tbuckley/cabot-search huggingface dataset:
Abstract SY22-02: Metabolic vulnerability of PTEN mutant cancer
Authors: Ramon E. Parsons
Journal: Cancer Research (2018)

Abstract Signaling pathways that act as drivers of cancer cell growth and proliferation activate metabolic pathways required to generate the building blocks required for cell doubling. Loss of PTEN activates PI3K, AKT and mTOR to stimulate glucose and glutamine flux to allow DNA replication. One of the metabolic pathways that is activated after deletion of both alleles of PTEN is the de novo pyrimidine synthesis pathway. PTEN null cells show evidence of increased DNA replication and low levels of damage at replication forks that can be rescued by providing supplementary uridine. Interruption of de novo pyrimidine synthesis with an inhibitor of dihydroorotate dehydrogenase (DHODH) increased DNA damage at replication forks of PTEN null cells that ultimately led to chromosome breaks detected in mitosis and cell death. This cellular vulnerability to inhibition of DHODH was rescued with uridine, demonstrating the specificity of the effect. Exploration of the mechanism that led to vulnerability of PTEN null cells demonstrated that it was due to defective ATR signaling at replication forks that was a consequence of activated AKT, which phosphorylate and attenuate TOPBP1 and CHK1. Complementation of PTEN null cells with mutants of TOPBP1 and CHK1 that cannot be phosphorylated by AKT rescued the cells from DNA damage and cell death due to inhibition of DHODH. Tumor cell lines lacking PTEN tended to be more sensitive to DHODH inhibition than PTEN wild type cells were. In conclusion, the attenuated ATR signaling and increased flux of nucleotides to newly synthesized DNA at replication forks makes PTEN mutant cells vulnerable to disruption of de novo pyrimidine synthesis. Citation Format: Ramon E. Parsons. Metabolic vulnerability of PTEN mutant 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 SY22-02.
Abstract 5508: ANKRD52 inhibited tumor metastasis in lung adenocarcinoma
Authors: Ting-Fang Lee, Yen-Fan Lin, Ying-Pu Liu, Cheng-Wen Wu
Journal: Cancer Research (2018)

Abstract Cancer metastasis is an ultimate challenge in our effort to fight cancer as a life-threatening disease. A member of ankyrin repeat proteins, ankyrin repeat domain 52 (ANKRD52), is studied here to be involved in the regulation of lung adenocarcinoma metastasis. Ankyrin repeat proteins are known to function as a platform for protein-protein interactions, and ANKRD52 was shown to interact with protein phosphatase 6 (PP6). Immunohistochemistry staining in lung adenocarcinomas tissues revealed low ANKRD52 expressing in stage-IV patients compared to those in stages I to III. Overexpressed ANKRD52 prevented lung cancer formation in the xenograft model. Using lung cancer cell lines, ANKRD52 knockdowns showed significantly increased cell mobility while forced expression decreased cell mobility. Using mass spectrometry analysis, p21-activated kinases (PAK1) was identified to interact with ANKRD52. The regulation of PAK1 phosphorylation by the ANKRD52-PP6 complex is essential to cell mobility. Our model demonstrated a novel anti-metastatic protein, ANKRD52, that regulates cell mobility through interacting with PP6 leading to PAK1 dephosphorylation. Citation Format: Ting-Fang Lee, Yen-Fan Lin, Ying-Pu Liu, Cheng-Wen Wu. ANKRD52 inhibited tumor metastasis in lung adenocarcinoma [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 5508.
Abstract 1298: Mapping the comprehensive landscape of missense-mutation neoantigens across the human genome
Authors: HoJoon Lee, Stephanie U. Greer, Hanlee P. Ji
Journal: Cancer Research (2018)

Abstract Specific somatic mutations in cancer genomes result in amino acid alterations and derivative novel immunogenic peptides called neoantigens. The MHC molecule mediates the immunologic presentation of these cancer mutation-derived peptides. Based on a limited number of polymorphisms, the configuration of the MHC molecule is one of the major factors in determining whether mutated peptides can elicit immune response or not. To provide insight in the full diversity of potential neoantigens across the entire human genome, we identified all possible amino acid substitutions and estimated their potential binding affinities to the 86 MHC genotypes. As a first step, we evaluated every possible nucleotide changes at every single position using exons and related alternative transcripts as defined by the Consensus Coding Sequence (CCDS) resource. We evaluated 159 million (M) possible nucleotide changes among ~31,000 autosomal transcripts from ~ 19,000 genes. Overall, this comprised a genome sequence “space” of 53 M nucleotides. Among this coding regions space, we evaluated 123 M candidate nonsynonmous mutations. Among these mutations, we identified short mutated peptides of nine amino acids in length across this mutation space. We estimated the binding affinity of all mutated peptides across 86 MHG polymorphisms. Based on the predicted binding affinity, 0.6% ~ 1.0 % were found to be potential strong binders to the one of MHC molecules while 1.7% ~ 2.5% of them are weak binder to the one of MHC molecules. HLA-A0201 had the high number of potential candidate neoantigens. The KRAS cancer had candidate epitopes that binds to &amp;gt;50 different MHC molecules include KRAS D12V, which is very hot spot, that make epitopes that binds to 30 MHC molecules. In addition, we mapped the frequencies of missense mutations observed in TCGA and COSMIC to these candidate neoantigens. For releasing the results of our study, we are developing the “Immunogenomic Explorer” available at http://genomeportal.stanford.edu/immune. This portal enables users to explore the potential immunogenic epitopes from genes of their interest such as KRAS. Users can search by HLA genotypes as well. This web interface allows researchers to address important questions regarding their immunotherapy or cancer vaccine. Citation Format: HoJoon Lee, Stephanie U. Greer, Hanlee P. Ji. Mapping the comprehensive landscape of missense-mutation neoantigens across the human genome [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 1298.
Abstract 17519: Distinct Impacts of Sleep-disordered Breathing on Glycemic Variability in Patients With and Without Heart Failure
Authors: Kei Nakata, Takayuki Miki, Masaya Tanno, Toshiyuki Yano, Atsuko Muranaka, Atsushi Kuno, Wataru Ohwada, Masashi Mizuno, Yuki Tatekoshi, Tetsuji Miura
Journal: Circulation (2016)

Introduction: Sleep-disordered breathing (SDB) is highly prevalent in patients with heart failure (HF) and diabetes mellitus (DM) and contributes to poor cardiovascular outcomes. Elevated glycemic ...
Abstract 5214: Tumor cell-derived complement components C1r and C1s promote growth of cutaneous squamous cell carcinoma
Authors: Pilvi Riihilä, Liisa Nissinen, Mehdi Farshchian, Markku Kallajoki, Atte Kivisaari, Seppo Meri, Reidar Grénman, Sirkku Peltonen, Juha Peltonen, Veli-Matti Kähäri
Journal: Cancer Research (2018)

Abstract The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing worldwide. We have analyzed the role of complement components C1r and C1s in the progression of cSCC. Analysis of cSCC cell lines (n=8) and normal human epidermal keratinocytes (NHEK)(n=11) with oligonucleotide arrays, RNA-seq and quantitative RT-PCR revealed significantly elevated C1r and C1s mRNA levels in cSCC cell lines. Western blot analysis showed increased production of C1r and C1s in cSCC cells compared to NHEKs. The mRNA levels for C1r and C1s were markedly elevated in cSCC tumors (n=6) compared to normal skin (n=11) in vivo. Immunohistochemical analysis for C1r and C1s revealed strong tumor cell specific expression of C1r and C1s in invasive sporadic cSCCs (n=164) and recessive dystrophic epidermolysis bullosa-associated cSCCs (n=16), whereas the expression of both was clearly lower in cSCC in situ (n=63), in premalignant epidermal lesions (actinic keratoses, n=61), and in normal skin (n=9). Knockdown of C1r and C1s expression with two specific siRNAs inhibited proliferation of cSCC cells and growth of human cSCC xenograft tumors in vivo. These results provide evidence for the role of tumor cell-derived C1r and C1s in the progression of cSCC independently of C1q and identify these serine proteinases as putative therapeutic targets in unresectable and metastatic cSCC. Citation Format: Pilvi Riihilä, Liisa Nissinen, Mehdi Farshchian, Markku Kallajoki, Atte Kivisaari, Seppo Meri, Reidar Grénman, Sirkku Peltonen, Juha Peltonen, Veli-Matti Kähäri. Tumor cell-derived complement components C1r and C1s promote growth of cutaneous squamous cell carcinoma [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 5214.
Abstract LB-043: Generation of clonal CRISPR/Cas9-edited human iPSC derived cellular models and its applications in physiologically relevant assays
Authors: Chetana M. Revankar, Erik Willems, Rex Lacambacal, Tufan gokirmak, Jordan Dizon, Jacquelyn Webb, Raquel Vega, David Piper
Journal: Cancer Research (2018)

Abstract Induced pluripotent stem cell (iPSC)-derived cells are widely used in disease models, safety testing and phenotypic and functional assays. The CRISPR/Cas9 system has revolutionized genome editing thus enabling rapid generation of disease models. Cutting edge technologies like genome editing paired with iPSC-derived cell models have reshaped our approach to disease modeling in vitro. Although, CRISPR/Cas9 has had huge impact on generation of complex cellular models, there are challenges in replicating disease-in-a-dish. One of the challenges is the implementation of genome editing tools in iPSC, particularly issues associated with editing tools delivery, cell recovery and clonal isolation of genome-edited cells. Here, we describe a workflow that facilitates the generation and isolation of clonal CRISPR-edited iPSCs through the use of a novel toolset. We observed high genome editing efficiency using an iPSC line that stably expresses the Cas9 protein and obtained improved survival of the iPSCs after delivery of the editing tools through culture in StemFlex™ medium, a novel PSC culture system. Furthermore, we have demonstrated that single edited iPSCs can be isolated through the combination of an optimized cell sorting method and expanded as single cell clones with reagents that support single cell survival. Through this workflow we have generated several iPSC lines carrying disease relevant SNP mutations. These tools and workflows not only contribute to improved success in the derivation of homogenous genome edited human iPSC clones but also provide novel alternatives to study disease-causing mutations in vitro. Additionally, we have also tested these cell models in commonly used cell health assays. These cell models can be further used to generate organoids to mimic conditions found in tissues. iPSC- derived cell models not only permit the study of disease mechanism in the cell types specifically affected in the disease but also deepen our understanding of the molecular mechanisms and in turn help development of novel therapeutics. Citation Format: Chetana M. Revankar, Erik Willems, Rex Lacambacal, Tufan gokirmak, Jordan Dizon, Jacquelyn Webb, Raquel Vega, David Piper. Generation of clonal CRISPR/Cas9-edited human iPSC derived cellular models and its applications in physiologically relevant assays [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 LB-043.
Abstract 4665: Neurotensin receptor-based targeted delivery of thymoquinone for non-small cell lung cancer
Authors: Santosh Kumar Singh, James W. Lillard, Rajesh Singh
Journal: Cancer Research (2018)

Abstract Non-small cell lung cancer (NSCLC) is a very recalcitrant cancer, accounting for 80% to 85% of all lung cancer diagnoses. About 40% of NSCLC are adenocarcinomas. Thus, there is an urgent need to identify targeted therapies, specifically for NSCLC. Although, multiple signaling molecules have now been identified within the last decade, among them Neurotensin receptor 1 (NTSR1) have afforded an improved understanding of the underlying pathology and significant heterogeneity of NSCLC. NTSR1 belongs to the G-protein coupled receptors (GPCR) superfamily that has been shown numerous oncogenic effects in tumor initiation, progression, proliferation, apoptosis, and metastasis. In the present study, we used a novel method for targeted delivery of Thymoquinone (TQ), a constituent of Nigella sativa at the desired location. We described a proprietary planetary ball milling (PBM) approach that uses a natural polysaccharide (starch; FDA approved) to create a drug-polysaccharide nanoparticle as a core that is subsequently coated with poly (ϵ-caprolactone) / poly (ethylene glycol) copolymer and conjugated with anti-NTSR1-mAb, which allows binding to high-affinity NTSR1 receptors presents on NSCLC. Our tissue microarray data show higher expression of NTSR1 in lung cancer patients, which were negligible in normal cells. These studies were further confirmed by targeting NTSR1 in lung cancer cell lines NCI-H1563, NCI-H1975 and MRC-5 using our novel anti-NTSR1 conjugated, and TQ encapsulated PBM nanoparticle and further, validated using flow cytometry, immunofluorescence, qRT-PCR and western blot techniques. Our result showed the PBM nanoparticles encapsulated with TQ rapidly internalized and depolymerized the microtubule network by inducing apoptosis. The up-regulation of pro-apoptotic (BAX, BID) and down-regulation of anti-apoptotic (BCL-2, MCL-1) makers to confirm the targeted delivery of PBM-NPs to the tumor cells. This study strongly suggests anti-NTSR1-mAb conjugated PBM-NPs has its application to drugs targeting for the treatment of NSCLC. In summary, this study combines innovative ideas with an innovative technology to create new therapeutics and a new strategy to improve the treatment of NSCLC and has the potential to create a new class of targeted treatments for advanced lung cancer. Citation Format: Santosh Kumar Singh, James W. Lillard, Rajesh Singh. Neurotensin receptor-based targeted delivery of thymoquinone for non-small cell lung 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 4665.
Abstract 2658: Molecular characterization of renal cell carcinoma: A potential three microRNA prognostic signature
Authors: Soum D. Lokeshwar, Andre R. Jordan, Sarrah S. Lahorewala, Vinata B. Lokeshwar
Journal: Cancer Research (2018)

Abstract Introduction and Objective: With 10% survival at 5-years, metastatic disease presents poor prognosis for renal cell carcinoma (RCC) patients. Prognosis can be improved if biomarkers that predict disease outcome are identified and validated. Aberrantly expressed microRNAs (miRs) promote (RCC) growth and metastasis and are potentially useful biomarkers for metastatic disease. However, consensus of a clinically significant miRNA signature has not been established. The objective of this study was to identify a miRNA signature for predicting clinical outcome in RCC patients using a four-pronged interconnected discovery and validation approach. Methods: Differentially expressed miRs were identified and analyzed in 113 specimens (Normal kidney: 59; tumor: 54). In the discovery phase, miRNA-profiling was initially performed in matched normal and tumor specimens from 8 patients, followed by validation in 16 additional specimens. Seven miRs that were significantly aberrantly expressed in miRs in both discovery phases were analyzed by qPCR and their levels were correlated with RCC subtypes and clinical outcome. miRNA signature was confirmed in a TCGA dataset of 241 RCC specimens. Results: Discovery phase identified miR-21, miR-142-3p, miR-142-5p, miR-150 and miR-155 as significantly upregulated (2-4-fold) and miR-192, miR-194 as downregulated (3-60-fold) in RCC; miR-155 distinguished small tumors (&amp;lt; 4 cm) from benign oncocytomas. miR-142-5p levels were significantly up-regulated in patients with lymph node positive disease and metastasis (P=0.0002). A 3-miR combination, miR-21+142-5p+194 significantly but negatively correlated with metastasis (P=0.0017; OR: 0.53) and disease-specific mortality (P=0.018; OR: 0.37). The signature had high sensitivity (86.7 - 93.3%) and specificity (82 - 87%) to predict metastasis and disease-specific mortality. In the TCGA dataset, the 3-miR signature significantly and negatively associated with metastasis (P=0.019; OR: 0.54) and overall survival (P=0.0919; OR: 0.37). Conclusion: The interconnected discovery-validation approach identified a novel signature of 3 aberrantly expressed miRs as a potential prognostic indicator for disease outcome among RCC patients. Early detection of metastasis using the validated qPCR assay for the 3-miR signature may allow early intervention for improving patient prognosis. Citation Format: Soum D. Lokeshwar, Andre R. Jordan, Sarrah S. Lahorewala, Vinata B. Lokeshwar. Molecular characterization of renal cell carcinoma: A potential three microRNA prognostic signature [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 2658.
Abstract 1945: Degradation of ERG transcription factor as a targeted therapy in B-cell and T-cell acute lymphoblastic leukemia
Authors: Xiaoju Wang, Caleb Cheng, Yuanyuan Qiao, Lanbo Xiao, Cynthia Wang, Abhijit Parolia, Arul Chinnaiyan
Journal: Cancer Research (2018)

Abstract Acute lymphoblastic leukemia (ALL) occurs in children and adults and is one of the most common forms of pediatric cancer. The ideal individualized therapy for B- and T-cell ALL heavily depends on the present molecular drivers. However, even with the success of ALL therapy, only a few strategies target disease-specific molecular lesions. Philadelphia chromosome positive (Ph+) ALL, which harbors the BCR:ABL1 rearrangement, are sensitive to tailored inhibitors. Unfortunately, most ALL cases in both children (97-98%) and adults (70-80%) are Ph-; therefore, agents designed to directly target other molecular lesions are urgently needed. ERG, an ETS-family transcription factor, plays a key role in hematopoietic differentiation, megakaryopoiesis, and megakaryoblastic leukemia associated with Down syndrome. ERG overexpression is predictive of a poor prognosis in acute myeloid leukemia and T-ALL. Transgenic expression of ERG causes T-ALL in mice and knockdown of ERG reduces human T-ALL cell proliferation. We have previously identified a consensus peptide (EIPs) that specifically binds to and leads to the proteosomal degradation of the ERG protein in prostate cancers having the TMPRSS2:ERG gene fusion. Here, we demonstrated that wild type ERG was overexpressed at the mRNA and protein levels in a subset of B- and T-cell ALLs, but not in precursor CD4+, CD8+, or CD19+ cells. Pull-down assay found that streptavidin-linked beads were enriched for ERG proteins. Treatment of EIPs induced proteolytic degradation of ERG protein in Hal-01 cells, and therefore selectively inhibited ERG-driven cell growth and proliferation. More importantly, structure-based optimization created the next generation of ERG degraders (EIPv2). EIPv2 treatment significantly decreased ERG protein in Hal-01 cells starting from 3 hrs and nearly depleted ERG proteins at 48 hrs, resulting in 10-fold more potency than EIPs (IC50=2.3µM vs 25.7µM for EIPv2 and EIPs, respectively). Together, our results validate the development of peptidomimetics for ERG depletion as a targeted therapy for ALL. Unlike small-molecule antagonists, which require continuous dosing that eventually induces drug resistance, most protein degraders have relatively higher and longer pharmacological effects without requiring continuous exposure to high doses. Such an approach can abolish the presence of an oncoprotein, which, in theory, can overcome resistance to target inhibitors. Citation Format: Xiaoju Wang, Caleb Cheng, Yuanyuan Qiao, Lanbo Xiao, Cynthia Wang, Abhijit Parolia, Arul Chinnaiyan. Degradation of ERG transcription factor as a targeted therapy in B-cell and T-cell acute lymphoblastic leukemia [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 1945.
Abstract 1454: Glutamate dehydrogenase 1 mediates metabolic reprogramming and promotes tumor metastasis through CamKK2-AMPK signaling in LKB1-deficient lung cancer
Authors: Sumin Kang, Lingtao Jin, Chaoyun Pan, Jaemoo Chun
Journal: Cancer Research (2018)

Abstract Although elevated glutaminolysis has been demonstrated in cancer cells, the precise mechanism by which glutaminolysis is exploited to promote tumor metastasis has not been elucidated. Lung cancer frequently metastasizes and is the leading cause of cancer-related death worldwide. Loss of LKB1 is associated with increased metastasis and poor prognosis in lung cancer, but the development of targeted agents in LKB1-deficient lung cancer is still in its infancy. Our recent study reveal that glutamate dehydrogenase 1, upregulated upon detachment via the transcription factor pleomorphic adenoma gene 1 (PLAG1), provides anti-anoikis and pro-metastatic signals in LKB1-deficient lung cancer. Mechanistically, the GDH1 product alpha-KG activates CamKK2 by enhancing its substrate AMPK binding and triggers CamKK2-mediated AMPK signaling, which contributes to energy production that confers anoikis resistance. The effect of GDH1 on AMPK is evident in LKB1-deficient lung cancer, where AMPK activation predominantly depends on CamKK2. Targeting GDH1 with the small molecule GDH1 inhibitor R162 led to attenuated anoikis resistance and tumor metastasis in an LKB1-deficient lung patient-derived xenograft model. Correlation studies between GDH1 signaling and metastatic cancer progression in lung cancer patients further validated the clinical relevance of our finding. Our study provides insight into the molecular mechanism by which GDH1-mediated metabolic reprogramming of glutaminolysis mediates lung cancer metastasis. This knowledge could be leveraged for the development of effective therapeutic strategies for patients with LKB1-deficient lung cancer. Citation Format: Sumin Kang, Lingtao Jin, Chaoyun Pan, Jaemoo Chun. Glutamate dehydrogenase 1 mediates metabolic reprogramming and promotes tumor metastasis through CamKK2-AMPK signaling in LKB1-deficient lung 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 1454.