bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 289: The combination of CD40 agonism and PD-L1 blockade enhances anti-tumor immunity in a mouse syngeneic orthotopic pancreatic tumor model
Authors: Luheshi Nadia , Coates-Ulrichsen Jane , Harper James , Davies Gareth , Legg James , Wilkinson Robert 
Published: August 2015

Abstract
Infiltration of immunosuppressive myeloid cells into tumors correlates with poorer prognosis in many cancer types. The immunosuppressive effects of these cells help to create a microenvironment that may inhibit responses to T cell-directed immunotherapies. Anti-CD40 agonistic antibodies (αCD40) promote myeloid cell maturation, license cross-presentation of antigens to cytotoxic T cells, and enhance direct macrophage tumoricidal activity. We tested the hypothesis that αCD40 can improve responses to PD-L1 blockade via enhancing anti-tumor immunity in a syngeneic orthotopic mouse model of pancreatic cancer (Pan02). Whilst PD-L1 blockade alone had limited effect on tumor growth, we demonstrated that αCD40 drove antigen presenting cell maturation and systemic immune activation, inhibiting tumor growth and improving overall survival. αCD40 also induced upregulation of PD-L1 both systemically and within the tumor microenvironment. Furthermore, the combination of αCD40 and PD-L1 blockade led to enhanced tumor growth inhibition and improved anti-tumor immunity compared to either monotherapy alone. These data provide further support for the potential benefits of re-educating tumor myeloid cells.
Citation Format: Nadia Luheshi, Jane Coates-Ulrichsen, James Harper, Gareth Davies, James Legg, Robert Wilkinson. The combination of CD40 agonism and PD-L1 blockade enhances anti-tumor immunity in a mouse syngeneic orthotopic pancreatic tumor model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 289. doi:10.1158/1538-7445.AM2015-289
Abstract 293: Therapeutic effects of the bromodomain inhibitors JQ1 and I-BET 762 on pancreatic cancer
Authors: Leal Ana S. , Williams Charlotte R. , Sporn Michael B. , Liby Karen T. 
Published: August 2015

Abstract
Pancreatic cancer is expected to be the second most deadly cancer by 2030 with very few effective therapeutic options to improve patient survival. Bromodomain inhibitors (JQ1 and I-BET 762) are a new generation of chemotherapeutic drugs that target BET proteins, impairing their ability to bind to acetyl modified lysines and therefore interfering with transcriptional initiation and elongation. BET proteins regulate several genes responsible for cell cycle, apoptosis and inflammation. I-BET 762 is currently in clinical trials for cancer and has the advantage of oral administration.
Kras is one of the most common mutated genes in pancreatic cancer (90%); however its protein is a difficult drug target. p-Erk, responsible for several pathways regulating cell survival, is a downstream effector of Kras that has been shown to be essential for the progression and maintenance of pancreatic cancer. LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) and LSL-KrasG12D/+;Pdx-1-Cre (KC) mouse models are commonly used to study pancreatic cancer. KPC mice develop the full spectrum of pancreatic cancer by an average age of 20 weeks. The KC mouse model is commonly used to study pancreatic cancer progression after stimulation with a pancreatic inflammatory agent, such as cerulein.
JQ1 and I-BET 762 reduce the protein levels of p-ERK 1/2 in cells lines derived from a pancreatic tumor or ascites of KPC animals. JQ1 and I-BET 762 are also effective at inhibiting cell growth in human pancreatic cells harboring Kras mutations. When KC mice are injected with LPS to induce inflammation and pancreatitis, p-ERK 1/2 protein levels are significantly increased. This model is being used to test the effects of JQ1 and I-BET 762 after a single LPS injection, in KC mice.
Pancreatic cancer is driven by several cytokines and chemokines, including CCL2 and IL-6, which recruit and regulate the inflammatory cells (macrophages, T cells and MDSC (Myeloid derived suppressor cells) cells) in the tumor. Levels of IL-6 and CCL2 in cell lines developed from KPC mice are reduced when treated with JQ1 and I-BET 762. KC mice stimulated with LPS also have higher levels of CCL2 and IL-6 than mice stimulated with saline.
In conclusion this study showed that the bromodomain inhibitors JQ1 and I-BET 762 had positive effects in suppressing targets of inflammation in pancreatic cancer.
We thank James Bradner for the generous gift of JQ1.
Citation Format: Ana S. Leal, Charlotte R. Williams, Michael B. Sporn, Karen T. Liby. Therapeutic effects of the bromodomain inhibitors JQ1 and I-BET 762 on pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 293. doi:10.1158/1538-7445.AM2015-293
Abstract 2933: The apoptotic mechanism of action of SKI-178, a novel Sphingosine kinase 1 selective inhibitor
Authors: Dick Taryn E. , Hengst Jeremy , Kale Vijay , Colledge Ashley , Yun Jong K. 
Published: August 2015

Abstract
We previously developed SKI-178 as a novel Sphingosine kinase 1 (SphK1) selective inhibitor that is cytotoxic toward a broad panel of cancer types. Herein, we sought to determine the mechanism-of-action of SKI-178-induced cell death. We present evidence that SKI-178 induces prolonged mitosis followed by apoptotic cell death through the intrinsic apoptotic cascade. Further examination of the mechanism-of-action (MOA) of SKI-178 implicated c-Jun NH2-terminal kinase (JNK) and cyclin-dependent protein kinase 1 (CDK1) as critical factors required for SKI-178-induced apoptosis. In cell cycle synchronized human AML cell lines, we demonstrate that entry into mitosis is required for apoptotic induction by SKI-178 and that CDK1, not JNK, is required for SKI-178-induced apoptosis. We further demonstrate that the sustained activation of CDK1 during prolonged mitosis, mediated by SKI-178, leads to the simultaneous phosphorylation of the pro-survival Bcl-2 family members, Bcl-2 and Bcl-xl, as well as the phosphorylation and subsequent degradation of Mcl-1. Moreover, multi-drug resistance mediated by MDR-1 and/or pro-survival Bcl-2 family member over-expression did not affect the sensitivity of AML cells to SKI-178. In addition to AML, we extend the MOA of SKI-178 to include various solid tumor cell lines, including pancreatic cancer and glioblastoma. Taken together, we provide evidence that SKI-178 induces apoptosis in a CDK1-dependent manner and is not a substrate for MDR1, making it a promising chemotherapeutic candidate for the treatment of various cancer types, including those known to be drug resistant.
Citation Format: Taryn E. Dick, Jeremy Hengst, Vijay Kale, Ashley Colledge, Jong K. Yun. The apoptotic mechanism of action of SKI-178, a novel Sphingosine kinase 1 selective inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2933. doi:10.1158/1538-7445.AM2015-2933
Abstract 2943: Novel combination therapy of DNMT inhibitor SGI-110 and PARP inhibitor BMN-673 (talazoparib) for BRCA-proficient ovarian cancer
Authors: Pulliam Nicholas , Taverna Pietro , Lyons John , Nephew Kenneth P. 
Published: August 2015

Abstract
Ovarian cancer (OC) is initially chemoresponsive but the majority of patients relapse after first line platinum-, taxane-based chemotherapy. Recurrence has been shown to be associated with increased DNA damage response (DDR) mediated by poly-(ADP)-ribose polymerase 1/2 (PARP1/2), which can be therapeutically targeted by PARP inhibitors (PARPi). Although PARPi are indicated for platinum-responsive, BRCA-mutated OC, most OC patients have BRCA-proficient disease. Based on our previous studies supporting a role for DNA methylation in chemoresistant OC, mediated by the enzyme DNA methyltransferase 1 (DNMT1), and reports on a functional role for DNMT1 in DNA double strand break repair mediated by BRCA1/2, we hypothesized that combining DNMTi and PARPi will impair BRCA-mediated DDR, resulting in cytotoxicity in OC cells. A panel of OC cell lines, including A2780 (platinum sensitive, BRCA-wild type (wt)), A2780-cp and HeyC2 (platinum resistant, BRCA-wt) and Kuramochi (platinum resistant, BRCA2 mutant) were examined for cell growth using colony formation assays after treatment with DNMTi SGI-110 (5, 20, or 100nM) and PARPi talazoparib (1 or 10nM), alone or in combination. Combination treatment schemas consisted of: 1) “priming”: SGI-110 for three days, 24 hour recovery, then talazoparib treatment on Day 5 or 2) “co-administration”: talazoparib administration on day 1 and SGI-110 treatment on days 1-3. Colony formation was inhibited by talazoparib alone in all cell lines but in a dose-dependent manner. Decreased colony formation after SGI-110 alone (20 or 100 nM) was observed only in Kuramochi cells. Combination drug treatments resulted in significant reductions in colony formation. For example, regardless of BRCA and platinum sensitivity status, co-administration of SGI-110 and talazoparib reduced (P&lt;0.05) cell survival, albeit%survival was dependent on drug dose and OC cell line. In general, priming with SGI-110 prior to treatment with talazoparib reduced (P&lt;0.05) survival of A2780, Kuramochi and HeyC2 (majority of combinations tested); however, decreased (P&lt;0.05) survival of A2780-cp was observed only after priming with 100 nM SGI-110. In summary, talazoparib combined with SGI-110 displayed effective cytotoxicity in OC cell lines harboring either wt- or mutant-BRCA, indicating that this DNMTi-PARPi drug combination impairs BRCA-mediated DDR and may represent an effective treatment regimen for OC.
Citation Format: Nicholas Pulliam, Pietro Taverna, John Lyons, Kenneth P. Nephew. Novel combination therapy of DNMT inhibitor SGI-110 and PARP inhibitor BMN-673 (talazoparib) for BRCA-proficient ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2943. doi:10.1158/1538-7445.AM2015-2943
Abstract 2972: Genomic classification of cutaneous melanoma
Authors: Watson Ian R. , Wu Chang-Jiun , Zou Lihua , Gershenwald Jeffrey E. , Chin Lynda ,   on behalf of the Melanoma Analysis Working Group and The Cancer Genome Analysis Research Network
Published: August 2015

Abstract
We describe here the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 resected primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification based on the pattern of the most prevalent significantly mutated genes into one of four subtypes: mutant BRAF, RAS, NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of mutations in KIT, focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We find no significant outcome correlation with genomic classification, but samples assigned to a transcriptomic subclass enriched for immune gene expression are significantly associated with improved patient survival. That favorable prognosis of the ‘immune’ transcriptomic subclass is associated with high LCK protein expression, a T-cell marker, and presence of lymphocyte infiltrate on pathology review. This clinicopathological and multi-dimensional analysis suggests prognosis of melanoma patients with nodal metastases is influenced by immunobiology of the tumor stroma, offering insights to further personalize therapeutic decision-making.
Citation Format: Ian R. Watson, Chang-Jiun Wu, Lihua Zou, Jeffrey E. Gershenwald, Lynda Chin, on behalf of the Melanoma Analysis Working Group and The Cancer Genome Analysis Research Network. Genomic classification of cutaneous melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2972. doi:10.1158/1538-7445.AM2015-2972
Abstract 2974: Comprehensive and integrative genomic characterization of diffuse lower grade gliomas
Authors: Brat Daniel J. ,   The Cancer Genome Atlas (TCGA) Research Network
Published: August 2015

Abstract
Background: Diffuse low and intermediate grade gliomas (LGG; WHO grades II and III) have highly variable clinical behaviors that are not optimally predicted by histology; some are indolent, while others quickly progress to glioblastoma. Uncertainty is compounded by inter-observer variability in diagnosis, in part due to modest correlation between histology and biologic classes. Mutations in isocitrate dehydrogenase (IDH), TP53, ATRX, and co-deletion of chromosomes 1p and 19q are implicated as clinically relevant LGG markers.
Methods: We performed a comprehensive genome-wide analysis of 293 LGG, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA and microRNA expression and targeted protein expression. Molecular data was integrated with clinical outcomes to identify biologically robust LGG subtypes.
Results: We uncovered 19 mutated genes, including recognized drivers and novel mutations. Unsupervised clustering of genome-wide data from RNA-, DNA- and DNA methylation platforms uncovered concordant classification of three robust, non-overlapping LGG subtypes that were captured with highest correlation by IDH and 1p/19q status. The large majority of IDH wild-type LGG showed strikingly similar genomic aberrations and clinical behavior to primary glioblastoma. Nearly all IDH-mutant LGG lacking 1p/19q co-deletion had mutations in TP53 (94%) and ATRX inactivation (86%). IDH-mutant, 1p/19q-co-deleted LGG had most favorable clinical outcomes and harbored mutations in CIC, FUBP1, NOTCH1 and the TERT promoter.
Conclusions: Integration of genome-wide data from multiple platforms cleanly delineates three LGG molecular subtypes concordant with IDH and 1p/19q status: IDH-mutant LGG are either 1p/19 co-deleted or TP53 mutant, whereas most IDH wild-type LGG are molecularly and clinically similar to glioblastoma. Overall, results support a molecular-based, clinically relevant classification for implementation into routine clinical practice.
Citation Format: Daniel J. Brat, The Cancer Genome Atlas (TCGA) Research Network. Comprehensive and integrative genomic characterization of diffuse lower grade gliomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2974. doi:10.1158/1538-7445.AM2015-2974
Abstract 3019: GIPC high expression rescues BRCA2 deficiency and promotes tumorigenesis
Authors: Ding Xia , Sharan Shyam K. 
Published: August 2015

Abstract
Breast cancer is the most prevalent cancer in women worldwide and mutation in breast cancer susceptible gene 2 (BRCA2) is one of the genetic factors conferring highest risk (40-70%) of developing breast cancer. Although BRCA2 proteins are known to maintain genomic stability mainly by homologous recombination-mediated DNA repair, a detailed mechanism of how BRCA2 loss induces tumorigenesis remains unclear. Interestingly, BRCA2 null mice display embryonic lethality, while inactivation of both alleles of BRCA2 in tumor cells renders them able to survive and are predisposed to tumorigenesis only when there are mutations in BRCA2 genetic interactors. In the current study, we tried to identify such genes using a mouse embryonic stem cell (mESC)-based insertional mutagenesis screen. In mESCs with one knockout allele of Brca2 and the other allele flanked by loxP sites, cell death can be induced by Cre-mediated loss of the conditional allele. To identify genes whose up-regulation can rescue cell death induced by loss of BRCA2, we transduced these mESC with murine stem cell retrovirus (MSCV) expressing Cre recombinase. We obtained Brca2-null mESCs that were rescued by the viral insertion and used them to clone the viral insertion sites. We identified several candidate genes that were up-regulated in viable mESCs. One of these genes encodes a PDZ domain-containing protein, GIPC3, and expression of Gipc3 mRNA was elevated 3 to 4-fold in the rescued clone. We were able to rescue lethality of Brca2-null mESC by overexpressing GIPC3. The rescued cells lost RAD51 foci formation in response to irradiation and were hypersensitive to DNA damaging agents and exhibited an overall increase in genomic instability. Mechanistically, GIPC3 can bind to APPL1 and APPL2, two adaptor proteins involved in AKT-mediated cell survival pathway. We found an increased level of the active form of AKT in GIPC3-rescued cells, and a knock down of APPL1 and APPL2 blocked the rescue by GIPC3 overexpression. We found that the Gipc3 transgene can partially rescue the lethality of Brca2 null embryos and contribute to tumorigenesis in K14-Cre; Brca2cko/cko mice. Besides GIPC3, another GIPC family member, GIPC1 can also rescue BRCA2 loss-induced lethality in mESCs. Oncomine analysis showed Gipc2 mRNA up-regulation in BRCA1 deficient human breast tumors, suggesting the possibility that high expression of all the GIPC family members (GIPC1, 2 and 3) might facilitate BRCA1 or BRCA2-loss induced tumorigenesis.
Citation Format: Xia Ding, Shyam K. Sharan. GIPC high expression rescues BRCA2 deficiency and promotes tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3019. doi:10.1158/1538-7445.AM2015-3019
Abstract 3038: G quadruplex stabilization induces mitophagy in S. cerevisiae
Authors: Stundon Jennifer 
Published: August 2015

Abstract
G-quadruplex (G4) DNA structures are stable planar structures held together by multiple G-G base pairs. G4 structures are thought to affect transcription and other chromosomal processes but their presence in vivo is also expected to slow replication fork progression. Previous work from our lab demonstrates that the S. cerevisiae Pif1 5′ to 3′ DNA helicase is a particularly potent unwinder of G4 structures in vitro1. In addition, cells lacking the Pif1 helicase exhibit replication fork slowing and DNA breakage at G4 motifs, chromosomal sequences that form intra-molecular G4 structures in vitro1,2. In addition, treating yeast in vivo with the G4 stabilizing drug PhenDC3 increases G4-mediated genome instability3.
We treated a collection of 4,783 S. cerevisiae strains that each contained a single gene deletion with PhenDC3 to search for genes that are sensitive or resistant to PhenDC3. We will discuss results showing that several yeast genes that affect maintenance of mitochondrial DNA and autophagy induction are hypersensitive to PhenDC3. Using fluorescent microscopy and immunoblotting, we further demonstrate that treatment of wild type S. cerevisiae cells with PhenDC3 induces autophagy, and more specifically, mitophagy. Moreover, cells lacking Pif1 are themselves activated for autophagy.
Reference:
1 Paeschke, K. et al. Pif1 family helicases suppress genome instability at G-quadruplex motifs. Nature 497, 458-+, doi:10.1038/nature12149 (2013).
2 Paeschke, K., Capra, J. A. & Zakian, V. A. DNA replication through G-quadruplex motifs is promoted by the Saccharomyces cerevisiae Pif1 DNA helicase. Cell 145, 678-691, doi:10.1016/j.cell.2011.04.015 (2011).
3 Piazza, A. et al. Genetic instability triggered by G-quadruplex interacting Phen-DC compounds in Saccharomyces cerevisiae. Nucleic Acids Res 38, 4337-4348, doi:10.1093/nar/gkq136 (2010).
Citation Format: Jennifer Stundon. G quadruplex stabilization induces mitophagy in S. cerevisiae. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3038. doi:10.1158/1538-7445.AM2015-3038
Abstract 3054: Bioenergetic signature of stromal cells defines the aggressiveness of prostate cancer
Authors: Vayalil Praveen Kumar , Landar Aimee 
Published: August 2015

Abstract
Cancer-associated fibroblasts, though derived from multiple lineages, share common as well as unique characteristics and play a critical role in various aspects of neoplasia. Their activities range from contributing to tumor formation to promoting the growth and invasion of tumors. They also promote angiogenesis, provide a metabolically friendly tumor environment, and confer resistance to chemotherapy and radiation. Clinical trials targeting stromal cells were disappointing. The reason underlying this failure has been ascribed to the fact that stromal cells do change during cancer progression to aggressive form. As the cancer progresses, both prostate cancer cells as well as stromal cells have to ‘functionally adapt’ to the microenvironment within the tumor mass and mutually support their growth in a hostile environment. The major environmental factor that molds the biology of cancer cells and stromal components is low oxygen tension within the tumor. The key cellular organelle that is functionally affected by exposure to different oxygen tensions is the mitochondria. In this study we present the data on the progressive changes in the stromal cell mitochondrial function in relation to the aggressiveness of prostate cancer at atmospheric oxygen and at different oxygen tensions. This study reveals the potential use of mitochondrial functional assay for the screening of compounds that specifically target the bioenergetics of stromal cells. This information may also unravel the metabolic interaction between tumor- microenvironment that contributes to tumor development and progression of prostate cancer and potential mechanism of resistance to therapy offered by stromal cells.
Citation Format: Praveen Kumar Vayalil, Aimee Landar. Bioenergetic signature of stromal cells defines the aggressiveness of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3054. doi:10.1158/1538-7445.AM2015-3054