bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4623: Notch3 in lung adenocarcinoma pathogenesis and heterogeneity
Authors: Marini Kieren D. , Leung Stanley , Lee Alex , Sweet-Cordero Alejandro 
Published: August 2019

Abstract
Lung cancer is the leading cause of cancer related death worldwide. Non-small lung cancer accounts for 85% of diagnoses and the predominant subtype is lung adenocarcinoma (LUAD). LUAD has a less than 20% response rate to conventional chemotherapy and despite identification of several therapeutic targets, the majority of diagnoses continue to lead to death, highlighting the need for better treatments. Notch signaling in mammals is complex, with multiple receptors, ligands and modifiers. Notch ligands at the surface of one cell interact with receptors on an adjacent cell, triggering cleavage and nuclear translocation of the intracellular domain which interacts with Rbpj/Csl to control the transcription of target genes. In LUAD, significant evidence suggests that Notch plays an oncogenic role.
Previously, we identified a population of Tumor Propagating Cells (TPC), which had greater capacity for tumor formation and are enriched after treatment with cisplatin. The TPC population was defined by the expression of CD24, ITGB4 and was Notch high. Further functional validation showed that specifically Notch3 contributes to this propagation phenotype and is key in establishing functional intra-tumoral heterogeneity. However, the TPC population is still heterogeneous and likely only a subset of these cells are true TPCs. Furthermore, the gene expression signature of the mouse TPCs has prognostic significance in human LUAD, however the TPC population hasn’t been defined in human patients, limiting our ability to target the Notch pathway therapeutically.
To assess the heterogeneity of the mouse TPC population we performed FACS on tumors from KrasLSLG12D; Tp53flox/flox; YFPLSL twelve weeks after tumor initiation via AdCre. Tumors were sorted for bulk population (YFP+Lin-) and for TPC (YFP+Lin-CD24+ITGB4+Notchhi) population and single cell sequencing was performed using the 10X genomics platform. We hypothesize that aberrant Notch3 signaling is a critical pathway for survival in at least some LUAD and that Notch activation leads to gene expression changes that are important for driving human LUAD maintenance. Patient-derived xenografts (PDX) more closely recapitulate important aspects of human cancer, particularly with regards to the role of intratumoral heterogeneity and self-renewal pathways. To characterize Notch3 expressing cells in human LUAD, we performed FACS on our cohort of LUAD PDXs and sorted the Notch3+ population. We found expression of Notch3 and expression of Notch ligand Jagged2 in all LUAD tumors regardless of driver mutation.
Citation Format: Kieren D. Marini, Stanley Leung, Alex Lee, Alejandro Sweet-Cordero. Notch3 in lung adenocarcinoma pathogenesis and heterogeneity [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 4623.
Abstract 4626: Use of integrated genomic analyses in patient-derived tumor model to discover new clinical indications for the multikinase inhibitor drug candidate, DBPR216
Authors: Kuo Ching-Chuan , Jiaang Weir-Torn , Ou Jing-Jim , Chen Chiung-Tong , Hsu Shu-Ching , Shih Chuan , Lin Li-Mei , Sun Manwu , Wang Yi-Hsin , Huang Zih-Ting , Chang Jang-Yang , Ueng Shau-Hua 
Published: August 2019

Abstract
Developing realistic preclinical models using clinical samples that reflect complex tumor biology is critical to advancing cancer research. Patient-derived preclinical tumor models are the optimal tool for understanding drug action patterns and resistance mechanisms. In order to improve the capability of drug R&D in our institute (NHRI-IBPR), we have generated several patient-derived xenograft (PDX) models and characterized the genomic signature and responsiveness to standard-of-care (SOC) therapy. DBPR216, an orally bioavailable multikinase inhibitor, showed potent effect for treatment of gastrointestinal stromal tumors (GISTs) and acute myeloid leukemia (AML) through targeting of c-KIT and FLT-3, respectively. In order to further discover other indications of DBPR216 for clinical application, we investigated the anti-tumor effect of DBPR216 in several in-house PDX models. Among them, we found that DBPR216 was effectively to suppress PDX tumor growth in the immuno-deficient mice in two colorectal adenocarcinoma PDX models, C008 and C015. These PDX models showed similar genomic features with original tumor samples from patients when test using targeted sequencing of cancer related genes. To further identify if DBPR216 is superior to other kinase inhibitors and SOC therapy, we used in vitro PDX cell proliferation assay to quickly examine the anti-tumor effect of DBPR216 compared to a panel of therapeutic drugs. The result demonstrated that DBPR216 appeared to be superior in potency to kinase inhibitors (Regorafenib, Afatinib, Sunitinib, and Imatinib) and SOC therapy (Irinotecan, 5-FU, and Oxaliplatin). Combining the kinase profiling of DBPR216 and mutational analysis of C008 and C015 PDX models, we proposed that DDR2, FLT1, PDGFRα, PDGFRβ, RET, and SRC may be the potential targets of DBPR216 in these PDX models, and need further elucidation. Taken together, we found that DBPR216 exhibits potent anticancer effect against colorectal cancer and may bring the better opportunity than Regorafenib, a therapeutic agent for metastatic colorectal cancer in clinical. DBPR216 is now under preclinical development for further IND submission.
Citation Format: Ching-Chuan Kuo, Weir-Torn Jiaang, Jing-Jim Ou, Chiung-Tong Chen, Shu-Ching Hsu, Chuan Shih, Li-Mei Lin, Manwu Sun, Yi-Hsin Wang, Zih-Ting Huang, Jang-Yang Chang, Shau-Hua Ueng. Use of integrated genomic analyses in patient-derived tumor model to discover new clinical indications for the multikinase inhibitor drug candidate, DBPR216 [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 4626.
Abstract 4627: Mutant p53 regulation in a Li-Fraumeni mouse model
Authors: Terzian Tamara , Plehaty Molly , Sobhani Nema , Stevens Wanida , Marasligiller Stefan , Srinivas Tara , Mylavarapu Rohan , Clarke Yvonne , Arbab Farinaz , Podell Brendon , Bronson Roderick 
Published: August 2019

Abstract
The p53 tumor suppressor is maintained mainly at low physiological levels in normal cells by its two major inhibitors, Mdm2 and Mdm4. Mdm2 is a E3 ubiquitin ligase while Mdm4 binds to p53 and inhibits its transactivation activity. Deletion of either inhibitor results in p53-dependent embryonic lethality in mice. p53 is one of the most commonly mutated genes in human cancer. While we have gained considerable knowledge about wild-type p53 regulation and mode of action, our understanding of the oncogenic activity of mutant p53 lags behind. We know that mutant p53 is regulated in the same manner as wild-type p53. In a mouse model of Li-Fraumeni syndrome, Mdm2 binds and inhibits the hot spot mutant p53R172H (p53R175H in humans). Here we show that Mdm4, like Mdm2, regulates p53R172H stability in vivo, and that endogenous Mdm2 cannot compensate for this stabilization. Thus, mutant p53 mice that lack Mdm4 have stable high levels of p53R172H and display accelerated tumor development and an increased range of tumor types, compared to mutant p53 mice. Furthermore, when we compared mutant mice with the loss of two different alleles of both negative regulators, Mdm2 and Mdm4, we observed an even higher level of p53. This finding reveals that several tissues can tolerate high expression of oncogenic p53 and indicates a collaborative activity of these inhibitors in regulating mutant p53. The analysis of these mice uncovered new and unexpected functions of mutant p53 that we will discuss for the first time at the AACR 2019 meeting.
Citation Format: Tamara Terzian, Molly Plehaty, Nema Sobhani, Wanida Stevens, Stefan Marasligiller, Tara Srinivas, Rohan Mylavarapu, Yvonne Clarke, Farinaz Arbab, Brendon Podell, Roderick Bronson. Mutant p53 regulation in a Li-Fraumeni 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 4627.
Abstract 4632: A new mouse model for rapid identification of key factors driving prostate cancer progression and invasiveness
Authors: Riedel Maria , Bakiri Latifa , Berthelsen Martin F. , Borre Michael , Vendelbo Mikkel H. , Wagner Erwin F. , Thomsen Martin K. 
Published: August 2019

Abstract
Prostate Cancer is amongst the most frequently diagnosed malignancies and the second leading cause of cancer-related death in men worldwide accompanied by an increasing incidence. Until now its heterogeneity has been a major challenge in the establishment of good in vivo models for fast validation of potential driver genes.
Classic in vivo models are costly, time-consuming and often target the majority of the prostate epithelium. We successfully introduced a novel prostate cancer mouse model based on CRISPR/Cas9 technology, ensuring multiplexed gene editing.
In this model, specific in vivo gene editing was obtained in murine prostate epithelium cells of a transgenic mouse strain, harboring the CRISPR associated protein 9 (Cas9) endonuclease. Prostate epithelium cells were transduced by an Adeno-associated virus (AAV), carrying multiple single guide RNAs (sgRNA).
Genetically different viral constructs were designed, each expressing different sgRNA combinations against Pten, representing the main driver in prostate cancer, tumor suppressor Trp53 and either one of the AP1 transcription factor subunits Junb or Fos, or tumor suppressor Smad4.
Since viral transduction occurs in only a few cells, edited cell clones can clonally expand and undergo a natural selection process. Furthermore, the simultaneous gene knockouts reflect the human scenario of tumor heterogeneity.
Mouse prostates were isolated and analyzed three to nine months post-injection to obtain insight on whether or not a gene appears crucial for tumor development in a specific tissue and wherein different gene combinations correlate with tumor severity. Histological analysis revealed increased proliferation, increased AKT activation, as well as invasiveness in samples with multiple gene knockouts compared to controls with single Pten knockout. Furthermore, loss of SMAD4 accelerated cancer progression when compared to the loss of the AP-1 transcription factor. Surprisingly, knockout of Trp53 was rarely observed in prostate samples while it occurred frequently in other tumor types in the same model system. This indicates that knockout of Trp53 may not be required for prostate cancer initiation.
Overall, we established an in vivo model system of simultaneous, multiplexed gene editing in the prostate epithelium to address the biological cross-talk between various, altered pathways in prostate cancer initiation and progression.
Citation Format: Maria Riedel, Latifa Bakiri, Martin F. Berthelsen, Michael Borre, Mikkel H. Vendelbo, Erwin F. Wagner, Martin K. Thomsen. A new mouse model for rapid identification of key factors driving prostate cancer progression and invasiveness [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 4632.
Abstract 4641: Metabolic reprogramming of the breast contributes to a cancer promoting milieu
Authors: Marino Natascia , German Rana , Rao Xi , Sandusky George , Jacobsen Max , Cao Sha , Storniolo Anna Maria 
Published: August 2019

Abstract
In addition to the accumulation of pro-oncogenic mutations in the epithelial cells, the tumorigenic process involves the dysregulation of the interactions between the epithelial cells and their microenvironment, as well as alterations within the microenvironment itself. The latter is composed of endothelial cells, immune cells, fibroblasts, unaffected epithelium, and adipocytes. Increasing evidences support that cell transformation progresses in a potentially cancer-promoting microenvironment context, also known as field cancerization model. Therefore, it is critical to investigate changes occurring in both the epithelial compartment and the surrounding microenvironment to understand how breast cancer initiates.
In our preliminary study, we analyzed the transcriptome profile of microdissected breast tissue compartments (epithelium, stroma and adipose tissue) from tissue biopsies obtained from women who donated their histologically normal tissue two-to-five years before breast cancer diagnosis (here labeled pre-cancer), and matched healthy control donors. In the pre-cancer breast epithelium we detected a significant increase in lipid metabolism-related genes including lipases (HSL, LPL) and perilipins (PLIN1, PLIN4), which mediate the release of fatty acids from triacylglycerol storage, and ELOVL5 and ELOVL7, which generate oleic acid. Moreover, Acyl-CoA Synthetase Medium Chain Family Member 1, ACSM1, involved in the activation of lipoic acid, an essential cofactor for mitochondrial metabolism, is also upregulated in pre-cancer breast tissue. Upregulation of genes involved in metabolic activation is observed also in the stroma and adipose tissue compartments. Interestingly, the transcriptome profiling of the pre-cancer breast stroma shows the downregulation of genes coding for several immune cell markers as compared with the healthy controls. Immunohistochemical staining of CD45 confirms a significant reduction in immune cells in the pre-cancer versus matched healthy control breasts. This finding suggests the prevalence of an immune-suppressive environment in the breast long before the clinical diagnosis of breast cancer.
Understanding the changes occurring in the cancerized field is critical for elucidating 1) the involvement of microenvironment in cancer initiation 2) the role of histologically normal yet genetically altered surgical margins in risk of disease recurrence upon lumpectomy for early breast cancer diagnosis, and 3) the mechanisms of field cancerization in the contralateral breast.
Citation Format: Natascia Marino, Rana German, Xi Rao, George Sandusky, Max Jacobsen, Sha Cao, Anna Maria Storniolo. Metabolic reprogramming of the breast contributes to a cancer promoting milieu [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 4641.
Abstract 4649: Duplex Sequencing detects rare subclonal variants that mark early carcinogenesis and preneoplastic clonal evolution
Authors: Valentine Charles C. , Fielden Mark , Young Robert , Higgins Jake , Williams Lindsey , Li Tan , Kulkarni Rohan , Minocherhomji Sheroy , Risques Rosana , Danaher Patrick , Salk Jesse 
Published: August 2019

Abstract
Cancer is a disease of somatic evolution, characterized by the natural selection of genomic mutations that facilitate enhanced cell survival and proliferation. Although many thousands of tumor genomes have now been sequenced, our ability to identify early genetic patterns of clonal selection in both humans and model organisms have been hampered by inadequately sensitive methodologies for identifying mutations during the long period between their occurrence and the final outgrowth of a clinically apparent tumor.
Sensitive molecular tests are capable of measuring minute levels of cancer cells in tissue samples, however no existing method is satisfactory at scaling to high-throughput detection at the rate of one cancer-associated variant per more than a million normal cells. NGS is used to study the genetic variation in cell populations, although the accuracy of standard NGS methods limit our ability to detect sub-clones below ~1%. Duplex Sequencing (DS) is a sensitive NGS error-correction method which increases the accuracy of base calls by more than 100,000-fold. DS enables precise reconstruction of the original double-stranded source molecule while overcoming both chemical and technical artifacts that arise during library preparation and sequencing.
Here we present the use of Duplex Sequencing, in both human and mouse tissues, for measuring sub-clones at allelic fractions less than 1×10-4 for an early glimpse into pre-neoplastic evolution. We illustrate how, merely weeks after mutagen exposure, we observe emerging clones of cells bearing cancer-driving mutations in histologically normal mouse tissue. Furthermore, we illustrate how similar patterns of clonal selection can be seen in multiple otherwise healthy tissues of humans as part of normal aging. We discuss how variations in the pattern and rate of accumulation of rare cancer-associated mutations offers a new preclinical tool for evaluating carcinogenicity of chemicals, as well as a potential clinical tool for assessing life-integrated carcinogenic processes and cancer risk in humans.
Citation Format: Charles C. Valentine, Mark Fielden, Robert Young, Jake Higgins, Lindsey Williams, Tan Li, Rohan Kulkarni, Sheroy Minocherhomji, Rosana Risques, Patrick Danaher, Jesse Salk. Duplex Sequencing detects rare subclonal variants that mark early carcinogenesis and preneoplastic clonal evolution [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 4649.
Abstract 4654: Hotspot mutations in the core spliceosomal protein SF3B1 promote breast tumorigenesis
Authors: Liu Bo , Ki Michelle , Abdel-Wahab Omar , Chandarlapaty Sarat 
Published: August 2019

Abstract
The core RNA splicing factor SF3B1 is targeted by recurrent hotspot mutations in leukemias and solid tumors with the K700E substitution observed in 2% of unselected breast cancer patients. These mutations promote usage of aberrant intron proximal 3’ splice sites. In breast cancer, the links between these aberrant splicing events and the transformed phenotype are not well understood. Here, we integrated findings from multiple genetically modified model systems and human tumor specimens to understand the contributions of mutant SF3B1 to breast cancer pathogenesis. To identify the aberrant splicing events in breast cancers specifically, we first performed RNA-seq analyses of MCF10A breast epithelial cells with CRISPR knock-in of the K700E mutation. Dysregulation of splicing at over 1,000 splice junctions was discovered, most of which involve the use of alternative 3’ splice sites. Gene expression analysis revealed upregulation of expression of NFκB pathway genes in the SF3B1 mutant cells. SF3B1 mutant cells showed higher phosphorylation of RelA (p65) and, accordingly, greater migration in wound-healing assays. Mis-splicing of exon 5 in MAP3K7, a gene encoding a central regulator of NFκB pathway, significantly reduced MAP3K7 protein expression in SF3B1 K700E mutant cells. Consistent with these data, pharmacologic MAP3K7 inhibition in SF3B1 wild-type breast cells increased phosphorylation of RelA. To further understand the effects of the K700E mutation on breast cancer development and progression, we generated a conditional knock-in mouse model, in which Sf3b1 K700E mutant allele was activated through MMTV promoter-controlled expression of Cre recombinase in mammary epithelium. Accelerated tumor formation was not identified in the mammary gland of these mice. However, RNA-seq analysis of mammary epithelial cells from the Sf3b1 K700E mutant mice revealed dysregulation of alternative splicing including Map3k7. As we found the majority of SF3B1 k700E mutations to co-occur with activating mutations in the PI3K pathway, we additionally introduced the Pik3ca H1047R mutant allele, by mating the MMTV-Cre Sf3b1 K700E mice with Rosa26-Pik3ca H1047R knock-in line. Markedly decreased survival was observed in double mutant animals, which developed mammary tumors faster, compared with single mutant controls. Overall, these data reveal that breast cancer-associated Sf3b1 mutations induce the NFkB pathway to promote invasion and cooperate with the PI3K pathway to accelerate mammary tumor development.
Citation Format: Bo Liu, Michelle Ki, Omar Abdel-Wahab, Sarat Chandarlapaty. Hotspot mutations in the core spliceosomal protein SF3B1 promote breast tumorigenesis [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 4654.
Abstract 4678: Targeting MEK in EGFR amplified glioma stem like cells induces differentiation
Authors: Park Soon Young , Piao Yuji , Martinez-Ledesma Emmanuel , Dong Jianwen , Khan Sabbir , Mittal Sandeep , Zhang Ze-yan , Sulman Erik P. , Balasubramaniyan Veerakumar , Groot John F. de 
Published: August 2019

Abstract
The median survival for patients with recurrent glioblastoma is nine to twelve months highlighting the need for better therapeutic strategies for this deadly disease. The revolution in cancer genomics has identified multiple amplification events as potential targets for therapeutic intervention in many cancers including glioblastoma. Multiple factors such as incorrect patient selection, inadequate drug delivery across the blood brain barrier, acquired resistance and drug-target heterogeneity may all lead to clinical failure of targeted therapies. Receptor tyrosine kinase (RTK) signaling mediated by EGFR and PDGFR account for the core RTK signaling alterations in glioblastoma. EGFR-amplification (in ~40%) and PDGFR amplification (in ~12%) are detected in receptor tyrosine kinase- dysregulated glioblastoma. The first generation or second-generation EGFR tyrosine kinase small molecule inhibitors failed to show long term therapeutic benefit in glioblastoma patients. Through an unbiased high-throughput screen utilizing our glioma stem-like cells (GSCs) we identified that glioblastoma cells harboring EGFR amplification are uniquely vulnerable to mitogen-activated protein kinase (MEK) inhibitors. MEK inhibition induces apoptosis in EGFR amplified cells at low concentration. Furthermore, RNA sequence analysis of MEK inhibition revealed upregulation of genes related to differentiation in MEK sensitive glioma stem cells. Based upon these in vitro studies we are currently investigating MEK inhibition in a GBM xenograft mouse model. Overall our data suggest that the MEK inhibition could be a potential therapeutic target in a selective group of glioblastoma patients.
Note: This abstract was not presented at the meeting.
Citation Format: Soon Young Park, Yuji Piao, Emmanuel Martinez-Ledesma, Jianwen Dong, Sabbir Khan, Sandeep Mittal, Ze-yan Zhang, Erik P. Sulman, Veerakumar Balasubramaniyan, John F. de Groot. Targeting MEK in EGFR amplified glioma stem like cells induces differentiation [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 4678.