bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2599: Pleiotropic effects of PPARD accelerate colorectal tumorigenesis progression and invasion
Authors: Liu Yi , Deguchi Yasunori , Tian Rui , Wei Daoyan , Wu Ling , Chen Weidong , Xu Weiguo , Xu Min , Liu Fuyao , Gao Shen , Jaoude Jonathan C. , Chrieki Sarah P. , Moussalli Micheline J. , Gagea Mihai , Morris Jeffrey S. , Broaddus Russell , Zuo Xiangsheng , Shureiqi Imad 
Published: August 2019

Abstract
APC mutations activate aberrant β-catenin signaling to drive colorectal cancer (CRC) initiation. CRC progression however requires additional molecular mechanisms. PPAR-delta (PPARD) is a downstream target of β-catenin and upregulated in CRC. PPARD germline genetic deletion has however been reported to promote intestinal tumorigenesis in Apcmin mice, which has questioned PPARD effects on β-catenin aberrant activation and CRC. Addressing this knowledge gap is important because PPARD is a druggable protein. Mice with targeted PPARD overexpression/deletion into intestinal epithelial cells (IECs) were bred with mice with intestinally targeted ApcΔ580 mutation via CDX2-cre (ApcΔ580) or CDX2-cre-ERT2 (ApcΔ580-TMX). APCΔ580 mice treated with PPARD agonist (GW501516) or antagonist (GSK3787), and human CRC organoid cells were also tested. PPARD expression was examined in human CRC invasive fronts and their paired colorectal adenomas and cancer centers. PPARD’s mechanisms to promote CRC were screened by Functional Proteomics Reverse Phase Protein Assay (RPPA) and subsequently validated in in-vitro and in-vivo studies. PPARD overexpression/deletion in IECs in mice augmented/suppressed β-catenin activation via upregulation/downregulation of BMP7/TAK1 signaling and strongly promoted/suppressed CRC .PPARD downregulation by siRNA in human CRC organoid cells inhibited BMP7/β-catenin signaling and suppressed organoid self-renewals. GW501516 enhanced while GSK3787 suppressed CRC tumorigenesis in ApcΔ580 mice. PPARD expression was significantly higher in human CRC invasive fronts versus their paired invasive tumor centers and adenomas. RPPA and validation studies identified PPARD upregulation of multiple other pro-invasive pathways: PDGFRβ, connexin 43, AKT1, EIF4G1 and CDK1, Our data demonstrate that PPARD strongly potentiates multiple pro-tumorigenic pathways to promote CRC progression and invasiveness.
Citation Format: Yi Liu, Yasunori Deguchi, Rui Tian, Daoyan Wei, Ling Wu, Weidong Chen, Weiguo Xu, Min Xu, Fuyao Liu, Shen Gao, Jonathan C. Jaoude, Sarah P. Chrieki, Micheline J. Moussalli, Mihai Gagea, Jeffrey S. Morris, Russell Broaddus, Xiangsheng Zuo, Imad Shureiqi. Pleiotropic effects of PPARD accelerate colorectal tumorigenesis progression and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2599.
Abstract 2606: Genetic contribution of MYC to the development of primary prostate cancer
Authors: Whitlock Nichelle C. , Trostel Shana , Atway Rayann , Walton Elizabeth , Capaldo Brian J. , Ye Huihui , Sowalsky Adam G. 
Published: August 2019

Abstract
Despite the predictive value of Gleason score (Gs), the molecular characteristics and associated biology that underpin specific Gleason patterns (Gp) remain understudied. Based on previous data showing increased MYC activity in higher-grade Gp4 versus lower-grade Gp3 tumor foci and addressing the paradox that prostate cancer is not hyper-proliferative, we sought to examine the genetic contribution of MYC to locally-advanced prostate cancer development. We screened a series of Gs7 cancers in which the Gp3 and Gp4 components were adjacent and represented contributing elements of the index lesion. Tumor foci were collected by laser capture microdissection based on MYC staining and purified for RNA; transcriptome profiling was performed. To further guide our bioinformatics analyses, we generated a LNCaP prostate cancer cell line harboring MYC knockdown. RNA-seq and ChIP-seq was performed to identify differentially bound regions of the cistrome that correlate with altered gene expression and elucidate potential mechanism(s) of action for MYC in primary prostate cancer. In contrast to other reports, MYC knockdown had the effect of increasing global transcription. Moreover, the publicly available Cancer Genome Atlas (TCGA) prostate cancer dataset was curated according to MYC status based on extreme case design using reverse phase protein assay data. Preliminary results show: (1) increased MYC protein levels, but not proliferation, in Gp4 tumor foci as compared to adjacent Gp3, (2) distinct histology and biology based on MYC tumor status, and (3) found recurrent enrichment for gene sets cross-referencing differentially expressed genes between TCGA, tissue, and our engineered cell line. Of note, we observed recurrent enrichment for the Acosta Proliferation Independent MYC Targets Up gene set, which correlated with MYC activity. When this gene set was cross-referenced between all three datasets, the gene NOLC1 was identified. Nucleolar and coiled-body phosphoprotein 1 (NOLC1) plays an important role in rRNA synthesis and ribosome biosynthesis; its role in tumorigenesis appears context dependent. NOLC1 was found to be positively correlated with MYC expression and may thus contribute to MYC-driven prostate cancer. Although further cases are needed to determine the frequency at which NOLC1 drives MYC-driven prostate cancer, our results suggest a novel role for MYC in mediating development of locally-advanced prostate cancer.
Citation Format: Nichelle C. Whitlock, Shana Trostel, Rayann Atway, Elizabeth Walton, Brian J. Capaldo, Huihui Ye, Adam G. Sowalsky. Genetic contribution of MYC to the development of primary prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2606.
Abstract 2625: Identification of CTX-30916 as a novel antagonist of progesterone receptor signaling pathways
Authors: Lala Deepak , Haque Tasir 
Published: August 2019

Abstract
Breast cancer is the most commonly diagnosed cancer in women and the second leading cause of cancer related death in women. Progesterone is a major mitogen in the adult human mammary epithelium that, in addition to estrogen, is a key driver of breast cancer cell proliferation. Activated PR signaling through MAPK-driven phosphorylation of the progesterone receptor (PR) is also an important driver of breast cancer stem cells. PR expression is associated with the presence of estrogen receptor-alpha (ESR1) mutations that are constitutively active and linked to resistance in the clinic in response to aromatase inhibitors, antiestrogens and CDK4/6 inhibitors. Thus, PR may play a role in tumor relapse and resistance in the clinic and blocking both estrogen and progesterone receptors would likely be an effective approach in 2L treatment for patients with advanced breast cancer. There is great interest in evaluating antiprogestins in the clinic in combination with antiestrogens or CDK4/6 inhibitors. Apristor®, an extended release formulation of onapristone, a full antagonist of PR, that has efficacy in multiple in vivo and in vitro models in combination with antiestrogestins and CDK4/6 inhibitors, is currently being evaluated in several human clinical trials.
In this study we have examined the in vitro properties of CTX-30916, a novel mono-N-desmethyl analog of onapristone. CTX-30916 binds potently to PR and acts as an antagonist in cell-based transfection assays. CTX-30916 displays selectivity against other steroid receptors in binding assays and is also a potent inhibitor of T47D breast cancer cell proliferation. Interestingly, CTX-30916 leads to a unique co-regulator binding pattern in the Microarray Assay for Real-time Co-regulator-Nuclear receptor interaction (MARCoNI) assay compared with onapristone and mifepristone indicating that the co-regulator peptide-PR interaction landscape is different between the various antiprogestins. These data suggest that CTX-30916 binding to PR leads to a distinct receptor conformation and antagonizes PR signaling pathways in cancer through a unique mechanism of action compared to other antiprogestins.
Citation Format: Deepak Lala, Tasir Haque. Identification of CTX-30916 as a novel antagonist of progesterone receptor signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2625.
Abstract 2643: TNFAIP2 interacts with EGFR to modulate EGF-induced EGFR auto-phosphorylation and internalization and sequential ERK1/2 activation in nasopharyngeal carcinoma cells
Authors: Liu Hao-Ping , Wu Chih-Ching 
Published: August 2019

Abstract
TNFAIP2 (TNF-α-inducible protein 2) is identified as an angiogenic and proinflammatory factor and is essential for formation of tunneling nanotubes connecting between remote cells. Cancer-associated TNFAIP2 overexpression is first demonstrated in nasopharyngeal carcinoma (NPC) and is significantly correlated with poor survival of patients. We previously revealed that TNFAIP2 is associated with actin filaments, inducing actin remodeling and membrane protrusion and promotes cell motility of NPC cells. To elucidate functional roles of TNFAIP2 in cancer progression, we exploited co-immunoprecipitation (co-IP) coupled with mass spectrometry (MS)-based proteomic analysis to identify interacting proteins of TNFAIP2 in NPC cells. Epidermal growth factor (EGF) receptor (EGFR) is one of the identified candidates and is frequently overexpressed in various cancer types. We validated the interaction between TNFAIP2 and EGFR in two types of NPC cell lines; nevertheless, the interaction of TNFAIP2 with EGFR was reduced along with EGF stimulation. Reciprocal domain mapping analyses and immunofluorescence staining further demonstrated that the C-terminal amino acid residues 461-520 of TNFAIP2, which are dispensable for its association with the plasma membrane, are required for TNFAIP2 interaction with EGFR. On the other hand, the intracellular juxtamembrane domain (amino acids 645-689) and kinase domain (amino acids 690-945) of EGFR are needed for its interaction with TNFAIP2. Furthermore, EGF-triggered internalization of EGFR was significantly interfered in TNFAIP2-knockout NPC cells generated using the CRISPR-Cas9 system, accompanied by alleviated auto-phosphorylation of EGFR on the 1068 and 1173 tyrosine residues and subsequent activation of downstream ERK1/2. This impairment of liganded EGFR-transduced signaling in TNFAIP2-knockout NPC cells was correlated with a decrease in cell migration as revealed by transwell migration assays. These data collectively reveal a novel role of TNFAIP2 in modulation of EGF-triggered EGFR activation and sequential signaling transduction through protein-protein interactions. Efforts are made to pursue if the aforementioned events involve modulation of EGFR oligomerization or recruitment of internalized activated EGFR into endosomes. The results could shed light on how TNFAIP2 promotes cancer progression via coordinating with EGFR and the impact of TNFAIP2 on EGFR-targeted cancer therapy.
Citation Format: Hao-Ping Liu, Chih-Ching Wu. TNFAIP2 interacts with EGFR to modulate EGF-induced EGFR auto-phosphorylation and internalization and sequential ERK1/2 activation in nasopharyngeal carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2643.
Abstract 2659: IRE1á-dependent increase of Gá12, a gep oncogene, augments ER stress-induced catastrophic cell death
Authors: Tak Jihoon , Kim Tae Hyun , Kim Sang Geon 
Published: August 2019

Abstract
Hepatocellular carcinoma (HCC) belongs to the most deadly types of cancer since it has a poor prognosis due to its aggressive metastatic phenotype. Endoplasmic reticulum (ER) stress is closely associated with the incidences of a variety of liver diseases including liver injury, regeneration, fibrosis, cirrhosis and often HCC. G protein-coupled receptor (GPCR) signals lead to activation of their downstream pathways through G proteins. Previously, we reported that Gα12 overexpression enhances HCC malignancy, promoting cancer migration and microvascular invasion. However, the role of Gα12 in ER stress-associated pathophysiology in the liver was unclear. Given the link between ER stress and HCC malignancy, this study investigated the effect of ER stress on Gα12, the role of Gα12 in ER stress-mediated hepatocyte death, and the underlying pathway. In the analyses of RNA-sequencing data from mouse liver or primary mouse embryonic fibroblasts challenged with ER stress, Gα12 and C/EBP homologous protein (CHOP) levels correlated with each other. Increases in Gα12 level by unfolded protein response (UPR) under ER stress condition was verified using primary hepatocytes or hepatocyte-derived cell line, confirmative of the close association between Gα12 and UPR. Of note, enforced Gα12 expression under ER stress condition augmented IRE1α level in a RhoA/Rock-dependent pathway. Among the canonical pathways, IRE1α gene silencing distinctly inhibited Gα12 induction elicited by ER stress in hepatocytes. Consistently, overexpression of IRE1α enhanced Gα12 level upon tunicamycin treatment. Similar outcomes were obtained in cells or mice treated with acetaminophen, a representative liver toxicant inducing ER stress response. Overall, our results provide evidence that IRE1α-dependent increase of Gα12 potentiates ER stress response in the liver as mediated by the RhoA-ROCK pathway, enhancing catastrophic death of hepatocytes.
Citation Format: Jihoon Tak, Tae Hyun Kim, Sang Geon Kim. IRE1á-dependent increase of Gá12, a gep oncogene, augments ER stress-induced catastrophic cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2659.
Abstract 2665: Zinc dysregulation as an emerging molecular target in epithelial cancers
Authors: Perer Jessica , Justiniano Rebecca , Hua Anh , Wondrak Georg T. 
Published: August 2019

Abstract
Zinc plays an established role in structure and function of enzymes and transcription factors, and zinc signaling has now been recognized as a molecular determinant of epithelial differentiation and cell fate. Intracellular zinc homeostasis is regulated by zinc importers (ZIPs encoded by the SLC39A gene family). Cumulative evidence suggests that dysruption of zinc homeostasis is an emerging hallmark of various tumor types, characterized by downregulation of ZIP expression upstream of intracellular zinc depletion. In nonmelanoma skin cancer (NMSC) examined in TMA format we have observed downregulation of ZIP2 (involved in epidermal differentiation) that occurs with zinc depletion and impaired differentiation. Likewise, in pancreatic ductal adenocarcinoma (PDAC) tumor tissue, downregulation of ZIP3 and zinc depletion are detectable. We therefore tested feasibility of pharmacological induction of intracellular zinc overload for chemotherapeutic intervention. Using the small molecule ionophore ZnPT (zinc pyrithione) as an experimental chemotherapeutic, rapid induction of zinc overload followed by metal stress response signaling and cell death were observable in a panel of malignant epithelial cell lines (NMSC: SCC-25; HaCaT-ras II-4; PDAC: BxPC-3, MIA PaCa-2, PANC-1). Remarkably, PDAC cell lines displayed nanomolar sensitivity to ZnPT-induced cytotoxicity. In BxPC-3 cells, pronounced upregulation of stress response gene expression (MT2A, HSPA6, HMOX1) and signaling (p-p38, p-eIF2α, HO-1) was detectable within one hour of ZnPT exposure. Accumulation of protein-ubiquitin conjugates further substantiated the rapid occurrence of ZnPT-induced proteotoxic stress and UPR, consistent with a role of ZnPT in the inhibition of proteasome-associated deubiquitinating enzymes (DUBs). Next, we confirmed NMSC-directed anti-tumor activity of ZnPT in a photocarcinogenesis SKH1 mouse model, followed by exploratory chemotherapeutic intervention targeting BxPC-3 PDAC xenografts. Taken together, our data suggest that ZIP-based dysruption of intracellular zinc homeostasis may be a valid molecular target in specific epithelial cancers. [This research was funded in part by NCI: P30 CA023074 & R03 CA230949.]
Citation Format: Jessica Perer, Rebecca Justiniano, Anh Hua, Georg T. Wondrak. Zinc dysregulation as an emerging molecular target in epithelial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2665.
Abstract 2694: A first-in-class small-molecule modulator of the p300/CBP interactome exhibits broad efficacy in xenograft models of solid tumors and hematologic malignancies
Authors: Hentsch Bernd , Cattori Valentino , Labelle Marc , Kessler Ulrich 
Published: August 2019

Abstract
Background: Dysregulation of the cellular transcription machinery is a fundamental feature of cancer. E1A binding protein (p300) and CREB binding protein (CBP) are two closely related paralog transcription co-activators involved in the expression of oncogenic drivers in cancer cells.
Methods: Small molecule ligands of the CH1/TAZ1 domain of p300/CBP were rationally designed and optimized for their anti-proliferative activity in vitro. Subsequent characterization focused on their ability to modulate downstream biological processes controlled by p300/CBP, including hormone-dependent androgen receptor signalling, the HIF-1 alpha/VEGF pathway and reactivation of p53 in HPV-positive carcinomas.
The in vivo efficacy of this novel compound class was assessed in a variety of patient and cell line derived xenograft models, and pharmacodynamic effects were investigated.
Results: Several modulators of p300/CBP exhibited anti-proliferative effects at low nanomolar concentrations in more than 60 cancer cell lines inducing both senescence and apoptosis in a highly context dependent manner. Transcriptome analyses revealed the downregulation of various drivers of cell cycle progression.
Once daily oral administration triggered strong growth-inhibitory effects in several xenograft models up to complete tumor eradication at well tolerated doses. p300/CBP dependent biomarkers like VEGF (colon cancer) and PSA (prostate cancer) were significantly downregulated in the tumors of treated animals. In an orthotopic model of acute myeloid leukemia, the growth of primary tumors and metastasis was almost completely inhibited.
Conclusions: Reprogramming the transcriptional profile of cancer cells by modulation of p300/CBP activity by targeting the CH1/TAZ1 domain represents a novel and broadly applicable approach for the treatment of cancer. The presented data illustrate the clinical potential of this new class of therapeutics against a broad variety of tumor types, including prostate and colon cancer as well as hematological malignancies.
Citation Format: Bernd Hentsch, Valentino Cattori, Marc Labelle, Ulrich Kessler. A first-in-class small-molecule modulator of the p300/CBP interactome exhibits broad efficacy in xenograft models of solid tumors and hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2694.
Abstract 2701: Functionally specialized subsets of exhausted CD8+ T cells mediate tumor control and differentially respond to checkpoint blockade
Authors: Miller Brian C. , Sen Debattama R. , Abosy Rose Al , Bi Kevin , Virkud Yamini V. , LaFleur Martin W. , Yates Kathleen B. , Lako Ana , Felt Kristen , Naik Girish S. , Manos Michael , Gjini Evisa , Hodi F. Stephen , Rodig Scott J. , Sharpe Arlene H. , Haining W. Nicholas 
Published: August 2019

Abstract
T cell dysfunction in the tumor microenvironment (TME) is a hallmark of many cancers. Reinvigoration of T cell function by PD-1 checkpoint blockade can result in striking clinical responses, but is only effective in a minority of patients. The basis for T cell dysfunction in the TME, as well as the mechanisms by which anti-PD-1 therapy acts on dysfunctional T cells are not fully understood. Here we show that anti-PD-1 therapy acts on a specific subpopulation of CD8+ tumor-infiltrating lymphocytes (TILs) in melanoma mouse models, which can also be found in patients with melanoma. We find that dysfunctional CD8+ TILs possess canonical epigenetic and transcriptional features of T cell exhaustion, mirroring those seen in chronic viral infection. Similar to chronic viral infection, exhausted CD8+ TILs contain a subpopulation of “progenitor exhausted” T cells that have a distinct regulatory state. Progenitor exhausted TILs also have critical functional attributes that are not shared by the majority “terminally exhausted” TILs: they retain more polyfunctionality, persist following transfer into tumor-bearing mice, and differentiate to repopulate terminally exhausted TILs in the TME. As a result, progenitor exhausted CD8+ TILs are better able to control tumor growth than terminally exhausted cells. Progenitor exhausted, but not terminally exhausted, CD8+ TILs can respond to anti-PD-1 therapy but this occurs without reversion of their exhausted epigenetic state. Human melanomas contain CD8+ T cells with a progenitor exhausted phenotype and patients with a higher fraction of this subpopulation in their tumors have a significantly longer duration of response to combination checkpoint blockade therapy. Therefore, approaches to expand progenitor exhausted CD8+ T cells in the tumor microenvironment may be an important component of improving checkpoint blockade response.
Citation Format: Brian C. Miller, Debattama R. Sen, Rose Al Abosy, Kevin Bi, Yamini V. Virkud, Martin W. LaFleur, Kathleen B. Yates, Ana Lako, Kristen Felt, Girish S. Naik, Michael Manos, Evisa Gjini, F. Stephen Hodi, Scott J. Rodig, Arlene H. Sharpe, W. Nicholas Haining. Functionally specialized subsets of exhausted CD8+ T cells mediate tumor control and differentially respond to checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2701.