol-Hee Kim, Nam-Soon Kim. A squalene epoxidase-cholesterolaxis drives colorectal cancer progression and metastatic dissemination [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 2769.
Abstract 2776: Mitochondrial calcium uniporter in pancreatic cancer metastasis and metabolic stress resistance
Authors: Wang Xiuchao , Lin Shengchen , Sun Jianwei , Kang Jiaxin , Hao Jihui , Yang Shengyu 
Published: August 2019

Abstract
Despite recent advances in cancer diagnosis and therapeutic modalities, the prognosis for pancreatic ductal carcinoma (PDAC) remains very poor. Most PDAC patients succumb to local and distant metastasis soon after the initial diagnosis. Therefore understanding molecular mechanisms underlying PDAC metastasis is crucial to the development of more effective PDAC therapies. Here we examined the role of mitochondrial calcium uniporter (MCU), a mitochondrial inner membrane calcium channel responsible for mitochondrial Ca2+ uptake, in pancreatic cancer metastasis and progression. We discovered that MCU is overexpressed in PDAC when compared to adjacent pancreatic tissues. MCU overexpression in PDAC patients is significantly associated with PDAC lymph node metastasis, histologic grade and pTNM stage. We also found that higher levels of MCU in PDAC patients was associated with worse overall survival (OS, P&lt;0.01) and relapse-free survival (RFS, P&lt;0.05) after surgical resection of tumors. MCU knockdown inhibits the PDAC cell motility, invasiveness, metabolic stress resistance and chemoresistance in cell culture models and PDAC metastasis in an orthotopic xenograft mouse model. Mechanistically, MCU controls the activation of the Keap1-Nrf2 signaling pathway through promoting mitochondrial ROS production and the oxidation of mitochondrion-recruited Keap1. Our data support that MCU regulates cancer cell metabolic stress resistance and oxidative stress response to drive PDAC metastasis and progression. Inhibiting MCU expression or blocking mitochondrial calcium influx may be an attractive approach for treating metastatic PDAC.
Citation Format: Xiuchao Wang, Shengchen Lin, Jianwei Sun, Jiaxin Kang, Jihui Hao, Shengyu Yang. Mitochondrial calcium uniporter in pancreatic cancer metastasis and metabolic stress resistance [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 2776.
Abstract 2802: In situ detection of PD-1+CXCL13+CD8+ T cells in non-small cell lung cancer
Authors: Li Na , Zhang Bingqing , Jhaveri Niyati , Zhang Zhifu , Wang Xin , Sun Hongzhe , Zhou Ying , Anderson Courtney , Ma Xiao-Jun 
Published: August 2019

Abstract
Recent reports identified one subset of intratumoral CD8+ cytotoxic T lymphocytes (CTLs) in non-small cell lung cancer (NSCLC) that are PD-1high with distinct molecular and functional properties. Strikingly, these cells produce very high levels of CXCL13 mRNA and protein, which may mediate immune recruitment. Furthermore, the presence of PD-1high CD8+ T lymphocytes are strongly predictive for both response and survival in NSCLC patients treated with PD-1 blockade. Thus, it is of great value to develop a practical biomarker assay to specifically detect these cells in formalin-fixed paraffin-embedded (FFPE) tumor biopsies. In this study, we combined the highly sensitive and specific RNAscope multiplex fluorescent RNA in situ hybridization (ISH) assay detecting CXCL13 and PDCD1 mRNAs with immunohistochemistry (IHC) detecting CD8 protein in a single tissue section to directly visualize PD-1+CXCL13+CD8+ T lymphocytes in NSCLC tissues. Two NSCLC tissue microarrays (TMAs) consisting of 63 independent patient FFPE samples were stained with full automation using the Leica BOND RX instrument. The resulting slides were scanned, and the images were analyzed using the Perkin Elmer Phenochart software. 57 of the 63 TMA cores were available for image analysis. Each tissue core was first examined under 4X magnification, then snapshot images of three independent 40X fields with enriched CD8+ cells (if present) were taken. CD8+ cells, CXCL13+ cells, and PD-1+ cells in each snapshot were counted. Every snapshot contained both stromal and tumor regions. 43 samples contained high (&gt;20) CD8+ CTLs whereas 14 samples contained low (≤20) CD8+ CTLs across the three snapshots. Interestingly, PD-1+CXCL13+CD8+ cells were detected in both high and low CTL tumors. Five of 57 tumors carried high percentages of PD-1+CXCL13+CD8+ cells (&gt;10% of CD8+ CTLs), with three from high CTL tumors and two from low CTL tumors. These results demonstrate that this fully automated multiplexed RNAscope dual ISH/IHC assay allows for co-localization of RNA and protein biomarkers in single cells with morphological context. The ability to detect RNA and protein in a single slide-based assay enables immune profiling applications to include biomarkers such as secreted proteins and non-coding RNAs that are difficult or impossible to detect by IHC.
Citation Format: Na Li, Bingqing Zhang, Niyati Jhaveri, Zhifu Zhang, Xin Wang, Hongzhe Sun, Ying Zhou, Courtney Anderson, Xiao-Jun Ma. In situ detection of PD-1+CXCL13+CD8+ T cells in non-small cell lung cancer [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 2802.
Abstract 2804: Metabolic-immunoregulatory role of CCRK-mTOR signaling in NAFLD-associated hepatocellular carcinoma
Authors: TANG Wenshu , ZHOU Jingying , YANG Weiqin , FENG Yu , MOK Myth , CHENG Alfred Sze 
Published: August 2019

Abstract
Obesity increases the risks of steatosis, non-alcoholic steatohepatitis (NASH) and HCC development. Non-alcoholic fatty liver disease (NAFLD) associated-hepatocellular carcinoma (HCC) is a male-predominant cancer mainly caused by metabolic disorder. Our previous findings demonstrated that cell cycle-related kinase (CCRK), through upregulates mTORC1 pathway, resulting in deregulated lipid/glucose metabolism and tumorigenesis (Nat Communs accepted). In this study, we further elucidate that CCRK activates mTORC1 through SLC3A2 and SLC7A5 dependent amino acid transportation. We performed comprehensive immune cell profiling in a high-fat high-carbohydrate diet (HFHC)-induced obesity and NASH murine model and uncovered activation of CCRK-mTORC1 signaling cascade and specific induction of myeloid-derived suppressor cell (MDSC), reduction in CD8+ T cells, which subsequently enhanced tumor growth of orthotopically-implanted HCC tumor cells. Notably, treatment of the mTORC1/C2 dual kinase inhibitor vistusertib (AZD2014), currently undergone phase I/II clinical trials, abrogated mTORC1/SREBP2 signaling and metabolic dysregulation especially cholesterol levels. Further immune profiling in liver and blood of AZD2014 treated mice will be performed. Furthermore, mTORC1/SREBP2 positively associated with cholesterol level in the streptozotocin (STZ)-HFHC induced spontaneous NAFLD-HCC mouse model, which will be utilized to further study the therapeutic effect of vistusertib in vivo. Collectively, this study will elucidate the metabolic-immunosuppressive role of CCRK-mTOR signaling in NAFLD-associated HCC and further provide insights into development of therapeutic strategies against the CCRK-mTOR reinforced NAFLD-HCC. This project is supported by Collaborative Research Fund C4017-14G and the Focused Innovations Scheme 1907309.
Citation Format: Wenshu TANG, Jingying ZHOU, Weiqin YANG, Yu FENG, Myth MOK, Alfred Sze CHENG. Metabolic-immunoregulatory role of CCRK-mTOR signaling in NAFLD-associated hepatocellular 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 2804.
Abstract 2805: DFMO and 5-azacytidine increase M1 macrophages in the tumor microenvironment of an ovarian cancer mouse model
Authors: Travers Meghan , Brown Stephen , Dunworth Matthew , Holbert Cassandra , Casero Robert , Zahnow Cynthia 
Published: August 2019

Abstract
Although ovarian cancer has a low incidence rate encompassing roughly 1% of all new cancers, it remains the most deadly gynecologic malignancy. Our lab has designed a novel combination therapy which combines a DNA methyl transferase inhibitor (DNMTi) and ornithine decarboxylase inhibitor that together, alter the tumor microenvironment to inhibit ovarian tumor growth. Previous work has demonstrated that the DNMTi 5-Azacytidine (AZA) activates type I interferon signaling (Li, 2014, Chiappinelli, 2015) to increase IFNγ+ T cells and NK cells and reduce the percentage of macrophages and myeloid derived suppressor cells (MDSCs) in the tumor microenvironment (Stone, 2017). To improve the efficacy of epigenetic therapy, we hypothesized that the addition of α-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor may decrease activity of MDSCs through inhibition of arginase. Immunocompetent C57Bl/6 mice were injected with syngeneic mouse ovarian surface epithelial (MOSE) tumor cells (ID8-VEGF-Defensin) and subsequently treated with AZA, DFMO, or combination AZA+DFMO. After several weeks, mice developed hemorrhagic ascites that was drained, processed and stained for cell-surface markers and analyzed by flow cytometry to identify T cells, NK cells, and macrophages. We found that in vivo AZA, DFMO, and AZA+DFMO significantly increased survival in mice, decreased tumor burden, and caused recruitment of activated (IFNγ+) CD4+ T cells, CD8+ T cells, and NK Cells compared to vehicle. The combination therapy had a striking increase in survival when compared to single agent treatment; however, the difference in recruited lymphocytes was less striking. Instead, combination therapy led to the most dramatic decrease in immunosuppressive cells such as M2 polarized macrophages and increase in tumor-killing M1 macrophages. Using a CSF1R blocking antibody, we found that depleting macrophages in this model reduced the efficacy of AZA+DFMO treatment, and resulted in fewer M1 macrophages in the tumor microenvironment. We thus conclude that our novel combination therapy modifies macrophage polarization in the tumor microenvironment, recruiting M1 macrophages and prolonging survival. We hypothesize that this treatment regimen could have a widespread impact on macrophage-rich tumors in general, and plan to test this hypothesis in additional tumor models.
Citation Format: Meghan Travers, Stephen Brown, Matthew Dunworth, Cassandra Holbert, Robert Casero, Cynthia Zahnow. DFMO and 5-azacytidine increase M1 macrophages in the tumor microenvironment of an ovarian cancer mouse model [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 2805.