bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-75: Blood-based molecular detection of acquired resistance to anti-EGFR therapies in colorectal cancer patients.
Authors: Siravegna Giulia , Bianchi Andrea Sartore , Cassingena Andrea , Bencardino Katia , Diaz Luis A. , Sausen Mark , Velculescu Victor E. , Nicolantonio Federica Di , Siena Salvatore , Bardelli Alberto 
Published: August 2014

Abstract
The anti EGFR monoclonal antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancer patients. The clinical efficacy of EGFR inhibitors is limited by the development of acquired resistance, which typically occurs within 3-12 months since starting of therapy. We recently reported that secondary KRAS mutations are responsible for acquired resistance in approximately 50% of patients (Misale et al.; Diaz et al., Nature 2012). We reasoned that the detection of KRAS mutant alleles in the plasma of cetuximab treated patients may enable the early identification of secondary resistance to anti EGFR blockade before radiographic documentation of relapse. Using the highly sensitive BEAMing approach we have examined cell-free circulating tumor DNA (ctDNA), a form of "liquid biopsy". KRAS mutant alleles emerged in the circulation of approximately 50% of patients treated with anti-EGFR antibodies months before radiographic documentation of disease progression. The liquid biopsy approach was then used to select patients in which KRAS mutations did not emerge during anti-EGFR therapy. Exome sequencing identified amplification of the MET proto-oncogene in biopsies from patients who did not develop KRAS mutations. Using an innovative approach, we find that MET amplification can be identified in a non-invasive manner through the examination of ctDNA months before relapse becomes clinically manifest. As multiple anti-MET therapeutic strategies are available, these findings offer immediate novel opportunities to design clinical studies.
Citation Format: Giulia Siravegna, Andrea Sartore Bianchi, Andrea Cassingena, Katia Bencardino, Luis A. Diaz, Mark Sausen, Victor E. Velculescu, Federica Di Nicolantonio, Salvatore Siena, Alberto Bardelli. Blood-based molecular detection of acquired resistance to anti-EGFR therapies in colorectal cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-75. doi:10.1158/1538-7445.AM2013-LB-75
Abstract LB-80: ATRX loss refines the classification of anaplastic glioma and is a favorable prognostic marker.
Authors: Wiestler Benedikt , Capper David , Holland-Letz Tim , von Deimling Andreas , Pfister Stefan M. , Platten Michael , Weller Michael , Wick Wolfgang 
Published: August 2014

Abstract
Mutation / loss of ATRX expression has been described in anaplastic gliomas. The present study explored the role for ATRX status in the molecular classification of anaplastic gliomas and the impact of ATRX status on survival in the biomarker cohort of the NOA-04 trial.
Patients (n=123) of the NOA-04 trial were analyzed for ATRX expression using immunohistochemistry. ATRX status was correlated with age, reference histology, IDH, 1p/19q and MGMT status, and the efficacy endpoints of the NOA-04 trial.
Loss of ATRX expression was detected in 42% of anaplastic astrocytomas, 24% of anaplastic oligoastrocytomas and 10% of anaplastic oligodendrogliomas. It was restricted to IDH mutated tumors and almost mutually exclusive with 1p/19q co-deletion. Anaplastic oligoastrocytoma harboring ATRX loss shared a similar clinical course with anaplastic astrocytoma. Survival analysis showed a separation of IDH mutant tumors into two groups based on ATRX status: Tumors with ATRX loss have a significantly better prognosis (median time to treatment failure 1758 days [95% CI 1316 days - to not reached] vs. 968 days [95% CI 496 days - to not reached], log rank test, p = 0.0044). Independent of histological subtype, patients whose tumors harbored ATRX loss had a longer overall survival when initially treated with radiotherapy rather than with chemotherapy (p = 0.03).
ATRX status helps to re-classify oligoastrocytomas, since ATRX loss is a hallmark of astrocytic tumors. Furthermore, ATRX loss defines a subgroup of tumors with a favorable prognosis and predicts benefit from radiotherapy.
Citation Format: Benedikt Wiestler, David Capper, Tim Holland-Letz, Andreas von Deimling, Stefan M. Pfister, Michael Platten, Michael Weller, Wolfgang Wick. ATRX loss refines the classification of anaplastic glioma and is a favorable prognostic marker. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-80. doi:10.1158/1538-7445.AM2013-LB-80
Abstract SY05-03: Mechanisms regulating stemness in skin cancers.
Authors: Blanpain Cedric 
Published: August 2014

Abstract
Cancer stem cells (CSCs) have been described in various cancers by their ability to reform secondary tumours upon transplantation into immunodeficient mice.
Using different approaches in mice, we have recently shown that squamous skin tumors contain stem cells that present the ability to reform the parental tumor upon transplantation (Lapouge et al. EMBO J 2012) or by their ability to fuel tumor growth using lineage tracing experiments (Driessens et al Nature 2012).
To define the mechanisms that regulate skin cancer stem cells, we transcriptionally profiled cutaneous CSCs at different stages of tumor progression. We uncovered a set of genes, which are enriched in CSCs irrespective of the stages of tumor progression and another set of genes, which are upregulated in CSCs only during malignant progression. We used genetic gain and loss of function in mice to unravel how some of these genes regulate tumor stemness and stimulate malignant transition in vivo within their natural environment. I will discuss how the combination of extrinsic factors such as the vascular niche (Beck et al. Nature 2011) and intrinsic factors regulate the renewal and invasive properties of CSCs during skin cancer progression.
This work is supported by WELBIO, the FNRS, the European Research Council (ERC) and the EMBO Young Investigator Program.
Citation Format: Cedric Blanpain. Mechanisms regulating stemness in skin cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY05-03. doi:10.1158/1538-7445.AM2013-SY05-03
Abstract SY08-01: AMPK and mTOR in nutrient signaling, metabolism, and autophagy regulation.
Authors: Kim Joungmok , Russell Ryan , Yuan Haxin , Guan Kun-Liang 
Published: August 2014

Abstract
Autophagy is a stress response protecting cells from unfavorable conditions, such as nutrient starvation. The cellular energy sensor AMPK and key growth controller mTOR, both are regulated by nutrient status, play major roles in autophagy regulation. The class III phosphatidylinositol-3 kinase, Vps34, forms multiple complexes and regulates both intracellular vesicle trafficking and autophagy induction. We show that AMPK plays a key role in regulating different Vps34 complexes. AMPK inhibits the non-autophagy Vps34 complex by phosphorylating Vps34 and suppresses overall PI(3)P production and protects cells from starvation. In parallel, AMPK activates the pro-autophagy Vps34 complex by phosphorylating Beclin1 to induce autophagy. Atg14L, an autophagy essential gene present only in the pro-autophagy Vps34 complex, inhibits Vps34 phosphorylation but increases Beclin1 phosphorylation by AMPK. As such, Atg14L dictates the differential regulation (either inhibition or activation) of different Vps34 complexes in response to glucose starvation. In addition, the Vps34 complex is regulated by mTOR, which is inhibited by nutrient starvation. mTOR phosphorylates Beclin to inhibit the autophagy specific Vps34 complex. Our study reveals an intricate molecular regulation of Vps34 complexes by AMPK and mTOR in nutrient stress response and autophagy.
Citation Format: Joungmok Kim, Ryan Russell, Haxin Yuan, Kun-Liang Guan. AMPK and mTOR in nutrient signaling, metabolism, and autophagy regulation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY08-01. doi:10.1158/1538-7445.AM2013-SY08-01
Abstract SY09-01: Inflammatory networks and cancer immune surveillance.
Authors: Vonderheide Robert H. 
Published: August 2014

Abstract
Cancer-associated inflammation is felt to restrain tumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA) for which a massive infiltration of immunosuppressive leukocytes into tumor stroma accompanies cancer growth. Gr-1+ CD11b+ cells, often called myeloid-derived suppressor cells (MDSCs), are a key feature of cancer inflammation in this disease, but the crosstalk between Gr-1+ CD11b+ cells and PDA tumor cells remains incompletely understood. In a genetically engineered mouse model of invasive PDA, Gr-1+ CD11b+ myeloid cells accumulate in primary and metastatic lesions and potently inhibit proliferation of antigen-specific T cells. Among the many cytokines and chemokines produced by PDA tumors, GM-CSF was both necessary and sufficient to drive proliferation and differentiation of c-kit+Gr-1negCD11bneg splenocytes from tumor-bearing mice into functional MDSCs. In vivo, abrogation of GM-CSF accomplished either with neutralizing antibodies or shRNA inhibited the recruitment of Gr-1+ CD11b+ cells to the tumor microenvironment and blocked tumor development. This inhibition of tumor growth was reversed by in vivo CD8 T cell depletion. These findings demonstrate that tumor-derived GM-CSF regulates a major component of myeloid inflammation and T cell immunity in PDA and suggest new targets with therapeutic potential for disrupting cancer inflammation and enhancing immunity. To test if these findings extend to other gastrointestinal cancers, such as esophageal squamous cell carcinoma, a second genetically engineered mouse model of cancer that recapitulates esophageal squamous cell carcinoma was evaluated. In this model, desmoplasia and a prominent myeloid inflammatory response around early and advanced lesions are observed, associated with tumor prand strikingly, tumor progression was significantly halted when this inflammation was eliminated. Thus, there is a common theme among epithelial-derived upper gastrointestinal tumors by which tumor-derived factors drive an inflammatory program that fosters tumorigenesis and tumor invasion, at least in part through the inhibition of anti-tumor immunity.
Citation Format: Robert H. Vonderheide. Inflammatory networks and cancer immune surveillance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY09-01. doi:10.1158/1538-7445.AM2013-SY09-01
Abstract SY11-03: Circulating tumor DNA as a non-invasive diagnostic and research tool.
Authors: Rosenfeld Nitzan 
Published: August 2014

Abstract
In patients with solid malignancies, cell-free DNA carrying tumor-specific sequences can be found in body fluids such as blood plasma. This circulating tumor DNA (ctDNA) contains representation of the entire cancer genome, broken down into short mutation-carrying fragments, whose relative levels vary in response to treatment and progression. Different approaches to the study of ctDNA can work together to provide a window for noninvasive analysis of the cancer genome and its dynamics. Quantification of ctDNA levels may be useful as a prognostic biomarker and to assess response to treatment. When cancer overcomes treatment and progresses, the fraction of mutant alleles in plasma DNA can reach levels of 10%~20% or more, which makes it possible to study cancer evolution noninvasively by whole-genome or exome analysis of plasma DNA. Sensitivity and resistance to targeted therapies are often associated with known mutations in hotspot loci or genes. In advanced cancer patients, the status of pre-defined mutations can be analyzed noninvasively using circulating plasma DNA as a liquid biopsy. Targeted sequencing of limited regions in circulating DNA can allow identification of de novo mutations, even when these are present as rare fragments. This also facilitates parallel quantification of multiple mutations in plasma, which can indicate the relative systemic burden of different mutations or clones. Routine monitoring for sensitizing and resistance-conferring mutations may provide a framework for rational adaptive cancer therapy, providing real-time information on mutation levels to guide treatment against the most aggressive or treatable clones.
Citation Format: Nitzan Rosenfeld. Circulating tumor DNA as a non-invasive diagnostic and research tool. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY11-03. doi:10.1158/1538-7445.AM2013-SY11-03
Abstract SY12-03: Multi-tumor analysis of TCGA data identifies expression commonalities across tumor types.
Authors: Hoadley Katherine A. , Fan Cheng , Wilkerson Matthew D. , Mose Lisle E. , Jefferys Stuart R. , Auman J. Todd , Parker Joel S. , Hayes D. Neil , Perou Charles M. 
Published: August 2014

Abstract
High dimensional assays, such as DNA microarrays for gene expression, have helped delineate the complexity and diversity of most major cancer types. The Cancer Genome Atlas (TCGA), with its goal to comprehensively genomically characterize over twenty different types of tumors, gives us a wealth of data to start looking at similarities across tumor types. Much of the current data is now generated using Massively Parallel Sequencing (MPS) approaches, which yields tens of millions of “reads” per sample. Illumina Hiseq-based mRNA-sequencing data for twelve tumor types representing over 3,500 samples were analyzed for patterns unique to each tumors, and patterns present across multiple tumor types. Tumor types tested included rectal adenocarcinoma, colon adenocarcinoma, lung squamous cell carcinoma and adenocarcinoma, uterine corpus endometrial carcinoma, ovarian serous cystadenocarcinoma, kidney clear cell, breast ductal and lobular carcinoma, glioblastoma multiforme, bladder carcinomas, acute myeloid leukemia, and head and neck squamous cell carcinoma. Tissue-specific expression was the dominant signature; however, there were similarities across sets of tumors including a common “squamous” pattern that was populated by tumors from three distinct anatomic sites.
Pathway or Module-based analysis also provided methods to comparisons across tissues. Cross tissue analysis of mRNA-seq data provides interesting observations of common tumor biology with potential insights into treatment.
Citation Format: Katherine A. Hoadley, Cheng Fan, Matthew D. Wilkerson, Lisle E. Mose, Stuart R. Jefferys, J. Todd Auman, Joel S. Parker, D. Neil Hayes, Charles M. Perou. Multi-tumor analysis of TCGA data identifies expression commonalities across tumor types. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY12-03. doi:10.1158/1538-7445.AM2013-SY12-03
Abstract SY17-01: BRAF and RAS signaling in melanoma: Basic biology to clinical exploitation.
Authors: Marais Richard M. 
Published: August 2014

Abstract
BRAF is mutated in about 45% of melanomas and its upstream activator NRAS is mutated in a further 30% of cases. We have developed mouse models of melanoma driven by these oncogenes. Expression of oncogenic BRAF in mature mouse melanocytes induces melanoma, whereas its expression in embryonic mouse melanocytes is embryonically lethal. In contrast, expression of oncogenic NRAS in mature melanocytes does not induce melanoma, but its expression in embryonic mouse melanocytes induces melanomas of the brain that bear the cardinal features of leptomeningeal melanocytosis in children. We are using these models and human xenograft of patient melanomas grown in immuno-compromised mice to study mechanisms of resistance to BRAF pathway inhibitors. We find that up-regulation of EGF receptor pathway signaling can mediate resistance to BRAF inhibitors by signaling through the PI3 kinase AKT pathway. A combination of a BRAF and EGF receptor inhibitor, or a broad specificity SRC inhibitor can overcome resistance, potentially offering second-line treatments to relapsed patients.
Citation Format: Richard M. Marais. BRAF and RAS signaling in melanoma: Basic biology to clinical exploitation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY17-01. doi:10.1158/1538-7445.AM2013-SY17-01
Abstract SY19-01: Chemical genetic investigations of protein and lipid kinase signaling.
Authors: Shokat Kevan M. 
Published: August 2014

Abstract
Kinases are highly regulated enzymes with diverse mechanisms controlling their catalytic output. Inhibitor discovery efforts for kinases have produced ATP-competitive compounds, allosteric regulators, irreversible binders, and highly specific inhibitors. These distinct classes of small molecules have revealed many novel aspects about kinase-mediated signaling and some have progressed from simple tool compounds into clinically validated therapeutics. My presentation will explore several small-molecule inhibitors for kinases highlighting elaborate mechanisms by which kinase function is modulated. A complete surprise of targeted kinase drug discovery has been discovery of ATP-competitive inhibitors that behave as agonists, rather than antagonists, of their direct kinase target. These studies hint at a connection between ATP binding site occupancy and networks of communication that are independent of kinase catalysis. Indeed, kinase inhibitors have been found that induce changes in protein localization, protein-protein interactions, and even enhancement of catalytic activity of the target kinase. The relevance of these findings to the therapeutic efficacy of kinase inhibitors and to the future identification of new classes of drug targets will be discussed.
Citation Format: Kevan M. Shokat. Chemical genetic investigations of protein and lipid kinase signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY19-01. doi:10.1158/1538-7445.AM2013-SY19-01
Abstract SY25-03: Haploinsufficiency in cancer: When half simply isn't good enough.
Authors: Solimini Nicole , Pavlova Natalya N. , Mermel Craig , Xu Qikai , Burrows Anna E. , Luo Ji , li Mamie , Beroukhim Rameen , Meyerson Matthew , Elledge Stephen J. 
Published: August 2014

Abstract
Breast cancer is a collection of diseases with distinct clinical behaviors and underlying genetic causes. We have searched genetically for genes that have cancer relevant phenotypes including genes that alter cellular proliferation, cellular transformation, cell survival, cellular senescence, and genes that are essential for the proliferation of cancer cells. We have approached this by the generation of libraries of shRNAs for loss of function experiments and libraries of ORFs for gain of function experiments. We will discuss these technologies and how they can be applied to the functional dissection of genes important for breast cancer. Using these technologies, we found evidence for wide-spread haploinsufficiency in cancer due to recurring hemizygous deletions. We propose a tumor suppressor hypothesis called the Cancer Gene Island model whereby, hemizygous deletions selledge regions containing a high density of negative growth regulators (STOP genes) and a low density of essential genes (GO genes). The deletions provide a proliferative advantage to cells through cumulative haploinsufficiency.
Citation Format: Nicole Solimini, Natalya N. Pavlova, Craig Mermel, Qikai Xu, Anna E. Burrows, Ji Luo, Mamie li, Rameen Beroukhim, Matthew Meyerson, Stephen J. Elledge. Haploinsufficiency in cancer: When half simply isn't good enough. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY25-03. doi:10.1158/1538-7445.AM2013-SY25-03
Abstract SY26-03: Innate immune sensing of tumors via the host STING pathway as a bridge to a spontaneous adaptive T cell response.
Authors: Gajewski Thomas Frank 
Published: August 2014

Abstract
Recent evidence has suggested that clinical responses to immunotherapeutic interventions occur predominantly in patients having a pre-existing anti-tumor immune response and a T cell-inflamed tumor microenvironment. It has therefore become critical to understand the mechanism by which a subset of patients generates this phenotype, which should instruct on how to deliberately facilitate generation of appropriate tumor-based inflammation and thereby expand the fraction of patients deriving clinical benefit from immunotherapy. However, the mechanisms by which innate immune responses become activated in response to cancer, and how they can bridge to spontaneous T cell priming against tumor antigens, have remained poorly defined. We recently reported that host type I IFN signals are required for a spontaneous T cell response against tumors. In the current work, we have mapped the sensing mechanism to one involving STING/TBK1/IRF3 which drives IFN-β transcription by host APCs. Spontaneous T cell responses against tumors were eliminated in mice deficient in STING or IRF3, and rejection of immunogenic tumors was abrogated. The tumor-derived ligand that triggers this pathway appears to be DNA. Using the DNA-specific dye DRAQ5 or EDU labeling and single cell ImageStream analysis, we demonstrated that in vivo transfer of tumor DNA to host APCs occurs in vivo; this was confirmed using PCR specific for tumor DNA. APC uptake of tumor DNA was associated with IFN-β mRNA induction and nuclear translocation of IRF-3, which were dependent upon host STING. We hypothesized that autophagosome provide a mechanism for delivery of protected tumor DNA into APCs. Inhibition of tumor cell autophagy using the chemical 3-MA, or shRNA silencing of Becn or ATG5, led to a marked reduction in the induction of host IFN-β production and spontaneous T cell responses in vivo. Our data suggest that tumor cell autophagy is required for optimal T cell priming against tumor antigens in vivo, that occurs through DNA-mediated activation of host IFN-β production through a STING-dependent pathway. Analysis of these biologic steps in human melanoma metastases is ongoing. Strategies to mimic activation of the STING pathway should be considered as a mechanism to create an inflamed tumor microenvironment with the hope of expanding the clinical efficacy of T cell-based immunotherapies.
Citation Format: Thomas Frank Gajewski. Innate immune sensing of tumors via the host STING pathway as a bridge to a spontaneous adaptive T cell response. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY26-03. doi:10.1158/1538-7445.AM2013-SY26-03