bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-73: SOX9 regulates EGFR/ERBB signaling in pancreatic cancer
Authors: Pinho Andreia V. , Grimont Adrien , Cowley Mark J. , Augereau Cecile , Mawson Amanda , Giry-Laterriere Marc , Steen Geraldine Van den , Waddell Nicola , Pajic Marina , Sempoux Christine ,   Australian Pancreatic Cancer Genome Initiative, Wu Jianmin , Grimmond Sean M. , Biankin Andrew V. , Lemaigre Frederic P. , Jacquemin Patrick , Rooman Ilse 
Published: May 2015

Abstract
The transcription factor SOX9 has recently been shown to have a role in the ontogenesis of pancreatic ductal adenocarcinoma (PDAC) through metaplastic changes in pancreatic acinar cells. Nevertheless, the mechanisms through which SOX9 operates remain to be explored.
We analyzed genomic and transcriptomic data from a cohort of surgically resected cases of PDAC (n=90) from the Australian Pancreatic cancer Genome Initiative (APGI). Genetic aberrations (mutation and copy number changes) in the SOX9 gene were found in 15% of patient tumors. Protein expression analysis revealed that most PDAC samples strongly express SOX9 protein and differential SOX9 expression correlates with patient survival. SOX9 gene expression was higher in the classical PDAC subtype, which relates with better patient outcome and increased response to epidermal growth factor receptor (EGFR)-directed therapy.
In patient tumors, we found that SOX9 expression correlates with expression of EGFR signaling pathway genes, including ErbB2. Analysis of patient-derived xenografts confirmed strong correlation of SOX9 and ErbB2 expression and manipulation of human tumor cell lines demonstrated that Sox9 regulates the expression of ErbB2.
We extended these findings by using a mouse model lacking pancreatic Sox9 expression where we found reduced expression of Egfr/ErbB signaling components. Sox9-deficient pancreatic acinar cells failed to generate PDAC precursor lesions and did not respond to EGF, indicating that Sox9 is required for Egfr/ErbB signaling pathway activity.
In conclusion, by using an integrative approach that combines human and mouse models data, we discovered a new function of SOX9 in the regulation of EGFR/ERBB signaling throughout pancreatic tumorigenesis. This provides a novel mechanistic insight of potential therapeutic significance for pancreatic cancer patients.
Citation Format: Andreia V. Pinho, Adrien Grimont, Mark J. Cowley, Cecile Augereau, Amanda Mawson, Marc Giry-Laterriere, Geraldine Van den Steen, Nicola Waddell, Marina Pajic, Christine Sempoux, Australian Pancreatic Cancer Genome Initiative, Jianmin Wu, Sean M. Grimmond, Andrew V. Biankin, Frederic P. Lemaigre, Patrick Jacquemin, Ilse Rooman. SOX9 regulates EGFR/ERBB signaling in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-73. doi:10.1158/1538-7445.AM2014-LB-73
Abstract LB-8: Design and development of a novel series of HDAC6-selective inhibitors for the treatment of cancer
Authors: Shuttleworth Stephen J. 
Published: May 2015

Abstract
Inhibition of the zinc-dependent histone deacetylase (HDAC) family of enzymes has been pursued as a clinical strategy in cancer for over a decade. HDACs regulate the expression and activity of numerous proteins involved in both cancer initiation and cancer progression; by removal of acetyl groups from histones, HDACs create a non-permissive chromatin conformation that prevents the transcription of genes that encode proteins involved in tumorigenesis. The current landscape of HDAC-targeting therapeutics has, however, been dominated by pan-inhibitors that regulate the activity of most, if not all, of the HDAC family members which, through dysregulation of expression of a myriad of genes, has led to agents with undesirable toxicities and narrow therapeutic margins. Recently, however, attention has begun to turn to the role of specific HDAC isoforms in tumorigenesis and, in turn, the development of more selective therapeutics. HDAC6 has emerged as a particularly interesting target as it plays an essential role in aggresomal protein degradation: specifically, HDAC6 binds polyubiquitinated misfolded proteins and recruits misfolded protein cargo to dynein motors for transport to aggresomes. Cells deficient in HDAC6 fail to clear these misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins, which leads to activation of apoptosis. This presentation will outline the design and development of a new class of highly-potent, selective and orally-active HDAC6 inhibitors with the potential in the treatment of multiple tumor types. Uniquely, this series of compounds has been designed such that selectivity levels for HDAC6 over other isoforms can be finely regulated, enabling the investigation of preferred levels of HDAC6 specificity for therapy.
Citation Format: Stephen J. Shuttleworth. Design and development of a novel series of HDAC6-selective inhibitors for the treatment of cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-8. doi:10.1158/1538-7445.AM2014-LB-8
Abstract LB-86: Dependent and independent tumor suppression function of ARF and p53 in murine BCC carcinogenesis in Ptch1+/- mice
Authors: Wang Grace Y. , Wood Carla , Hu Hiroe , Dolorito John , Libove Eileen , Eptein Ervin H. 
Published: May 2015

Abstract
Basal cell carcinoma (BCC), the most commonly diagnosed human cancer, is driven by aberrant activation of hedgehog (HH) signaling. In addition, we have found that p53 is a potent inhibitor of HH-driven BCC carcinogenesis - ablation of p53 in Ptch1+/- K14CreER2 p53fl/fl (PF mice) dramatically accelerates BCC formation with a shorter tumor latency and a 10 fold increase of tumor burden. To begin to determine how p53 is activated in this Ptch1+/- murine BCC model, we investigated the role of p19ARF in translating oncogene-induced stress (OIS) into p53 activation.
We bred Ptch1+/- mice with ARFGFP/GFP to generate Ptch1+/- ARFGFP/GFP (ARF mice), lacking functional ARF. In addition, we crossed ARF mice and PF mice to generate ARF/p53 double deletion mice (DD mice), treated ARF, PF and DD mice as well as Ptch1+/- (ARF+/+, p53+/+) with IR at mouse age 8w, and quantified BCC formation. .As assessed in age 5m skin biopsies, PF and DD mice had a significantly higher microscopic BCC tumor burden than did ARF and Ptch1+/- mice. There was no significant difference between PF and DD or between ARF and Ptch1+/-. ARF and PF mice developed visible BCC starting at 5-6 m. By contrast, DD mice had visible BCCs as early as age 4m, a statistically different age of onset. Consistent with our previous findings, Ptch1+/- mice did not form any visible BCCs until age 9 m or later. These data indicate that loss of functional ARF or of p53 promotes malignant conversion of microscopic BCCs to visible BCCs. However, only loss of p53, but not loss of ARF, enhances tumor initiation. To gain further insights in the molecular mechanisms differentiating these tumors, we examined the whole genome expression analysis by RNA-seq.
Taken together, our findings suggest that both ARF-dependent and -independent activation of p53 is involved in BCC carcinogenesis. ARF-mediated p53 activation, presumably via the OIS pathway, appears to be crucial in regulating malignant transformation of BCC, while ARF-independent p53 activation inhibits tumor initiation.
Citation Format: Grace Y. Wang, Carla Wood, Hiroe Hu, John Dolorito, Eileen Libove, Ervin H. Eptein. Dependent and independent tumor suppression function of ARF and p53 in murine BCC carcinogenesis in Ptch1+/- mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-86. doi:10.1158/1538-7445.AM2014-LB-86
Abstract LB-97: A novel anticancer bispecific antibody targeting VEGF and Dll4 inhibits tumor progression in lung and gastric cancer xenograft models
Authors: You Weon-Kyoo , Lee Dongheon , Choi Yu Bin , Kang Kyung Jae , Kim Dong In , Ahn Jin-Hyung , Jung Jinwon , Sung Eun-Sil , Goo Jun Seo , Jang Hyun Sook , Moon Kyung Duk , Lee Sang Hooon 
Published: May 2015

Abstract
Several angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway have been used for cancer treatment. However, VEGF inhibitors alone can promote tumor invasion and metastasis by increase of intratumoral hypoxia in some preclinical models. Emerging reports regarding angiogenesis suggest Delta-like-ligand 4 (Dll4) is a promising target to augment the effects of VEGF inhibitors. Dll4 blockade inhibits tumor progression by increasing nonproductive angiogenesis whereas VEGF blockade inhibits tumor progression by decreasing angiogenesis. To evaluate the effect by inhibiting both VEGF and Dll4 on tumor angiogenesis, we have developed HD105, a novel bispecific antibody targeting VEGF and Dll4, as the format of VEGF-binding IgG linked with Dll4-binding single-chain Fv. The bispecific antibody showed potent binding affinity against VEGF (KD: 3.4 x 10-12 M) and Dll4 (KD: 4.2 x 10-8 M), which are comparable with KD values of anti-VEGF antibody (9.8 x 10-10 M) and Dll4 single targeting antibody (5.5 x 10-9 M). The HD105 bispecific antibody also inhibited interaction of Dll4 and its receptor, Notch 1 (IC50: 1 nM ± 0.2). By using in vitro cell-based assays, the HD105 effectively blocked Dll4 as well as VEGF signaling pathways in endothelial cells, resulting in downregulation of Notch intracellular domain (NICD) and VEGFR-2/extracellular-signal-regulated kinase (ERK) phosphorylation. In addition, the HD105 more efficiently inhibited tumor progression than each single-targeting antibody in A549 human lung cancer and SCH human gastric cancer xenograft models. In conclusion, the novel bispecific antibody could be potentially developed as a clinically more efficacious therapeutic antibody.
Citation Format: Weon-Kyoo You, Dongheon Lee, Yu Bin Choi, Kyung Jae Kang, Dong In Kim, Jin-Hyung Ahn, Jinwon Jung, Eun-Sil Sung, Jun Seo Goo, Hyun Sook Jang, Kyung Duk Moon, Sang Hooon Lee. A novel anticancer bispecific antibody targeting VEGF and Dll4 inhibits tumor progression in lung and gastric cancer xenograft models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-97. doi:10.1158/1538-7445.AM2014-LB-97
Abstract PL03-01: Evolutionary dynamics of cancer in response to targeted therapy
Authors: Nowak Martin 
Published: May 2015

Abstract
Cancer is an evolutionary process. Cancer initiation and progression are caused by somatic mutation and selection of dividing cells. The mathematical theory of evolution can therefore provide quantitative insights into human cancer. I will discuss the role of chromosomal instability (CIN) and the accumulation of drivers and passengers in growing tumors. I will study success and failure of targeted therapy including combination of different drugs and evolution of resistance. A simple conclusion is that combination treatment can succeed, if the cancer requires at least two point mutations to gain resistance. From the perspective of preventing resistance, simultaneous therapy is highly recommended whereas sequential therapy is a recipe for almost certain treatment failure.
Further Reading
1. Bozic et al (2010). Accumulation of driver and passenger mutations during tumor progression. Proc Natl Acad Sci USA 107: 18545-18550.
2. Diaz et al (2012) The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486: 537-540.
3. Bozic et al (2013). Evolutionary dynamics of cancer in response to targeted combination therapy. eLife 2: e00747.
Citation Format: Martin Nowak. Evolutionary dynamics of cancer in response to targeted therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr PL03-01. doi:10.1158/1538-7445.AM2014-PL03-01
Abstract SY02-04: Overlapping mechanisms in CNS development and gliomagenesis
Authors: Rowitch David H. 
Published: May 2015

Abstract
Glioblastoma multiforme (GBM) is a lethal brain cancer resistant to therapy in part because of its highly invasive nature. GBMs are a highly vascular tumor with heterogeneous histological features, but they are generally considered to derive from glial lineage progenitors. We have defined Olig2, a bHLH transcription factor, as a critical determinant of oligodendrocyte progenitor identity during development. Olig2 is expressed in human GBMs, raising the possibility of similar features between oligodendrocyte progenitors and glioma-propagating cells, a concept is supported by expression profiling and mouse models. This talk will review functions for OPCs during development, including proliferation, migration into adult parenchymal tissue and angiogenesis. As such, there are provocative similarities between normal OPCs and progenitors for GBM.
Citation Format: David H. Rowitch. Overlapping mechanisms in CNS development and gliomagenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY02-04. doi:10.1158/1538-7445.AM2014-SY02-04
Abstract SY04-03: Gut microbiome-driven exposure to anti-inflammatory dietary bioactives in humans
Authors: Lampe Johanna Wyss 
Published: May 2015

Abstract
Chronic, low-grade systemic inflammation is hypothesized to be a risk factor for carcinogenesis. In humans, dietary patterns, foods, and dietary constituents are associated with concentrations of circulating inflammation biomarkers (e.g., CRP, IL-6, IL-18, and TNF-α); meat-based or “Western” diet patterns have been positively associated with inflammation markers, whereas vegetable- and fruit-based or “healthy” diet patterns have been inversely associated. The gut microbiome may contribute to chronic inflammation in part through its interaction with host diet. Diet influences amounts and types of gut microbes, and gut microbial metabolism of dietary constituents produces compounds that can be protective or harmful to the host. We have shown that differences in gut microbial metabolism and diversity of the microbial community among individuals accounts for some of the variation in human exposure to phytochemicals. Components of diet also serve as substrates for certain groups of bacteria, such that changes in diet can result in a gut microbial community with greater or lesser inflammatory potential. Our findings suggest that a greater understanding of diet-gut microbiome interactions may inform future cancer-prevention strategies.
Citation Format: Johanna Wyss Lampe. Gut microbiome-driven exposure to anti-inflammatory dietary bioactives in humans. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY04-03. doi:10.1158/1538-7445.AM2014-SY04-03
Abstract SY10-01: Understanding metabolic heterogeneity in cancer
Authors: DeBerardinis Ralph J. 
Published: May 2015

Abstract
Metabolic reprogramming is considered to be a hallmark of malignancy and a consequence of the mutations that cause cancer. Classical components of metabolic reprogramming include enhancements of nutrient uptake, aerobic conversion of glucose to lactate, and biosynthesis of proteins, lipids and nucleic acids. These activities are believed to collaborate to support states of supra-physiological stress resistance and proliferative capacity. However, recent work, primarily performed in cancer cell lines, has revealed an unexpected heterogeneity of metabolic programs that can support cancer cell survival and growth. It is unclear how these heterogeneous metabolic programs are regulated by the oncogenotype, and more importantly, which of the myriad activities observed in culture are relevant to bona fide tumor metabolism in vivo. I will discuss approaches to address these challenges. First, I will discuss ongoing efforts to use systematic analysis of cancer cell lines to link metabolic phenotypes with oncogenotypes, and to identify chemotherapeutic sensitivities associated with particular metabolic preferences. Second, I will describe efforts to probe metabolism in living tumors using a combination of stable isotope tracing and complementary methods. Finally, I will discuss approaches to merge metabolomics with non-invasive imaging to understand the development and consequences of metabolic heterogeneity within individual tumors.
Citation Format: Ralph J. DeBerardinis. Understanding metabolic heterogeneity in cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY10-01. doi:10.1158/1538-7445.AM2014-SY10-01
Abstract SY13-03: Signal pathways in prostate cancer stem cells
Authors: Witte Owen N. 
Published: May 2015

Abstract
New therapeutic strategies are needed to treat prostate cancer as it progresses to the castration resistant stage following treatment with drugs to reduce androgen production or interfere with androgen receptor function. Genetic analyses of DNA alterations and RNA expression show that multiple pathways can be involved in this cancer progression. An understanding of the cellular components needed to initiate prostate cancer and sustain it during the process of metastasis may help to elucidate new pathways for therapy. We have developed techniques to transform mouse and human benign prostate epithelial basal stem cells and define them as one cell of origin which can respond to multiple stimuli to produce cancers which are capable of maturing to more differentiated cell types including luminal, squamous and neuroendocrine phenotypes. Different subtypes of cells with the properties of cancer stem cells capable of transplantation of the cancer phenotype have been defined. Current work is focusing on the activation of specific kinase driven pathways to provide new targets for therapy in metastatic prostate cancer. We previously demonstrated that castration resistant prostate cancer (CRPC) tissues exhibit increased tyrosine phosphorylation, suggesting that enhanced tyrosine kinase activity may contribute to advanced disease. To identify specific kinase activation patterns in metastatic CRPC, we utilized phospho-tyrosine peptide enrichment and quantitative mass spectrometry using tissue from CRPC patients obtained at rapid autopsy. Evaluation of these rare metastatic CRPC samples for tyrosine phosphorylation and kinases revealed activated SRC, EGFR, RET, ALK, and other targets. Importantly, these kinase activation patterns exhibited intrapatient similarity and interpatient heterogeneity implying clonal origins of these lesions. To evaluate the function of these kinases in metastatic CRPC, we are analyzing their role during specific steps of the metastatic cascade. We hope our approach will improve an understanding of the mechanistic role of kinase activation in prostate cancer and identify promising therapeutic strategies targeting non-mutated kinases for metastatic CRPC.
Citation Format: Owen N. Witte. Signal pathways in prostate cancer stem cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY13-03. doi:10.1158/1538-7445.AM2014-SY13-03
Abstract SY23-02: Nanotechnology and single cell proteomics as a diagnostic tool
Authors: Heath James R. , Wei Wei , Shin Young Shik , Xue Min , Zhou Jing , Sutherland Alex , Yu Jing 
Published: May 2015

Abstract
Single-cell functional proteomics assays can connect genomic information to biological function through the use of quantitative and multiplex protein measurements. Tools for single-cell proteomics have developed rapidly over the past 5 years, and are providing approaches for directly elucidating phospho-protein signaling networks in cancer cells, or for capturing high-resolution snapshots of immune system function in cancer patients participating therapies that involve immune system engineering and manipulation. We discuss advances in single cell proteomics platforms, with an emphasis the types of data that can be obtained, and how analysis of that data can provide deep insights into either designing therapies, or understanding patient responses to therapies. I will provide illustrative examples of how microchip-based single cell functional proteomics platforms are being applied to both fundamental biology and clinical studies.
Citation Format: James R. Heath, Wei Wei, Young Shik Shin, Min Xue, Jing Zhou, Alex Sutherland, Jing Yu. Nanotechnology and single cell proteomics as a diagnostic tool. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY23-02. doi:10.1158/1538-7445.AM2014-SY23-02
Abstract SY33-04: Tumor suppression by the DNA damage response
Authors: Petrini John 
Published: May 2015

Abstract
The DNA damage response (DDR) is activated by oncogenic stress, but the mechanisms by which this occurs and the particular DDR functions that constitute barriers to tumorigenesis remain unclear. We established a mouse model of sporadic oncogene-driven breast tumorigenesis in a variety of mutant mouse strains with specific DDR deficiencies to reveal a novel role for the Mre11 complex (comprised of Mre11, Nbs1, and Rad50) in the response to oncogene activation. We demonstrate that the Mre11-mediated DDR suppresses tumorigenesis by inducing a G2 arrest and a program of chromatin alteration that, when compromised, results in oncogene-induced mammary hyperplasias that progress to invasive and metastatic breast cancers. In contrast, we provide genetic evidence that the intra-S checkpoint and the DNA damage-induced apoptosis functions of the DDR are dispensable for tumor suppression. These findings provide novel insight into the mechanism of DDR engagement by activated oncogenes, and reveal the particular DDR functions that must be overcome during tumorigenesis. We further demonstrate that impairment of these Mre11-dependent functions promotes metastatic dissemination, particularly upon secondary inactivation of the Ink4a-p19Arf (CDKN2a) locus. These findings provide insight into the mechanism of DDR engagement by activated oncogenes, and reveal a novel genetic interaction between the DDR and Ink4a-p19Arf pathways in suppression of oncogene-driven tumorigenesis and metastasis.
Citation Format: John Petrini. Tumor suppression by the DNA damage response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY33-04. doi:10.1158/1538-7445.AM2014-SY33-04