bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1932: Discovery of ENPP1 inhibitors as agonists of STING pathway
Authors: Sharma Sunil , Weston Alexis , Thode Trason , Gomez Eric , Kaadige Mohan , Vankayalapti Hariprasad 
Published: August 2018

Abstract
The discovery of STING (Stimulator of interferon genes) pathway and the second messenger 2′3′-cGAMP that activate it opened up several new possibilities for the development of anti-cancer and anti-pathogen therapeutics. STING is a pattern-recognition receptor anchored on endoplasmic reticulum and has pivotal roles in surveillance and innate immune response. Binding of 2′3′-cGAMP with STING induces conformational changes, which subsequently leads to perinuclear migration of STING and recruitment of TANK-binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3). TBK1 phosphorylates IRF3, which then translocates to the nucleus and drives the transcription of innate immune genes, including IFN-β. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is a dominant hydrolyzing enzyme of 2′3′-cGAMP. In ENPP-/- cells, 2′3′-cGAMP is more active in stimulating STING activation, and this is predicted to be due to increased half-life. Similarly, hydrolysis resistant 2′3′-cGAMP analogs are reported to be potent STING agonists. We hypothesized that inhibition of ENPP1 activity with an orally available small molecule would be a novel approach to activate STING pathway when compared with the cyclic dinucleotides (CDNs) due to their parenteral route of administration. We have utilized computational methods successfully discovered small molecule candidates that showed a strong binding affinity towards ENPP1. With the help of in vitro enzymatic inhibition and direct binding assays we have identified few lead candidates with an IC50 of &lt;100 nM. Cellular assays further showed target specific inhibition of ENPP1 activity and subsequent activation of STING pathway. Additionally, our lead series of compounds showed no effect on other members of the ENPP family, a kinome panel, and several epigenetic regulators, suggesting the specificity towards ENPP1. In summary, we have developed small molecule inhibitors of ENPP1 and one of our lead candidate's is currently under investigation for ADME-Tox, PK and efficacy. The results from these studies will be presented.
Citation Format: Sunil Sharma, Alexis Weston, Trason Thode, Eric Gomez, Mohan Kaadige, Hariprasad Vankayalapti. Discovery of ENPP1 inhibitors as agonists of STING pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1932.
Abstract 1987: Expansion of pancreatic cancer stem-like cells through PGE2 accumulation in inflammatory environment
Authors: Ishimoto Takatsugu , Arima Kota , Bu Luke , Uchihara Tomoyuki , Miyake Keisuke , Eto Tsugio , Itoyama Rumi , Baba Hideo 
Published: August 2018

Abstract
Chronic inflammation has a crucial role in cancer development and the progression of various tumors, including pancreatic ductal adenocarcinoma (PDAC). The arachidonate cascade is a major inflammatory pathway that produces several metabolites, such as prostaglandin E2 (PGE2). 15-hydroxyprostaglandin dehydrogenase (15-PGDH) participates in the degradation of PGE2 and has attracted attention in recent years. Although inhibition of 15-PGDH is reported to lead to PGE2 accumulation and expand tissue stem cell fraction, the role for pancreatic tumor progression is still unknown. The aim of this study is to elucidate the regulatory mechanism and functional role of 15-PGDH for cancer stem-like cell expansion during tumor progression in pancreas. We found that 15-PGDH expression is frequently down-regulated in PDAC cells and significantly correlated with the number of infiltrating macrophages in human PDAC tissues. Moreover, direct co-culture assay revealed that macrophage derived interleukin-1 beta down-regulates 15-PGDH expression in PDAC cells. Furthermore, pharmacological blockade of 15-PGDH led to PGE2 accumulation, and promoted growth and sphere formation through the expansion of ALDH1-positive cells. We also elucidated the molecular mechanism that PGE2 accumulation by 15-PGDH inhibition increases CYP26A1 expression and subsequently depletes all-trans retinoic acid, and results in ALDH1 up-regulation. Finally, genetic ablation of 15-Pgdh promoted tumorigenesis in KrasLSL-G12D; Ptf1aCre/+ mice through the expansion of ALDH1-positive cells. Our findings highlight the role and significance of PGE2 degradation pathway for PDAC tumor progression.
Citation Format: Takatsugu Ishimoto, Kota Arima, Luke Bu, Tomoyuki Uchihara, Keisuke Miyake, Tsugio Eto, Rumi Itoyama, Hideo Baba. Expansion of pancreatic cancer stem-like cells through PGE2 accumulation in inflammatory environment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1987.
Abstract 2: CXCR2+ tumor cells mediate vascular mimicry driving anti-angiogenic therapy (AAT) resistance in glioblastoma (GBM)
Authors: Angara Kartik P. , Borin Thaiz F. , Rashid Mohammad H. , Ara Roxan , Achyut Bhagelu R. , Arbab Ali S. 
Published: August 2018

Abstract
Glioblastoma (GBM) is a hypervascular and hypoxic neoplasia of the central nervous system with an extremely high rate of mortality. Owing to its hypervascularity, anti-angiogenic therapies (AAT) have been used as an adjuvant to the traditional surgical resection, chemotherapy, and radiation to normalize blood vessels and control abnormal vasculature. The benefits of AAT have been transient, and evidence of relapse exemplified in the progressive tumor growth following AAT reflects development of resistance and alternative neovascularization mechanisms in these resilient tumors to counter the AAT therapy insult. Vascular mimicry (VM) is the uncanny ability of tumor cells to acquire endothelial-like properties and lay down vascular patterned networks reminiscent of host endothelial blood vessels. The VM channels serve as an irrigation system for the tumors to meet with the increasing metabolic and nutrient demands of the tumor. In our current studies to understand the tumor-inherent mechanisms of AAT resistance, we identified a crucial pro-migratory and pro-angiogenic chemokine, CXCL8 or IL-8, to be highly upregulated in the GBM tumors treated with AAT. AAT-treated groups had significantly higher populations of CXCR2+ stem and endothelial-like subpopulations and these cells lined the VM-like vascular structures carrying functional RBCs in the tumors. These stem cell-like and endothelial-like populations were decreased following treatment with HET0016 or SB225002. Furthermore, knocking down CXCR2 led to smaller tumor size in the animals and improperly developed vascular structures without CXCR2+ GBM cells lining them. Also, HET0016 and SB225002 disrupt the tube-forming capability of U251 GBM cells in an in vitro Matrigel angiogenesis assay. This confirms our hypothesis that CXCR2+ GBM cells initiate VM and contribute to AAT resistance in GBM. Our present study suggests that tumor cell autonomous IL-8/CXCR2 pathway contributes to VM-mediated AAT resistance in GBM and that HET0016 and SB225002 have a great potential to target therapeutic resistance and can be combined with other chemotherapeutic agents in preclinical and clinical trials.
Citation Format: Kartik P. Angara, Thaiz F. Borin, Mohammad H. Rashid, Roxan Ara, Bhagelu R. Achyut, Ali S. Arbab. CXCR2+ tumor cells mediate vascular mimicry driving anti-angiogenic therapy (AAT) resistance in glioblastoma (GBM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2.
Abstract 2019: Extracellular ATP induces EMT and metastatic activities in non-small cell lung cancer cells
Authors: Cao Yanyang , Wang Xuan , Chen Xiaozhuo 
Published: August 2018

Abstract
Cancer is a leading cause of death worldwide. Metastasis, the spread of cancer cells from the primary tumors to distant organs, is responsible for approximately 90% of all cancer-related deaths. Metastasis is a multistep process in which loss of cell-cell adhesion, increased proteolysis, and cell motility have been shown to be critical steps. Recent studies have indicated that intratumoral ATP concentration is ~1,000 times higher than normal tissues of the same cell origins in the range of at least several hundred μM. Extracellular ATP (eATP), a tumor microenvironment molecule, potentially has a crucial role in supporting tumor invasion and metastasis. Our previous studies showed that eATP is internalized by cancer cells through macropinocytosis and other endocytosis and promotes cancer cell growth, survival, and drug resistance (1-4). Based on all these, we hypothesize that eATP functions as both a signaling molecule and an energy source to stimulate epithelial mesenchymal transition (EMT) and metastasis. Various bioassays were used in human non-small cell lung cancer (NSCLC) A549 and HOP-92 cells to test our hypothesis. Our results reveal that eATP treatment led to a substantially increased number of floating cancer cells, and these cells were viable and formed clones in clonogenic assays. Fence assay indicated that eATP not only induces cancer cell detachment but also increases the number of secondary colonies formed. Moreover, treatment of eATP induces a dose- and time-dependent increase in the migration and invasive capacities of the A549 and HOP-92 cells. Confocal images demonstrated that eATP induces the formation of F-actin-dependent filopodia necessary for cell migration. Using Western blot analysis, we found that the expression of epithelial markers was significantly reduced, while the mesenchymal markers were increased after eATP treatment. Purinergic receptor (PR) inhibitors and P2X7 receptor knockdown only slightly attenuated these effects, suggesting PR signaling is only partially responsible for eATP-induced migration and invasion. These results indicate eATP is an EMT and metastasis stimulator and imply novel targets for inhibiting/preventing metastasis.
References:
1. Qian Y et al. Cancer Lett 2014;351:242-51.
2. Chen X, Qian Y, Wu S. Free Radical Biol Med 2015;79;253-63.
3. Qian Y et al. Mol Cancer Res 2016;14(11):1087-96.
4. Wang X et al. Oncotarget 2017;8:87860-77.
Citation Format: Yanyang Cao, Xuan Wang, Xiaozhuo Chen. Extracellular ATP induces EMT and metastatic activities in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2019.
Abstract 2332: Necroptosis induction in triple negative breast cancer therapy
Authors: Nyinawabera Angelique , Gupta Smiti , Chandrabose Karthikeyan , Tiwari Amit K. 
Published: August 2018

Abstract
“Triple-negative” breast cancer (TNBC), is the most aggressive form of malignant mammary tumors that do not express three cell-surface receptors (estrogen receptor-α, progesterone receptor, and HER2/ERBB3). TNBC accounts for about 15 percent of breast cancer cases, with &gt;42,000 new cases each year and approximately 21,000 deaths. Currently there are no targeted treatments available for TNBC. We found an interesting target associated with TNBC, the mitochondrial fission protein GTPase, dynamin-related protein-1 (Drp1), for which one inhibitor (mdivi-1) is under active investigation. However, mdivi-1 has shown inconsistent antineoplastic activity, low potency and selectivity. This led us to use a 200,000-compound library of commercially available small molecules (Specs), in conjunction with the likely structure of the Drp1-mdivi-1 inhibitory complex, resulting in the identification of twelve thieno-pyrimidin-4-yl-hydrazinylidene class of compounds that were highly potent and selective Drp1 inhibitors. In our preliminary work we found one compound ANT4 with IC50 value of 180-220 nM that has up to 100-fold selectivity in different TNBC cells compared to normal breast cells and up to 30-fold compared to other normal cells. We discovered that ANT4 is a selective inhibitor of Drp1 and has a 100-fold greater affinity for the Drp1 complex. ANT4 inhibited TNBC colony formation, invasion and metastasis,150-fold more potently than Mdivi-1. Interestingly, we discovered that ANT4, in nanomolar range, selectively induced a unique non-apoptotic, necroptotic inducing (NANI) cell death in TNBC cells by increasing the expression of necroptotic cell death markers (RIP, p-RIP, MLKL, p-MLKL). Further, ANT4, inhibited the expression of pro-apoptotic proteins and enhanced the expression of anti-apoptotic proteins. In addition, ANT4 arrested the TNBC cells in S-phase without producing any significant nuclear condensation or release of reactive oxygen species (ROS). Further studies are underway to understand the Drp1 mediated NANI induction process in TNBC cells and to identify the structural requirements that are necessary for targeting cancers refractory to apoptosis. The findings of these studies will allow us to understand the biology of necroptosis-induced Drp1 inhibition and to develop this new class of small molecules for the treatment of TNBC patients.
Citation Format: Angelique Nyinawabera, Smiti Gupta, Karthikeyan Chandrabose, Amit K. Tiwari. Necroptosis induction in triple negative breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2332.
Abstract 2386: Identification of SIK1 as a potential therapeutic target for desmoplastic small round cell tumor
Authors: Hartono Alifiani B. , Lee Sean B. 
Published: August 2018

Abstract
Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and aggressive malignant cancer caused by the chromosomal translocation of t(11;22)(p13;q12) that produces a novel, aberrant transcription factor, EWS-WT1. EWS-WT1 is essential in the formation of DSRCT as well as for maintaining DSRCT cell growth. However, current research has not elucidated how EWS-WT1 leads to the oncogenesis of DSRCT. Through our integrative gene expression data, we identified Salt Inducible Kinase 1 (SIK1) as one of direct target genes of EWS-WT1 in JN-DSRCT-1 cell line. SIK1 is a member of the AMPK related kinases and is involved in gluconeogenesis and lipogenesis regulation, skeletal myocytes development, p53 dependent anoikis, and cell cycle regulation. Through our ChIP analysis, we showed that EWS-WT1 directly binds to a 2kb proximal promoter region of SIK1. Following SIK1 depletion, JN-DSRCT-1 cell proliferation sharply decreased, similar to the growth inhibition observed when EWS-WT1 is depleted. We further showed that cells do not transit to S phase when SIK1 is depleted, suggesting a critical role of SIK1 in cell cycle regulation in DSRCT. Taken together, we have established that EWS-WT1 directly activates SIK1 expression and promotes cell proliferation through SIK1. Therefore, our work identified SIK1 as a new potential therapeutic target in DSRCT.
Citation Format: Alifiani B. Hartono, Sean B. Lee. Identification of SIK1 as a potential therapeutic target for desmoplastic small round cell tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2386.
Abstract 2403: SGK-1-mediated ATP generation: A novel metabolic pathway that supports ECM-detached cell survival
Authors: Cockfield Jordan A. , Mason Joshua A. , Schafer Zachary T. 
Published: August 2018

Abstract
Successful metastasis requires cancer cells to overcome both anoikis -caspase dependent cell death triggered by extracellular matrix (ECM) detachment—and ECM-detachment-induced metabolic defects that compromise cell survival. While studies have begun to elucidate signal transduction cascades responsible for anoikis evasion, less is known about the precise signals cancer cells use to overcome ECM-detachment induced metabolic deficiencies. Previously, we discovered that oncogenic Ras utilizes a PI(3)K/SGK-1 signaling cascade in order to promote glucose-mediated ATP generation and survival of ECM-detached cells. We have expanded these studies and found that SGK-1 signaling is required in a variety of cell types and oncogenic backgrounds (during ECM-detachment) for glucose-derived ATP production and anchorage independent growth. Our data demonstrate that SGK-1 is required for glucose uptake due to its regulation of the GLUT1 transporter. SGK-1 appears to not only promote GLUT1 localization at the plasma membrane, but also to dramatically promote its transcription. Once inside the cell, SGK-1 promotes the flux of glucose into the glycolytic and pentose phosphate pathways (PPP). When further examining the mechanism by which SGK-1 promotes ATP generation, we surprisingly found that uncoupling the mitochondria did not impact the ability of SGK-1 to promote ATP generation. These data suggest that the TCA cycle is not required for SGK-1 mediated ATP generation. Intriguingly, ATP generation instead requires flux through the PPP and consequent production of glyceraldehyde-3-phosphate (G3P). PPP-derived G3P is shuttled back to glycolysis where ATP production robustly occurs. This metabolic pathway appears to be critical for the anchorage-independent growth of cancer cells as genetic or pharmacological disruption of glucose flux through the PPP significantly abrogates colony formation in soft agar in a variety of distinct cell lines. Overall, these data uncover a novel metabolic pathway downstream of SGK-1 that is highly conserved across multiple epithelial cancer cell lines during ECM detachment.
Citation Format: Jordan A. Cockfield, Joshua A. Mason, Zachary T. Schafer. SGK-1-mediated ATP generation: A novel metabolic pathway that supports ECM-detached cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2403.
Abstract 2488: Functional characterization of nuclear TYRO3 in colorectal cancer
Authors: Tsai Shaw-Jenq , Chien Chun-Wei , Chen Sih-Yu , Lin Shao-Chieh , Lin Bo-Wen , Lee Jenq-Chang 
Published: August 2018

Abstract
Colorectal cancer is one of most common death-related cancers worldwide. Aberrant expression of oncogenes is regarded as a predominant factor in colorectal cancer development. TYRO3 belongs to TAM (TYRO3, AXL, and MER) family, which is a subfamily of receptor tyrosine kinases. Our previous study discovered TYRO3, an oncogene overexpressed in colorectal cancer, promotes cell proliferation, metastasis, and tumor progression. Herein, we further identified that TYRO3 is present in nucleus of colon cancer cells using immunofluorescence staining in conjunction with confocal microscopy. By staining with three different antibodies recognizing N-terminal, central region, and C-terminal of TYRO3, respectively, we identified that central and C-terminal of TYRO3 is the fragment to be translocated to the nucleus. Transfection of exogenous Myc-TYRO3-GFP fusion protein further confirmed this finding. By bioinformatic tool prediction, we found there is a nuclear localization signal (NLS) and a nuclear export signal (NES) in TYRO3. To evaluate the function of nuclear TYRO3, we mutated NLS of TYRO3 and performed several functional studies. Results of immunofluorescent staining showed that after NLS mutation, TYRO3 cannot be translocated to nucleus, which was accompanied by distorted morphology. Furthermore, cancer cells transfected with NLS-mutated TYRO3 increased activated caspase-3 and number of apoptotic cells, suggesting nuclear localization of TYRO3 is essential for cell survival. Clinical data further support that levels of nuclear TYRO3 are a poor prognostic marker that is positively associated with colon cancer treatment failure and malignancy. These data support that nuclear TYRO3 is important for colon cancer cell survival and is a valuable biomarker for prognosis.
Citation Format: Shaw-Jenq Tsai, Chun-Wei Chien, Sih-Yu Chen, Shao-Chieh Lin, Bo-Wen Lin, Jenq-Chang Lee. Functional characterization of nuclear TYRO3 in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2488.
Abstract 2542: c-Jun and FOXO1 play key roles in the overexpression of oncogenic PKC-ι in human prostate and melanoma cell lines
Authors: Apostolatos Andre H. , Ratnayake Wishrawana S. , Islam Anisul , Apostolatos Christopher , Smalley Tracess , Acevedo-Duncan Mildred 
Published: August 2018

Abstract
Protein Kinase C-ι (PKC-ι) is an anti-apoptotic oncogene overexpressed in multiple cancers including prostate, melanoma, ovarian, breast, and glioma. We have previously shown that PKC-ι is part of a cycle that helps cancer cells avoid senescence by releasing the transcription factor NF-kB. Additionally, PKC-ι has an anti-apoptotic effect while promoting epithelial-mesenchymal transition in melanoma {Ratnayake, et al. Int. J. Oncol. 51(5), (2017), 1370-1382}. PKC-ι is activated externally by factors like loss of PTEN and TGFβ stimulation. However treatment with PKC-ι specific inhibitors downregulate expression of both PKC-ι and phosphorylated PKC-ι, suggesting PKC-ι plays a role in regulating its own expression. A previous study showed the ELK1 transcription factor to be a regulator of PKC-ι (Gustafson, et al. J. Biol. Chem 279(10), (2003), 9400-8}. In this study, transcription factors c-Jun, ISGF3, PAX3, EGR1, and FOXO1 which bind on or near the promoter sequence of the PRKCI gene, were analyzed for their role in PKC-ι regulation in prostate cancer cell lines (DU145 and PC3) and melanoma cell lines (SK-MEL-2 and MeWo). Each transcription factor was systematically silenced. Western blots revealed that treatment with either c-Jun or FOXO1 siRNA significantly altered expression of PKC-ι. Results showed c-Jun followed by FOXO1 are the two major transcription factors which involve in PKC-ι expression in prostate cells compared to FOXO1 in melanoma cells. This suggests that these transcription factors act as activators that regulate PKC-ι expression and can be downstream targets of PKC-ι. We found that regulation of PKC-ι expression was governed mainly through NF-κB pathway. siRNA knockdown of NF-κB p65 and application of NF-κB inhibitors confirmed the above observation. We have also used immuno-paired-antibody detection assay to determine which pathways were affected with PKC-ι inhibitor treatments other than NF-κB pathway. qPCR and microarray were performed to analyze the transcriptome of treated cells to match protein levels with mRNA levels. We have analyzed multiple targets both up and downstream of PKC-ι to determine the mechanism of PKC-ι self-regulation. Overall results suggest that PKC-ι inhibition downregulates its own expression making it a novel target in prostate and melanoma cancer treatment.
Citation Format: Andre H. Apostolatos, Wishrawana S. Ratnayake, Anisul Islam, Christopher Apostolatos, Tracess Smalley, Mildred Acevedo-Duncan. c-Jun and FOXO1 play key roles in the overexpression of oncogenic PKC-ι in human prostate and melanoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2542.