bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B68: Contributions of STAT3 to pro-tumorigenic alterations within the microenvironment during mammary tumorigenesis
Authors: Chuntova Polly , Bohrer Laura R. , Schwertfeger Kaylee L. 
Published: May 2016

Abstract
Inflammation has long been recognized as a possible trigger that contributes to tumor initiation. Numerous studies have shown that cells of both the innate and adaptive immune systems are able to support tumor formation and growth through secretion of growth factors and cytokines and by actively shielding the tumor from wider immune surveillance. As a result, inflammation is generally linked to worse patient outcome. However, depending on factors such as tumor size, extracellular matrix, and the complex composition of immune cell infiltrates, inflammation can promote both pro- and anti-tumor properties. Our studies focus on identifying novel mechanisms through which tumor-derived cytokines act in a paracrine manner to regulate the functions of infiltrating inflammatory cells in the tumor microenvironment. We have previously shown that activation of the fibroblast growth factor receptor-1 (FGFR1) oncogene results in the production of high levels of interleukin 6 (IL-6) family members by mammary epithelial cells. Histological examination of FGFR1-driven tumors revealed high levels of STAT3 activation in both tumor cells and macrophages. Thus, further studies focused on identifying mechanisms through which STAT3 activation in different cellular compartments contributes to mammary tumor growth. Initial studies focused on the consequences of STAT3 activation in epithelial/tumor cells. We found that epithelial cell STAT3 activation resulted in accumulation of the extracellular matrix component hyaluronan, which contributed to epithelial cell proliferation, survival and migration. In macrophages, STAT3 is the transcription factor required for transduction of the anti-inflammatory response initiated by interleukin-10. Ongoing experiments have revealed that in primary STAT3fl/fl cre+ bone marrow-derived macrophages, absence of STAT3 signaling reveals a profoundly enhanced pro-inflammatory phenotype. In vitro, treatment of macrophages lacking STAT3 with recombinant IL-6 results in prolonged activation of the proinflammatory STAT1, as well as upregulation of inflammatory molecules such as TNFα and CCL2. Ongoing experiments are aimed at evaluating the functional consequences of this altered tumor microenvironment in vivo during tumor initiation and growth. As anti-STAT3 therapies have began entering clinical trials for solid tumors (including breast tumors), understanding the mechanisms through which STAT3 promotes tumor growth and progression is critical for developing optimal therapeutic strategies.
Citation Format: Polly Chuntova, Laura R. Bohrer, Kaylee L. Schwertfeger. Contributions of STAT3 to pro-tumorigenic alterations within the microenvironment during mammary tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B68.
Abstract IA01: Potential applications of genomics in patients with metastatic breast cancer
Authors: André Fabrice 
Published: May 2016

Abstract
Genomic studies have shown that breast cancer includes large number of genomic segments. From this observation has arisen the concept that sequencing could be used to select breast cancer patients for new therapies. There are at least six applications of genomic tests to individualize therapy in breast cancer. In the present document and presentation, we will only focus on metastatic breast cancers.
First, genomic tests can be used to identify oncogenic drivers at the individual level. There are seven genomic alterations that are currently the focus on genomic-driven drug development. This includes AKT1 mutations, ERBB2 mutations, PIK3CA mutations, FGFR1 amplification, CCND1 amplification, BRCA1/2 mutations and PTEN mutations or loss. With the exception of CCND1, early phase trials have suggested that these genomic alterations could be associated with antitumor activity when targeted with the appropriate compound. Beyond the driver identification at the DNA level, some are developing RNA-based assays to identify pathway activation in individuals. As illustration, gene expression could assess mTOR, CDK4, AR, ER activations. Whether the assessment of pathway activation identifies patients eligible for targeted therapies is not yet proven.
The second application of genomics is the identification of genomic alterations involved in drug resistance. As illustration, it has been shown that ESR1 and PTEN mutations could be involved in the resistance to endocrine therapy or PI3K inhibitors. ctDNA could be the perfect tool to monitor appearance of these genomic alterations and treat patients accordingly.
The third application of genomics could be the identification of patients who are highly sensitive to immunotherapeutics. Several papers have shown that high mutation load and neoantigens could be associated with sensitivity to immune checkpoint inhibitors. During the conference, we will share some preliminary data on the mutational load and neoantigens in metastatic samples of breast cancer patients.
Genomics could also be used to identify mutational processes and DNA repair defect.
Finally, genomic assays could allow identification of patients with metastatic breast cancer who present a very poor outcome. Such assay could be used to identify a population of patients where fast track drug approval is needed.
Clinical trials are ongoing to determine whether the use of multigene assay could improve outcome in metastatic breast cancer patients, and which genes are associated with drug efficacy.
Citation Format: Fabrice André. Potential applications of genomics in patients with metastatic breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA01.
Abstract IA06: Spatial systems biology of cancer
Authors: Gray Joe 
Published: May 2016

Abstract
International efforts have now defined the genomic landscapes of most major human cancer types. The genomic landscape of breast cancer is particularly well described in several recent publications. The high level view of this disease suggests a remarkable level of inter- and intra-tumor heterogeneity, the presence of a few recurrent and many rare genomic aberrations and substantial genomic and epigenomic heterogeneity. The challenge now is to understand how these aberrations and tumor extrinsic influences from the microenvironment collaborate to deregulate aspects of cell differentiation, proliferation, apoptosis, DNA repair, senescence, motility and multiscale architecture that include cancer progression and response to therapy. To this end, the OHSU Center for Spatial Systems Biomedicine has deployed a suite of measurement technologies that enable high throughput assessment of changes in these endpoints to siRNA knockdown of genes found by the TCGA and international genomics efforts to be aberrant and/or involved in regulatory networks that are associated with differentiation subtype and/or differential response to therapy. These studies have revealed both recurrent and rare aberrations that strongly influence these endpoints as well as a range of molecular architectures that influence aspects of receptor tyrosine kinase signal transduction. This presentation will summarize the results of the siRNA knockdown experiments and focus on the concept that analysis of the architectural features influenced by genomic and epigenomic abnormalities will suggest new therapeutic approaches. Illustrative examples of architectural features revealed using advanced imaging approaches that suggest new approaches to the design of RTK targeted therapies include (a) Ras/Raf multimers associated with signal transduction, (b) actin associated microfilaments involved in ERBB2 signal transduction, and (c) intratumor heterogeneity in differentiation status that influences responses to a range of kinase inhibitors.
Citation Format: Joe Gray. Spatial systems biology of cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA06.
Abstract IA18: Development of targeted therapeutics using patient-derived xenografts
Authors: Lewis Michael T. 
Published: May 2016

Abstract
Clinically, breast cancers are divided into three distinct groups: those that express the estrogen hormone receptor (ER+) (which typically also express the progesterone hormone receptor (PR+), those that are amplified or overexpress the ErbB2 (HER2) oncogene (HER2+), and those that express none of these three markers (termed triple negative breast cancer TNBC). Unlike ER+ and HER2+ breast cancers, there are currently no targeted therapies against TNBC. Thus, the development of targeted therapies for TNBC is an active area of research.
Entry into the clinical trial pipeline is a major milestone in the process of drug development. However, human clinical trials have several inherent limitations including high cost and long time horizon. Add to these limitations the fact that many promising targeted therapeutics enter into this pipeline without detailed knowledge of the patient population most likely to respond, and without knowledge of particular drug combinations that might be more efficacious than others. As a consequence, the inherent limitations combined with lack of knowledge leads to a high frequency of failure, with failure late in the process costing extraordinary amounts of time and money.
In theory, many of the limitations of human trials can be overcome using an animal clinical trial platform that exploits collections of patient-derived xenograft (PDX) models that recapitulate much of the biology of the tumor of origin in the patient.
Our laboratory has developed a large collection of human breast cancer PDX with which we are evaluating a number of candidate targeted therapeutics alone and in various combinations, with a particular focus on overcoming chemotherapy resistance in TNBC. We show that animal clinical trials are feasible, and can be conducted efficiently, using minimal staff. Further, we demonstrate that results in animal clinical trials can be used to inform clinical trial design. We anticipate that insertion of animal clinical trials early in the drug development pipeline can streamline the drug development process and lead to more efficient evaluation of drug efficacy, saving both time and money. Ultimately, if robust genetic, epigenetic, or molecular predictors of differential treatment response can be identified in PDX models and applied clinically, it may be possible to avoid ineffective treatments, minimize exposure to cytotoxic agents, and ultimately increase survivorship.
Citation Format: Michael T. Lewis. Development of targeted therapeutics using patient-derived xenografts. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA18.
Abstract IA25: Deep sequencing of circulating tumor DNA for personalized cancer detection and monitoring
Authors: Diehn Max 
Published: May 2016

Abstract
Circulating tumor DNA (ctDNA) represents a promising biomarker for sensitive, specific, and dynamic detection of disease burden in cancer patients. Additionally, ctDNA analysis allows non-invasive access to cancer genomes and therefore can be used for non-invasive tumor genotyping and monitoring of resistance mutations. In this presentation I will describe technical aspects of ctDNA detection and emerging clinical results from recent studies employing ctDNA analysis.
Citation Format: Max Diehn. Deep sequencing of circulating tumor DNA for personalized cancer detection and monitoring. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr IA25.
Abstract A22: Differentiation of human embryonic stem cells to sympathetic neurons: A potential model for understanding neuroblastoma pathogenesis
Authors: Carr-Wilkinson Jane , Prathalingam Nilendran , Pal Deepali , Forgham Helen , Lako Majlinda , Herbert Mary , Tweddle Deborah A. 
Published: May 2016

Abstract
Background and Aims: Neuroblastoma is an embryonal malignancy derived from neural crest cells which give rise to the sympathetic nervous system (SNS). One of the main therapeutic challenges in neuroblastoma continues to be the emergence of relapsed disease, which occurs in 50% of patients with high risk disease and is associated with resistance to therapy. Our aim was to differentiate human embryonic stem cells (hESCs) to sympathetic neurons (SN) to model normal human SNS development.
Results: Using the stromal-derived inducing activity (SDIA) of murine PA6 cells in combination with BMP4 and B27 neuronal supplement, H9 and a newly derived hESC line Ncl(R)14, were induced to differentiate to neural crest stem cells and SN. After 7 days of PA6 cell co-culture, mRNA expression of SNAIL and SOX-9 neural crest specifier genes and the neural marker Peripherin increased. Q-RT-PCR showed that expression of the pluripotency marker OCT 4 decreased, whereas p53 and LIN28B expression remained high at levels similar to SHSY5Y and IMR32 neuroblastoma cell lines. A marked increase in expression of the catecholaminergic marker Tyrosine Hydroxylase (TH) and the noradrenergic marker Dopamine Beta Hydroxylase (DBH) was observed by day 7 of differentiation. Fluorescence activated cell sorting for the neural crest marker p75, enriched for cells expressing p75, DBH, TH and Peripherin. SN were identified by immunofluorescence by co-expression of TH & Peripherin or DBH & PHOX2B in p75+ cells. Live cell analysis and imaging showed increased migration in p75+ cells compared with p75- cells, consistent with a migratory neural crest phenotype in-vitro.
Conclusions: We have established a model of nor-adrenergic SNS development using two hESC lines to improve our understanding of normal human SNS development and in future studies the pathogenesis of neuroblastoma.
Citation Format: Jane Carr-Wilkinson, Nilendran Prathalingam, Deepali Pal, Helen Forgham, Majlinda Lako, Mary Herbert, Deborah A. Tweddle. Differentiation of human embryonic stem cells to sympathetic neurons: A potential model for understanding neuroblastoma pathogenesis. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A22.
Abstract A25: Role of ABCB5 in progression and therapeutic resistance of glioblastoma
Authors: Banerjee Pallavi , Berg Gretchen , Wilson Brian J. , Guo Qin , Frank Markus H. , Frank Natasha Y. 
Published: May 2016

Abstract
Glioblastoma multiforme (GBM), one of the most lethal human cancers, is the most common and aggressive primary malignant brain tumor. Poor prognosis and high lethality result from tumor recurrence and extreme resistance to chemotherapeutic treatment. Compelling evidence suggests that GBM is a heterogeneous tumor composed of bulk tumor cells as well as of subpopulations of slow-proliferating cancer stem cells with tumor-initiating potential, which evade cell killing and are responsible for tumor recurrence. Current therapeutic strategies are thus aimed at eliminating these refractory tumor subpopulations to alleviate chemoresistance and recurrence of GBM. ATP-binding cassette member B5 (ABCB5) has been identified as a molecular marker for distinct subsets of chemoresistant tumor-initiating cell populations in diverse human malignancies, including malignant melanoma, hepatocellular carcinoma and colorectal cancer. Moreover, ABCB5 has been shown to functionally contribute to tumor progression and therapeutic resistance of human cancers. In the current study, we examined the potential role of ABCB5 in malignant growth and chemoresistance of GBM. We found ABCB5 to be co-expressed with GBM stem cell marker CD133 in all of three human GBM cell lines tested thus far, i.e. U87 MG, LN18 and LN229. Functional blockade of ABCB5 using an anti-ABCB5 monoclonal antibody (mAb) (clone 3C2-1D12) inhibited proliferation and survival of human GBM cells, and sensitized GBM cultures to Temozolomide (TMZ)-induced cell killing and apoptosis. Likewise, in vivo systemic administration of anti-ABCB5 mAb to immunodeficient (NSG) mice bearing human GBM xenografts resulted in significant reduction of tumor growth and sensitization of GBM tumors to TMZ therapy, underscoring the potential of ABCB5-targeting strategies for reversal of GBM chemotherapeutic resistance. Mechanistically, we found that ABCB5 blockade significantly altered molecules involved in cell cycle regulatory checkpoints to revoke TMZ-induced G2/M arrest, explaining how treatment with ABCB5 mAb is augmenting drug-mediated apoptosis. Overall, our data reveal a novel role of ABCB5 as a marker of GBM chemoresistance and show that functional ABCB5 blockade inhibits GBM tumor growth in vivo. These findings underline the potential clinical relevance and therapeutic importance of ABCB5 targeting as a novel therapeutic approach to GBM eradication.
Citation Format: Pallavi Banerjee, Gretchen Berg, Brian J. Wilson, Qin Guo, Markus H. Frank, Natasha Y. Frank. Role of ABCB5 in progression and therapeutic resistance of glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A25.
Abstract A29: JNK contributes to BMP loss induced intestinal tumorigenesis in Drosophila
Authors: Zhou Jun , Boutros Michael 
Published: May 2016

Abstract
Genetic instability and mutations are contributed to colon cancer development. For instance, loss of intestinal BMP signaling through mutation on SMAD4 and BMPR1A is a prominent cause of gastrointestinal cancers. The BMP pathway functions as a negative regulator of crypts and is taken to be essential for terminal differentiation. However the genetic causes and molecular mechanism of BMP loss induced tumorigenesis remains largely unknown. Here, we used Drosophila intestinal tumors generated by suppressing BMP/Dpp signaling as a model to investigate the genetic mutations are essential for tumor development. We found BMP loss induced Drosophila intestinal tumor displays cellular heterogeneity is similar to mammalian colon tumor, whereas Drosophila intestinal tumor contains stem cell, its progenitor cells (enteroblast), immatured enterocytes and enteroendocrine cells. In addition, we observed signaling molecules significantly upregulated in BMP defective tissue such as, STAT ligands (Upd, Upd2, 3), EGFR ligands (Spitz, Vein), Insulin receptor and JNK components (dFos, Puc). Through genetic gain and loss of function experiments, we showed JNK activity contributes to the BMP loss induced intestinal tumorigenesis. We observed high JNK activity inside BMP defective tumor using clonal analysis. The growth of BMP defective tumor can be strongly suppressed by JNK inhibition through genetic suppression (dFOS RNAi) or compounds feeding (SP600125 inhibitor). Furthermore, JNK activation through herozygous mutation in its negative regulator Puckered enhanced the BMP loss induced tumorigenesis and lethality. Hence, our data identify JNK activity is essential for the development of BMP defective intestinal tumor.
Citation Format: Jun Zhou, Michael Boutros. JNK contributes to BMP loss induced intestinal tumorigenesis in Drosophila. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A29.
Abstract A37: Tumor heterogeneity in SCLC: A role for endogenous Notch signaling
Authors: Lim Jing Shan , Ibaseta Alvaro , Yang Dian , Jahchan Nadine S. , Sage Julien 
Published: May 2016

Abstract
Small cell lung cancer (SCLC), a very aggressive neuroendocrine (NE) tumor of the lung, constitutes approximately 15% of all lung cancers and has a 5-year survival rate of only 5%. Resistance following initial chemotherapy and radiation treatments accounts for the high rate of recurrence and the overall poor prognosis of SCLC.
Through genomic sequencing of 100 human SCLC tumors, the group of Roman Thomas and Martin Peifer identified universal inactivation of RB and p53 and inactivating mutations in the NOTCH receptors in ~25% of the tumors. Accordingly, we found that activation of the Notch pathway in a pre-clinical mouse model for SCLC dramatically reduces the number of tumors and extends the survival of the mice. Acute Notch activation also inhibits NE gene expression and proliferation in SCLC tumor cells, providing further evidence for a tumor suppressive role for Notch in SCLC (George, Lim, et al., Nature, 2015).
Intriguingly, however, we recently identified a population of cells in mouse and human SCLC tumors that exhibit endogenous activation of the Notch pathway. This observation raises the question of why tumor cells would activate a tumor suppressive pathway. Consistent with the inhibitory role of the pathway in NE differentiation, these Notch-active SCLC cells comprise a slow-cycling, non-NE compartment within SCLC tumors. Lineage tracing experiments indicate that NE tumor cells generate these non-NE Notch-active cells during tumorigenesis. Importantly, our data suggest that these slow-growing Notch-active SCLC cells may function as tumor-derived stromal-like cells that confer a growth or protective advantage to the NE tumor cells under certain growth conditions.
In conclusion, Notch is a potent suppressor of SCLC. However, Notch may have pro-tumorigenic effects in SCLC, possibly under stress conditions. A better understanding of the molecular and cellular roles of Notch is required before therapeutic strategies manipulating the Notch pathway can be used in SCLC patients.
Citation Format: Jing Shan Lim, Alvaro Ibaseta, Dian Yang, Nadine S. Jahchan, Julien Sage. Tumor heterogeneity in SCLC: A role for endogenous Notch signaling. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A37.