bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-242: Identification of T-cell receptors targeting KRAS-mutated human tumors
Authors: Wang Qiong J. , Yu Zhiya , Hanada Kenichi , Restifo Nicholas P. , Yang James C. 
Published: July 2016

Abstract
KRAS is one of the most frequently mutated proto-oncogenes in human cancers, including pancreatic and colorectal cancers. The dominant oncogenic mutations of KRAS are single amino acid substitutions at codon 12, in particular G12D and G12V. The consistency, frequency, and tumor specificity of these “neo-antigens” make them attractive therapeutic targets. Recent data associates T cells targeting mutated antigens with clinical immunotherapy responses in patients with metastatic melanoma, lung cancer or cholangiocarcinoma. We successfully generated T cells from HLA-A11*01 transgenic mice and subsequently isolated HLA-A11*01-resticted T cell receptors (TCRs) highly reactive with the mutated KRAS variants G12V and G12D. Peripheral blood lymphocytes (PBL) transduced with these TCRs can recognize multiple HLA-A*11:01+ tumor lines bearing the appropriate KRAS mutations. In a xenograft model of large established tumor, adoptive transfer of these transduced PBL reactive with a mutated pancreatic cell line could significantly reduce its growth in NSG mice. The success of adoptive transfer of TCR-engineered T cells against melanoma and other cancers support clinical trials with these T-cells recognizing mutated KRAS in patients with a variety of common cancer types. A phase I/II clinical trial targeting KRAS G12V and G12D mutations with TCR-engineered PBL in HLA-A1101+ patients will be starting soon in the Surgery Branch NCI.
Citation Format: Qiong J. Wang, Zhiya Yu, Kenichi Hanada, Nicholas P. Restifo, James C. Yang. Identification of T-cell receptors targeting KRAS-mutated human tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-242.
Abstract LB-246: Next generation sequencing (NGS) reveals high mutation rates in established and potentially novel cancer genes involved in triple-negative breast cancer
Authors: Bemanian Vahid , Sauer Torill , Touma Joel , Vetvik Katja , Chen Ying , Kristensen Vessela , Bukholm Ida , Geisler Jürgen 
Published: July 2016

Abstract
Introduction. Following the development of novel targeted therapies for selected breast cancer (BC) patients (like HER-2 pos. BC), the subgroup of triple-negative breast cancer (TNBC) patients is still characterized by a poor prognosis and a lack of reliable tumor markers that might guide medical therapy. Methods. Genomic DNA was extracted from paraffin embedded formalin fixed (FFPE) tissue obtained from 77 consecutive patients diagnosed with a TNBC at our hospital. The DNA samples were analyzed by next-generation sequencing (NGS) using Human Breast Cancer GeneRead DNAseq Targeted Panel V2 (Qiagen). The panel consists of a collection of PCR primers for targeted enrichment of the coding region of 44 genes commonly mutated in breast cancer. Target enrichment and library construction was performed according to the GeneReader workflow (Qiagen) and paired end sequencing was performed on a NextSeq 500 sequencer (Illumina) running 2 × 150 bp chemistry Version 2. Data analysis including alignment to the reference genome hg19 and variant calling was performed using Qiagen's online Ingenuity Variant analysis. Results. The ingenuity variant analysis classified the genetic mutations according to their clinical significance into four groups: pathogenic, likely pathogenic, benign and likely benign. We present only mutations in genes that are characterized as pathogenic or likely pathogenic, where the term “likely pathogenic” indicates greater than 90% certainty of the mutation being pathogenic (as defined by the American College of Medical Genetics and Genomics). Genetic variations were mostly observed in a subset of 44 genes included in the breast cancer panel. The tumor suppressor genes TP53 as well as BRCA1 and BRCA2 represented the highest mutation rates (&gt;5%) among all TNBC samples. Interestingly, additional genes probably playing a pivotal role in breast cancer biology like EP300 and FGFR-1 were also found to be mutated at a high rate in TNBC. Conclusion. Next generation sequencing of samples obtained from primary TNBC patients confirmed a high level of pathogenic or likely pathogenic mutations in well-described key cancer genes like TP53, BRCA1/2, ATM, EGFR, RB1 and PIK3CA and frequently mutated additional genes (EP300, FGFR1) that will be further investigated.
Citation Format: Vahid Bemanian, Torill Sauer, Joel Touma, Katja Vetvik, Ying Chen, Vessela Kristensen, Ida Bukholm, Jürgen Geisler. Next generation sequencing (NGS) reveals high mutation rates in established and potentially novel cancer genes involved in triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-246.
Abstract LB-256: Clonogenic growth of androgen receptor-overexpressing models of castration recurrent prostate cancer cells becomes insensitive to receptor ligands when their complete cellular secretory milieu is restored
Authors: Patki Mugdha , Huang Yanfang , Ratnam Manohar 
Published: July 2016

Abstract
Evidence that androgen receptor (AR) overexpression causes castration recurrent prostate cancer (CRPC) cells to thrive on minimal residual post-castrate androgen is derived from studies of in vitro colony formation in the absence of cell-secreted factors or from studies demonstrating synergy between androgen and individual signaling pathways in isolation. We examined androgen-dependence using in vivo generated CRPC model cells overexpressing full length AR (C4-2 cells) or co-expressing a splice-variant (22Rv1 cells). The cells showed robust colony formation in conditioned media lacking androgenic activity derived from the same cells or from HEK293 fibroblasts. This effect was (i) not enhanced by androgen (ii) insensitive to blocking ligand-dependent transcriptional activity of AR, (iii) insensitive to mifepristone
(iv) AR-dependent, (v) associated with AR phosphorylation and (vi) similar to androgen-stimulation in sensitivity to signaling pathway inhibitors. This ligand-insensitive response of overexpressed AR to the total cellular secretory complement may limit interventions targeting hormonal factors in CRPC.
Citation Format: Mugdha Patki, Yanfang Huang, Manohar Ratnam. Clonogenic growth of androgen receptor-overexpressing models of castration recurrent prostate cancer cells becomes insensitive to receptor ligands when their complete cellular secretory milieu is restored. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-256.
Abstract LB-265: IRF8 is an essential transcriptional activator of iNOS although MDSCs up-regulate iNOS expression via an IRF8-independent mechanism
Authors: Ibrahim Mohammed M. , Paschall Amy V. , Redd Priscilla S. , Liu Kebin 
Published: July 2016

Abstract
Nitric Oxide Synthase (NOS) is a family of enzymes that catalyzes L-arginine metabolism to generate nitric oxide (NO). There are three main isoforms of NOS, named neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS or NOS2). These three distinct isoforms of NOS have different cellular localization, regulation, and catalytic properties. iNOS is the most extensively studied one among these three NOS isoforms. iNOS was originally identified in myeloid cells, and it is known that its expression is often induced after myeloid cell activation by endotoxins or cytokines to generate NO which then acts as a defense effector to suppress invading microorganisms or neoplastic cells. It is known that IFNγ signaling pathway and NF-κB synergistically regulate iNOS expression, and that IFN regulatory factor 8 (IRF8) enhances interaction between IFNγ signaling and NF-κB in regulation of iNOS expression. However, the molecular mechanism underlying iNOS expression regulation in myeloid cell lineage is still not fully understood. We report here that IRF8 is an essential transcription activator of iNOS in myeloid cells since IRF8-deficient myeloid cells lose iNOS expression. Furthermore, a key phenotype of IRF8 KO mice is the mass accumulation of CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs), suggesting that IRF8 is a key suppressor of MDSC differentiation under physiological conditions. On the other hand, accumulation of MDSCs is a hallmark of cancers and iNOS expression is dramatically elevated in tumor-induced MDSCs, despite that tumor-induced MDSCs exhibit diminished IRF8 expression. Furthermore, the IFNγ signaling pathway is impaired and NF-κB subunits are undetectable in tumor-induced MDSCs. Our data therefore indicate that iNOS expression is activated by an IRF8-independent mechanism that is also IFNγ and NF-κB-independent in tumor-induced MDSCs under pathological conditions. At the functional level, we determined that iNOS-KO mice exhibit lower tumor incidence as compared to WT mice. However, the sizes of established tumors are not different between iNOS-KO mice and WT mice. Taken together, our data determine that IRF8 is an essential transcriptional activator of iNOS expression in myeloid cells under physiological conditions, although iNOS expression is activated by an IFNγ-, NF-κB-, and IRF8-independent mechanism in tumor-induced MDSCs under pathological conditions. iNOS acts as a suppressor of tumor cell colonization but not tumor growth.
Citation Format: Mohammed M. Ibrahim, Amy V. Paschall, Priscilla S. Redd, Kebin Liu. IRF8 is an essential transcriptional activator of iNOS although MDSCs up-regulate iNOS expression via an IRF8-independent mechanism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-265.
Abstract LB-269: Engineering a vascularized 3D in vitro model of cancer progression
Authors: Magdeldin Tarig , Emberton Mark , Loizidou Marilena , Cheema Umber 
Published: July 2016

Abstract
Microenvironmental cues regulate the neo-vascularisation and angiogenic processes within a tumour. The hallmark of cancer is the ability of cancer cells to disseminate and invade to distant sites. The presence of a ‘leaky’ vasculature in the tumour microenvironment facilitates this migration of cancer cells. Using tissue-engineering strategies, we have developed a 3D in vitro cancer model (tumouroid), where we have engineered specific compartments for both the cancer mass and the surrounding stroma. We have utilized a biomimetic matrix for the cancer mass the stroma engineered of collagen I and laminin, and used plastic compression to increase the cell and matrix density by removal of interstitial fluid in collagen hydrogels. We created artificial cancer masses (ACMs) containing colorectal cancer cells (HT29 and HCT116) and nested them within collagen/laminin stromal surrounds (SS) (both ∼10% w/v collagen) containing human dermal fibroblasts (HDFs) and endothelial cells (HUVECs). We have delineated cell specific mechanisms to describe changes in the invasion pattern of cancer cells dependent upon the stromal composition and density. HT29 cells invaded as spherical aggregates of cells while HCT116 cells invaded as contiguous cell sheets. Multicellular cultures were maintained for up to 21 days and endothelial cell morphology was investigated using immunofluorescence of CD31. In HDF-HUVEC co-cultures, HUVECs formed highly branched (29.25 ± 3.86 branches) end-to-end networks with an average length and width of 197.4μm ± 87.5μm and 19μm ± 8.1μm respectively. In the presence of HT29 cancer cells, HUVEC network formation was considerably altered with HUVECs forming much longer and wider networks (456.8μm ± 136μm and 24.2μm ± 7μm) but significantly less interconnected (13.5 ± 5.1 branches). The loss of CK20 expression by the invading cancer epithelial cell sheet was also confirmed by immunofluorescence. The loss of CK20 expression has been known to correspond with high levels of microsatellite instability and overall poor prognosis1. These findings signify the importance of a biomimetic environment in which to culture cancer cells, to mimic the native physiological response of these cells. The tumouroid model is an important tool to study the effect of microenvironmental conditions on tumor malignancy in vitro and in vivo.
1. Kim, J. H., Rhee, Y., Bae, J. M., Cho, N. & Kang, G. H. Loss of CDX2/CK20 expression is associated with poorly differentiated carcinoma, the CpG island methylator phenotype, and adverse prognosis in microsatellite-unstable colorectal cancer. Am. J. Surg. Pathol. 37, 1532-41 (2013).
Citation Format: Tarig Magdeldin, Mark Emberton, Marilena Loizidou, Umber Cheema. Engineering a vascularized 3D in vitro model of cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-269.
Abstract LB-270: Inhibition of the stromal p38MAPK pathway abrogates breast cancer metastases
Authors: Stewart Sheila A. , Murali Bhavna , Su Xinming , Flanagan Kevin , Sponagel Jasmin , Luo Xianmin , Fu Yujie , Alspach Elise , Leahy Kathleen , Monahan Joseph , Weilbeacher Katherine 
Published: July 2016

Abstract
Bone metastasis is a devastating and fatal complication of breast cancer for which we lack effective therapies. Thus, identifying therapies that effectively limit metastases will significantly reduce comorbidities and improve long-term survival. Recently we demonstrated that the p38MAPK pathway sustains the pro-tumorigenic senescence-associated secretory phenotype (SASP) and targeting this pathway limits the tumor-promoting capabilities of senescent cells and cancer-associated fibroblasts (CAFs). Because we found that a significant percentage of p38MAPK-dependent SASP factors are expressed in the stroma associated with breast cancer lesions, we asked whether targeting p38MAPK could limit primary and metastatic breast cancer growth. While p38MAPK inhibition modestly limited primary tumor growth, we found that this inhibition significantly reduced breast cancer bone metastases by targeting the stromal compartment. Further, p38MAPK inhibition was as effective as paclitaxel at limiting tumor growth in the bone but in contrast to paclitaxel, which failed to protect from cancer-induced bone loss, p38MAPK inhibition also protected against devastating bone loss. This contrasts our p38MAPK approach from zoledronic acid, which limits bone loss but fails to slow tumor growth in already engrafted tumors. Analysis of the mechanism(s) responsible for this reduced metastasis suggests that p38MAPK inhibition specifically targets reactive and/or senescent osteoblasts within the bones of animals harboring metastatic lesions. Because we find that senescent osteoblasts are present in human bone, we postulate that they promote metastatic outgrowth and thus p38MAPK inhibition limits the pro-metastatic activities of these cells. Finally, we will present recent data from our clinically relevant preclinical model that demonstrates that inhibition of the p38MAPK pathway can drastically reduce metastasis from the primary site. We propose that p38MAPK is an important stromal-specific therapy for breast cancer metastasis to the bone.
Citation Format: Sheila A. Stewart, Bhavna Murali, Xinming Su, Kevin Flanagan, Jasmin Sponagel, Xianmin Luo, Yujie Fu, Elise Alspach, Kathleen Leahy, Joseph Monahan, Katherine Weilbeacher. Inhibition of the stromal p38MAPK pathway abrogates breast cancer metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-270.
Abstract LB-273: Identity card of tumor-infiltrating regulatory T cells in the context of tertiary lymphoid structures in lung cancer patients
Authors: DEVI Priyanka , Leveugle Sylvain , Goc Jeremy , Kaplon Helene , Germain Claire , Knockaert Samantha , Validire Pierre , Damotte Diane , Katsahian Sandrine , Fridman Wolf Herve , Sautes-Fridman Catherine , Lawand Myriam , Dieu-Nosjean Marie-Caroline 
Published: July 2016

Abstract
Regulatory T cells (Tregs) exert various suppressive mechanisms to dampen the host immune response which can help tumor cells to escape immune surveillance. However, the prognostic value of tumor-infiltrating Tregs (Ti-Tregs) is controversial. We described, tumor-associated tertiary lymphoid structures (TLS) in lung cancers, shown that they are critical for the local coordination and polarization of protective immunity and are able to imprint the behavior of intra-tumoral CD8+ T cells. The aim of the study was to determine the role of Ti-Tregs in the shaping of the local immune response in the context of TLS. We studied the differentiation, activation, immunosuppression, and immune checkpoint (ICP) status of Ti-Tregs in different areas of human lung tumors on a prospective cohort of 50 lung cancer specimens.
In lung cancer patients, CD3+FoxP3+ cells were detected in different zones of the tumor i.e. the tumor stroma (TLS and non-TLS areas) and to a lesser extend in tumor nests. They express CD4 and all markers of human Tregs. As observed for conventional CD4+ T cells, Ti-Tregs show central-memory and effector-memory phenotype. Based on the expression of activation, immunosuppression and ICP (gene and protein level), Tregs exhibit a fully activated phenotype in tumor compared to distant sites of NSCLC patients. Interestingly, Ti-Tregs display a common phenotype in TLS versus out TLS but with some key specificities regarding immune checkpoint expression.
In conclusion, the presence of several Ti-Treg subsets in lung tumor suggests they may use distinct mechanisms to exert their immunosuppressive functions in the different tumor areas.
Citation Format: Priyanka DEVI, Sylvain Leveugle, Jeremy Goc, Helene Kaplon, Claire Germain, Samantha Knockaert, Pierre Validire, Diane Damotte, Sandrine Katsahian, Wolf Herve Fridman, Catherine Sautes-Fridman, Myriam Lawand, Marie-Caroline Dieu-Nosjean. Identity card of tumor-infiltrating regulatory T cells in the context of tertiary lymphoid structures in lung cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-273.
Abstract LB-276: The identification and characterization of prostate adenocarcinoma tumor initiating cells
Authors: Agarwal Supreet , Hynes Paul , Lake Ross , Fang Lei , Tillman Heather , Beshiri Mike , Jansson Keith , Karthaus Wouter , Iaquinta Philip , Sawyers Charles , Kelly Kathleen 
Published: July 2016

Abstract
Primary prostate cancer is typically of luminal phenotype. However, little is known about the stem/progenitor properties of transformed luminal tumor cells as they fail to survive in culture. Using the organoid culture methodology, we show two distinct luminal progenitors in aggressive Pten/Tp53-null mouse model of prostate cancer. Not only did tumors contain previously described multipotent progenitors, but also a major population of committed luminal progenitors. The distinction between committed luminal and multipotent organoids was also evident in subcutaneous grafts as tumors of adenocarcinoma or multilineage histological phenotypes were observed, respectively. Moreover, using organoids we show that the self-renewing capacity of luminal-committed progenitors is a tumor-specific property, absent in benign luminal cells. Further, a significant fraction of luminal progenitors displayed resistance to in vivo castration as well as to androgen receptor inhibition ex vivo. Importantly, 3D organoid techniques have allowed us to relate our findings in humans as we can successfully grow similar luminal tumor populations from patient derived xenografts (PDXs) models of prostate cancer. In all, these data reveal two distinct luminal tumorigenic populations in mouse models of prostate cancer, providing insight into luminal tumor initiating cells in prostate cancer that can also influence response to therapy.
Citation Format: Supreet Agarwal, Paul Hynes, Ross Lake, Lei Fang, Heather Tillman, Mike Beshiri, Keith Jansson, Wouter Karthaus, Philip Iaquinta, Charles Sawyers, Kathleen Kelly. The identification and characterization of prostate adenocarcinoma tumor initiating cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-276.
Abstract LB-278: Cancer stem cells as the novel origin of cancer-associated fibroblast-like cells
Authors: Nair Neha , Vaidyanath Arun , Hoshikawa Kenta , Sanchez Calle Anna , Kasai Tomonari , Seno Masaharu 
Published: July 2016

Abstract
Cancer associated fibroblast (CAF) is an indispensible component of stromal microenvironment mediating cancer progression notably in breast, prostate and pancreatic carcinoma. CAF heterogeneity is attributed to its possible multiple origin majorly from tumor resident fibroblast, mesenchymal stem cells, epithelial cells. The present work analyses the possibility of cancer stem cells (CSC) as the source of CAF like cells. For this, we have used the model of CSC established in our laboratory derived from mouse induced pluripotent cells (miPSCs) by culturing with conditioned medium from cancer cell lines mimicking tumor microenvironment. In the present study, human breast cancer derived T47D and BT549 cells have been cultured to collect the conditioned medium. Since the green fluorescent protein (GFP) gene was integrated under the control of Nanog promoter in the miPSCs used in this study, the resulting CSCs was assessed by the expression of GFP for the undifferentiated state. The differentiation of CSCs was tracked by the attenuation of GFP.
The CSC population was multiplied by serial subcutaneous and orthotropic transplantation in nude mice. This population was further enriched by sphere formation. Then these spheres were allowed to differentiate into adhesive cells. The CAF-like cells were separated from the differentiated population. The expression of prominent CAF markers fibroblast specific protein (FSP), fibroblast activation protein (FAP), vimentin, collagen type1 α1, and smooth muscle actin (SMA) were assessed by real time PCR. Immuno-cytochemistry of the cells for the expression of FSP, FAP and SMA was further confirmed for the evidence that cancer stem cells should be a possible source of CAF. This model should elaborate the functional heterogeneity amongst CAFs and help design therapeutic interventions to inhibit such conversions.
Citation Format: Neha Nair, Arun Vaidyanath, Kenta Hoshikawa, Anna Sanchez Calle, Tomonari Kasai, Masaharu Seno. Cancer stem cells as the novel origin of cancer-associated fibroblast-like cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-278.