bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4193: Biochanin A in pancreatic cancer
Authors: Desai Vilas , Tadinada Satya Murthy , Lai James C K , Bhushan Alok 
Published: August 2018

Abstract
Pancreatic cancer, with its dismally low survival rate (&lt;5%), is one of the most aggressive forms of cancer and is the fourth leading cause of cancer-related deaths in the U.S. Gemcitabine, the first-line drug approved by the FDA, has been marginally effective as it improves survival by only six months. Epidemiologic studies have implicated a role for dietary isoflavones in lowering the incidence of different cancers in the Asian population. Isoflavones such as genistein, biochanin A and daidzein have been tested for their anticancer potential in different cancers; however, the clastogenic effect associated with genistein limits its therapeutic potential. Primarily used in management of hyperlipidemia and cardiovascular diseases, statins have been documented to exert antiproliferative effects. We hypothesized that a combination treatment of biochanin A and atorvastatin exerts enhanced anticancer effects on pancreatic cancer cells viz. AsPC1, PANC-1 and MIAPaCa-2. Our studies showed a decrease in cell viability on combination drug treatment with differential effects on mitogenic and cell signaling pathways in the cell lines investigated. In PANC-1 cells, biochanin A and atorvastatin combination treatment decreased invasiveness, dampened the expression of activated STAT3, and critical mediators of cell cycle progression. We also observed the involvement of enhanced proapoptotic effect of the combination treatment in AsPC-1 cell line and potential cell cycle arrest phenomenon in PANC-1 cells. Cell metabolism studies using seahorse XFp analyzer showed an increase in mitochondrial respiration and a decrease in glycolytic activity on combination treatment. Further, the XF-Plasma Membrane Permeabilizer (XF-PMP) assay used to evaluate the mitochondrial ETC complex activity showed a complete impairment of complex I and II (prominently), with MIAPaCa-2 being more susceptible to the combination treatment than AsPC1 and PANC-1. Together, the combination treatment-induced effects on pancreatic cancer cell lines may have potential implications in developing novel and improved therapies for the treatment of pancreatic cancer.
Citation Format: Vilas Desai, Satya Murthy Tadinada, James C K Lai, Alok Bhushan. Biochanin A in pancreatic 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 4193.
Abstract 4200: New potential therapeutic applications of WX-UK1, as a specific and potent inhibitor of human trypsin-like proteases
Authors: Oldenburg Emil , Schar Christine R. , Lange Eva , Plasse Terry F. , Abramson Danielle T. , Fathi Reza , Towler Eric M. , Levitt Mark , Jensen Jan K. 
Published: August 2018

Abstract
WX-UK1 (the active metabolite of upamostat) was originally developed as an inhibitor of the serine protease urokinase (uPA) with a Ki ~1 uM. To identify more sensitive targets, we performed a bioinformatic analysis of the ~200 human trypsin-like serine proteases, many of which play crucial roles in homeostasis and disease. Among these we selected a subset for biochemical analysis based on an inspection of modelled 3D structures of WX-UK1:protease complexes and sequence alignment of binding site residues. Samples of the selected proteases were prepared and characterized for their binding to WX-UK1; enzymatically with respect to inhibition constant (Ki) and by surface plasmon resonance with respect to dissociation constant (kd). We now report that WX-UK1 is a potent and specific inhibitor of five human serine proteases (trypsin-3, trypsin-2, trypsin-1 and matriptase-1 and trypsin-6), with Ki's down to the low nanomolar range, 19 nM for trypsin-3. Several of these serine proteases are known to be associated with cancer progression and metastasis. As a compound with an established clinical safety profile, targeted use of upamostat in oncology and extension to non-oncology indications may be assessed.
Citation Format: Emil Oldenburg, Christine R. Schar, Eva Lange, Terry F. Plasse, Danielle T. Abramson, Reza Fathi, Eric M. Towler, Mark Levitt, Jan K. Jensen. New potential therapeutic applications of WX-UK1, as a specific and potent inhibitor of human trypsin-like proteases [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 4200.
Abstract 4445: Post-transcriptional inhibition of PTPN23 by SND1: Potential mechanism for hepatocellular carcinoma
Authors: Jariwala Nidhi H. , Mendoza Rachel G. , Dawn Garcia , Zhao Lai , Subler Mark A. , Windle Jolene J. , Fisher Paul B. , Yidong Chen , Sarkar Devanand 
Published: August 2018

Abstract
Oncoprotein SND1 regulates gene expression at a post-transcriptional level in multiple cancers including hepatocellular carcinoma (HCC). Staphylococcal nuclease domains of SND1 function as an RNAse and tudor domain facilitates protein-oligonucleotide interaction. In the present study, we aimed to identify RNA interactome of SND1 to obtain better insights into gene regulation by SND1. RNA interactome was identified by immunoprecipitation of RNA using anti-SND1 antibody from human HCC cells followed by RNA-sequencing (RIP-Seq). With an adjusted p value of &lt;0.01 and &gt;2-fold enrichment over control, 282 mRNAs were identified to significantly associate with SND1 protein. We focused on the tumor suppressor PTPN23 because its regulation by SND1 and its role in HCC are not known. PTPN23 levels were downregulated in human HCC cells versus normal hepatocytes and in human HCC tissues versus normal adjacent liver as revealed by immunohistochemistry. In human HCC cells, knocking down SND1 increased and overexpression of SND1 decreased PTPN23 protein. RNA binding and degradation assays revealed that SND1 specifically binds to and degrades 3'-UTR of PTPN23 mRNA. Tetracycline-inducible PTPN23 overexpression in human HCC cells resulted in significant inhibition in proliferation, migration and invasion and in vivo tumorigenesis. PTPN23 induction caused inhibition in activation of c-Met, EGFR, Src and FAK, suggesting that as a phosphatase PTPN23 inhibits activation of these oncogenic kinases. The present study unravels a novel function of SND1 in targeting PTPN23 and identifies PTPN23 as a unique tumor suppressor for HCC. PTPN23 might function as a homeostatic regulator of multiple kinases restraining their activation.
Citation Format: Nidhi H. Jariwala, Rachel G. Mendoza, Garcia Dawn, Lai Zhao, Mark A. Subler, Jolene J. Windle, Paul B. Fisher, Chen Yidong, Devanand Sarkar. Post-transcriptional inhibition of PTPN23 by SND1: Potential mechanism for hepatocellular carcinoma [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 4445.
Abstract 4490: Autocrine and paracrine effects of miR-29 in hPSCs and PDAC cells
Authors: Factora Tricia , Briscoe Elise , Kwon Jason , Kota Janaiah 
Published: August 2018

Abstract
Pancreatic ductal adenocarcinoma (PDAC) continues to be one of the most lethal malignancies worldwide and responds poorly to current therapeutic modalities. Due to its late stage diagnosis and limited response to current treatments, it is imperative to develop novel and effective therapies for PDAC. Dense fibrotic stroma associated with PDAC abrogates drug perfusion into the tumor and activated pancreatic stellate cells (PSCs) are the major stromal cells responsible for stromal reaction. Furthermore, activated PSCs are known to secrete various factors causing autocrine effects to elicit sustained PSC activation and paracrine effects on cancer cells to promote tumor progression. Our previous work has shown that loss of miR-29 is a common phenomenon of both activated PSCs and pancreatic cancer cells, and its restored expression reduces stromal accumulation and cancer growth. In addition, conditioned media from miR-29 overexpressing PSCs reduces cancer cell viability. To extend our work on the role of miR-29 in tumor-stromal interactions, we examined how autocrine and paracrine signaling is affected by miR-29 overexpression in PSCs and cancer cells. We collected the conditioned media from miR-29a overexpressing human PSCs (hPSC-CM) or cancer cells (CC-CM) and cultured nascent PSCs or cancer cells to evaluate autocrine and paracrine effects. hPSCs and PDAC cells cultured in miR-29 hPSC-CM resulted in a significant reduction of cell viability. Likewise, miR-29 overexpressing CC-CM reduced the viability of hPSCs and cancer cells. Additionally, cancer cell migration was reduced when treated with miR-29 overexpressing hPSC- and CC-CM. Taken together, our results demonstrate that conditioned media collected from miR-29 overexpressing hPSCs and cancer cells reduces hPSC/cancer cell viability and cancer cell migration. Moreover, our findings highlight the important role of miR-29 in the autocrine/paracrine interactions between PSCs and cancer cells. In our future studies, we expect to identify the key factors that are regulated by miR-29 in tumor-stromal interactions.
Citation Format: Tricia Factora, Elise Briscoe, Jason Kwon, Janaiah Kota. Autocrine and paracrine effects of miR-29 in hPSCs and PDAC 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 4490.
Abstract 4541: MET gene copy number gains evaluated by NGS is more predictive than other methods to enrich for papillary RCC patients sensitive to savolitinib, a selective MET inhibitor
Authors: Frigault Melanie M. , Signoretti Sabina , Markovets Aleksandra , Stetson Daniel , Howat William , Roudier Martine , Haddad Vincent , Dougherty Brian , Choueiri Toni K. , Barrett J. Carl 
Published: August 2018

Abstract
There is no approved therapy specifically for the treatment of papillary renal cell carcinoma (PRCC). Advances in molecular profiling of PRCC have identified a segment of PRCC with 10% MET mutation rates (Linehan et al 2016). Chromosome 7 gain is a hallmark of PRCC and thought to occur at 50% frequency in PRCC (Jiang et al 1998). We undertook a retrospective analysis of archival tumors to evaluate MET pathway aberrations for correlation with efficacy in a phase II study of savolitinib (volitinib, AZD6094, HMPL-504) in patients with PRCC (NCT02127710). Archival diagnostic tumor samples were mandated for central confirmation of PRCC diagnosis, histological subtyping, and for exploratory biomarker analysis. Eighty-four archival tumors were obtained and profiled using four methods: H&E stain for PRCC histological subtype, immunohistochemistry (IHC) for c-Met protein expression (Ventana, CONFIRM), fluorescent in situ hybridization (FISH) for MET gene amplification (Abbott, VYSIS), and Next Generation Sequencing (NGS) as an orthogonal method for confirmation of MET amplifications, detection of HGF gene amplifications, MET mutations, chromosome 7 ploidy, and other exploratory genomic biomarkers (Foundation Medicine Inc., T7 panel). Eight patients with a confirmed partial response (PR) to savolitinib were used to define MET-driven PRCC. Retrospective analysis demonstrated that only NGS, not IHC, FISH or histological subtype, identified all PRs. NGS detected any one of the following biomarkers alone or in combination in PRs: chromosome 7 copy number gain, MET or HGF gene focal amplification, MET kinase domain mutations. The frequency of these biomarkers in the phase II population were 31.5%, 10%, 1%, and 7.5%, respectively and captured all responders (18% ORR); however, 42% of non-responders (PD and SD) were also classified as MET-driven by NGS. Focal MET amplifications were confirmed with MET FISH testing, but FISH was unable to identify gains in chromosome 7. IHC was not as sensitive as NGS (57% vs 100%) but had a higher specificity. Molecular characterization of MET status was more predictive of response to savolitinib than a classification based on pathology.
Citation Format: Melanie M. Frigault, Sabina Signoretti, Aleksandra Markovets, Daniel Stetson, William Howat, Martine Roudier, Vincent Haddad, Brian Dougherty, Toni K. Choueiri, J. Carl Barrett. MET gene copy number gains evaluated by NGS is more predictive than other methods to enrich for papillary RCC patients sensitive to savolitinib, a selective MET inhibitor [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 4541.
Abstract 4573: Localized synchrotron radiation in mice induces persistent systemic genotoxic events mediated by the functional immune system
Authors: Ventura Jessica , Lobachevsky Pavel , Palazzolo Jason , Forrester Helen , Haynes Nicole , Ivashkevich Alesia , Stevenson Andrew , Hall Christopher , Gorgoulis Vassilis , Hamilton John , Georgakilas Alexandros , Sprung Calr , Martin Olga A. 
Published: August 2018

Abstract
The discovery of the radiation-induced bystander effect has expanded knowledge of radiobiological mechanisms of ionizing radiation. A counterpart in vivo phenomenon is the radiation-induced abscopal effect (RIAE). It is not known how radiation settings affect non-targeted normal tissues and therefore the risk of adverse RIAE. At the Australian Synchrotron we examined systemic effects of microbeam radiotherapy (MRT) and broad beam (BB) configurations, in mice that were locally exposed to a very short pulse of a high dose-rate synchrotron beam (49 Gy/sec). We determined how radiation volume and dose impact the RIAE. C57BL/6 mice were irradiated with 10 or 40 Gy incident dose of MRT or BB in an 8x8, 8x1, or 2x2-mm area of the right hind leg. Blood samples, irradiated skin and a variety of normal unirradiated tissues were collected for DNA damage analysis of double-strand breaks (DSBs) quantified as gamma-H2AX foci and oxidatitive clustered DNA lesions (OCDL). OCDLs elevated in a wide variety of unirradiated normal tissues. In out-of-field duodenum, a trend for elevated apoptotic cells was observed, however DSBs elevated only after exposure to lower doses. These genotoxic events were accompanied by changes in concentrations of MDC, CCL2/MCP1, Eotaxin, IL-10, TIMP-1, VEGF, TGFβ-1 and TGFβ-2 plasma cytokines and by changes in frequencies of macrophages, neutrophils and T-lymphocytes in duodenum. Overall, systemic radiation responses were dose-independent (1). The MRT irradiations was repeated in immune-deficient mice: NSG, CCL2 knock-outs, and in C57BL/6 mice treated with anti-CSF1R antibody which effectively depletes macrophages. Strikingly, these effects and the abscopal innate and adaptive immune effector responses were completely or partially abrogated in the mice with various immune deficiencies, highlighting the role of the functional immune system in propagation of systemic genotoxic effects of radiation. These findings have implications for the planning of therapeutic and diagnostic radiation to reduce the risk of radiation-related adverse systemic effects. 1. Ventura et al, Cancer Research, e-pub (2017).
Citation Format: Jessica Ventura, Pavel Lobachevsky, Jason Palazzolo, Helen Forrester, Nicole Haynes, Alesia Ivashkevich, Andrew Stevenson, Christopher Hall, Vassilis Gorgoulis, John Hamilton, Alexandros Georgakilas, Calr Sprung, Olga A. Martin. Localized synchrotron radiation in mice induces persistent systemic genotoxic events mediated by the functional immune system [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 4573.
Abstract 4760: Joint modeling of longitudinal tumor dynamics and survival in non-small cell lung cancer (NSCLC) patients
Authors: Tong Xiao , Dunyak James , Zhou Diansong , Carlile David , Tomkinson Helen , Helmlinger Gabriel , Al-Huniti Nidal , Xu Hongmei 
Published: August 2018

Abstract
Objectives: Tumor size dynamics and survival are traditionally analyzed in a 2-stage approach, without consideration of joint dependencies. The objective of this analysis was to develop a joint model which associates tumor size dynamics and progression-free survival (PFS), to predict time-to-progression. Methods: Phase 2 trial data from selumetinib (AZD6244; ARRY-142886, MEK inhibitor), in NSCLC patients (SELECT-2; NCT01750281) were used to develop a joint model for tumor size dynamics and PFS. The analysis was performed using JM package in R. Treatment arm, KRAS mutation and WHO performance status were evaluated as covariates. Model was evaluated by survival estimation based on early time (e.g., first 3 months) tumor size data. The final joint model based on SELECT-2 data was then used to predict PFS of selumetinib in SELECT-1 (NCT01933932) phase 3 trial. Results: The joint model developed on SELECT-2 data identified a significant association (p value &lt;0.001) between the slope of the longitudinal tumor dynamic and PFS. WHO performance status was identified to be the only significant covariate. Furthermore, the model built on phase 2 data adequately predicted PFS of the SELECT-1 data, using SELECT-1 tumor size data within 4 months of treatment. Prediction confirmed no significant difference in PFS between active treatment arm and chemotherapy arm in SELECT-1 trial. Conclusions: Using selumetinib as an example, we showed that joint modeling of tumor size dynamics and PFS may provide a novel quantitative tool to predict long-term outcome in NSCLC based on early tumor size measurements.
Citation Format: Xiao Tong, James Dunyak, Diansong Zhou, David Carlile, Helen Tomkinson, Gabriel Helmlinger, Nidal Al-Huniti, Hongmei Xu. Joint modeling of longitudinal tumor dynamics and survival in non-small cell lung cancer (NSCLC) patients [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 4760.
Abstract 4780: A novel, potent and selective FGFR4 inhibitor, HM81422 in hepatocellular carcinoma with FGFR4-driven pathway activation
Authors: Lee JaeHo , Kang Hyunjeong , Koo Kyounghwa , Ha Youngeun , Lim Sun Young , Byun Joo-Yun , Yu Hyunkyung , Song Taehun , Lee Moonsub , Jung Seung Hyun , Kim Taewoo , Bang Hyojeong , Kim Eunyoung , Kang Jahoon , Lee Ho Jeong , Kim YoungHoon , Ahn YoungGil , Suh KweeHyun , Kim Sun-Jin 
Published: August 2018

Abstract
Introduction: Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the second most frequent cause of cancer-related death, however, treatment options are very limited. In recent studies, aberrant signaling through FGFR4 and its ligand, FGF19 have been identified as the oncogenic driver in a subset of HCCs and reported to be associated with poor prognosis. About 30% of HCC patients have altered FGF19/FGFR4 pathway signaling, therefore, the treatment with FGFR4 inhibitor may produce benefit. Materials and Method: Using the structure-based design, we have generated a novel, potent and selective FGFR4 inhibitor, HM81422 with irreversible-covalent binding mode, and evaluated its anti-tumor activity in a variety of HCC cell lines, HCC cell line xenografts and orthotopic grafts. Results: Biochemical selectivity assays demonstrated that HM81422 is highly selective towards FGFR4 compared to other FGFR isotypes as well as a panel of several kinases. The treatment of HM81422 to FGF19 amplified and overexpressed HCC cell lines led to suppression of FGF19/FGFR4 signaling pathway and concomitant reduction in cell viability in dose-dependent manner. Oral administration of HM81422 to mice bearing FGF19 altered HCC cells showed dose-dependent pharmacokinetics, pharmacodynamic modulation of FGFR4 signaling and antitumor efficacy in xenograft models. And HM81422 demonstrated inhibition of tumor growth in an orthotopic liver xenograft model of FGF19 altered HCC in nude mice. Conclusion: In conclusion, the treatment of HCC patients with a potent and selective FGFR4 inhibitor, HM81422, can be an attractive approach targeting approximately 30% of HCC patients by inhibiting altered FGF19-mediated signaling cascade. Further preclinical studies with HM81422 will be performed and reported soon.
Citation Format: JaeHo Lee, Hyunjeong Kang, Kyounghwa Koo, Youngeun Ha, Sun Young Lim, Joo-Yun Byun, Hyunkyung Yu, Taehun Song, Moonsub Lee, Seung Hyun Jung, Taewoo Kim, Hyojeong Bang, Eunyoung Kim, Jahoon Kang, Ho Jeong Lee, YoungHoon Kim, YoungGil Ahn, KweeHyun Suh, Sun-Jin Kim. A novel, potent and selective FGFR4 inhibitor, HM81422 in hepatocellular carcinoma with FGFR4-driven pathway activation [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 4780.
Abstract 4849: Targeting the lethal pediatric atypical teratoid/rhabdoid tumors with the DNA minor-groove binding agent quinacrine
Authors: Kaur Harpreet , Guo Huizi , Eberhart Charles G. , Raabe Eric H. 
Published: August 2018

Abstract
Atypical teratoid/rhabdoid tumors (AT/RT) are rare, incurable, and highly proliferative pediatric brain tumors. Discovering new targets and developing novel therapeutics are urgently needed for this devastating tumor. We have previously shown that AT/RT tumors and cell lines express increased amounts of the epigenetic modifier high mobility group AT-hook 2 (HMGA2). HMGA2 is a DNA-binding oncoprotein that regulates transcription during normal embryogenesis and in cancer stem cells. Targeting HMGA2 using short hairpins significantly decreased AT/RT cell growth and increased survival of xenografted mice in our studies. We hypothesized that pharmacological inhibition of HMGA proteins using DNA minor-groove binding drugs will decrease growth of AT/RT cell lines due to displacement of HMGA proteins from the DNA. We used the minor-groove binding agent quinacrine to test our hypothesis in 3 different AT/RT cell lines (BT37, CHLA-06 and CHLA-04). Quinacrine has been used in millions of humans to treat malaria and other parasitic infections and has a well known safety profile. Quinacrine penetrates the brain, and we can achieve micromolar levels of quinacrine in brain after oral administration. Quinacrine causes a dose-dependent reduction in AT/RT cell growth (MTS assay) and proliferation (BrdU incorporation) compared to vehicle-treated cells (P&lt;0.05). Additionally, treatment of AT/RT cells with quinacrine significantly increased apoptotic cell death (increased cleaved caspase-3 and cleaved PARP expression) in a dose-dependent manner compared to vehicle-treated cells (P&lt;0.05). Our results suggest that minor groove binding drugs like quinacrine are a viable potential treatment strategy for AT/RT. Future studies are aimed at testing the in vivo efficacy and validating the mechanism of action of quinacrine in AT/RT.
Citation Format: Harpreet Kaur, Huizi Guo, Charles G. Eberhart, Eric H. Raabe. Targeting the lethal pediatric atypical teratoid/rhabdoid tumors with the DNA minor-groove binding agent quinacrine [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 4849.