bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4088: Metabolic disease drivers of liver cancer, a new disease paradigm
Authors: Briggs Michael R. , Deshpande Dipti , Siegmund Nikole 
Published: August 2018

Abstract
Much of the global burden of HCC until recently has been caused by alcohol abuse and hepatitis viruses (HepB & HepC). With a vaccine for HepB being widely used in Asian countries and multidrug cocktails to effectively cure much HepC, these drivers of HCC will be reduced in the future. Ironically, HCC continues to be one of the few cancers growing in incidence. It is postulated that the global obesity epidemic is fueling a new etiology of HCC, through fatty liver disease, nonalcoholic steatohepatitis (NASH) and cirrhosis. Liver and pancreatic cancers are projected to continue to increase in incidence for the foreseeable future, and distressingly, for the first time, children are being diagnosed with NASH. We have undertaken the development of a mouse model of NASH leading to HCC and performed a longitudinal analysis of liver samples through the phenotypes of obesity and hyperglycemia, inflammation and fibrosis leading to hyperproliferative disease and HCC to begin to map out the pathways and biomarkers of this metabolically driven liver cancer for comparison to human clinical data and biomarkers of disease progression to HCC.
Citation Format: Michael R. Briggs, Dipti Deshpande, Nikole Siegmund. Metabolic disease drivers of liver cancer, a new disease paradigm [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 4088.
Abstract 4090: Generation of a new mouse to model pancreatic cancer-induced cachexia
Authors: Talbert Erin E. , Ladner Katherine J. , Cuitino Maria Cecilia , Leone Gustavo W. , Guttridge Denis C. 
Published: August 2018

Abstract
Of all cancers, pancreatic cancer causes the third most fatalities, and incidence rates of this devastating disease continue to rise. Further, pancreatic cancer presents with the highest incidence of cachexia, a syndrome of weight loss due to depletion of skeletal muscle and adipose tissue. Clinically, cachexia is associated with increased mortality, poor quality of life, poor treatment responses, and increased treatment complications. Although clearly the best way to prevent cachexia is to address the cancer, pancreatic cancer has proven challenging to treat, with a dismal 9% 5-year survival rate. We believe effective anti-cachexia therapy will improve the care of pancreatic cancer patients, but the development of these therapies will require animal models that accurately recapitulate the etiology of pancreatic cancer-induced cachexia. To improve on the current, non-pancreas tumor xenograft models of cachexia, we generated a genetically engineered mouse model (GEMM) of pancreatic cancer, where induction of Kras and loss of the tumor suppressor Pten occurs in the pancreas of postnatal mice, which we refer to as the KPP model. KPP mice progressively lose skeletal muscle and adipose mass as a result of their cancer. We find that KPP mice exhibit histologic features of pancreatic ductal adenocarcinoma and reach endpoint criteria at an average of 107 days of age. Beginning at approximately 75 days of age, KPP mice undergo progressive loss of existing skeletal muscle mass, resulting in decreased muscle function. We also find that muscle loss from KPP mice exhibits a gene expression signature that closely aligns with the gene expression signature in muscle from cachectic pancreatic cancer patients. In summary, we expect KPP mice to serve as a useful model to elucidate the underlying mechanisms of muscle loss in pancreatic cancer-induced cachexia and to evaluate potential anti-cachexia therapies.
Citation Format: Erin E. Talbert, Katherine J. Ladner, Maria Cecilia Cuitino, Gustavo W. Leone, Denis C. Guttridge. Generation of a new mouse to model pancreatic cancer-induced cachexia [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 4090.
Abstract 4099: Novel patient-derived 3D (PD3D) cell models and matched patient-derived xenografts (PDX) from peritoneal metastasis of colorectal cancer for drug testing and biomarker analysis
Authors: Regenbrecht Christian RA , Gambara Guido , Pachmayr Eva , Silvestri Alessandra , Dahlmann Mathias , Brzezicha Bernadette , Buettner Britta , Rau Beate , Keilholz Ulrich , Stein Urike , Walther Wolfgang 
Published: August 2018

Abstract
For patients with colorectal cancer (CRC) peritoneal metastases (PM) represent a terminal tumor stage with limited therapeutic options. To increase therapeutic efficacy and overall survival, availability of appropriate patient-derived 3D cell culture (PD3D) and patient-derived xenografts (PDX) models of PM could help improving the predictability of drug response for a specific tumor, but also foster the identification of novel biomarkers and therapeutic targets for CRC-PM patients. In this context, we generated the first scaffold-based PD3D and matching PDX models of CRC-PM as platform to test for chemotherapy response and to identify novel biomarkers.
For model establishment, surgical specimens were processed either for PD3D cell culture or transplanted subcutaneously (s.c.) onto immunocompromized NOD scid gamma (NSG) mice. For 3D cell culture models, tissue was dissected, digested and filtered before embedding into a scaffold matrix. For PDX models engrafted tumors were transferred to NMRI nu/nu mice for further passaging. They were characterized by histopathology, immunohistochemistry and gene expression analyses using real-time RT-PCR. Chemosensitivity of both sibling models was evaluated on a panel of conventional chemotherapeutic and of targeted drugs.
The same panel of drugs was used in 15 matched PD3D/PDX models and revealed individual response patterns both in PD3D and PDX. Most interestingly, different drug response pattern was observed in models derived from tumor tissue of the omentum vs. tissue from the peritoneum of the same patient.
Our results demonstrate, that matched models maintain basic characteristics such as the morphology of the patient tumor in early passages, reflect heterogeneous response rates, and can be used as preclinical platform for translational studies of potential clinical use.
Citation Format: Christian RA Regenbrecht, Guido Gambara, Eva Pachmayr, Alessandra Silvestri, Mathias Dahlmann, Bernadette Brzezicha, Britta Buettner, Beate Rau, Ulrich Keilholz, Urike Stein, Wolfgang Walther. Novel patient-derived 3D (PD3D) cell models and matched patient-derived xenografts (PDX) from peritoneal metastasis of colorectal cancer for drug testing and biomarker analysis [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 4099.
Abstract 4109: Multi-modality imaging to interrogate lipidome changes during melanoma progression in zebrafish
Authors: Henderson Fiona , Johnston Hannah , Jones Emrys , Foster Duncan , Nagaraju Raghavendar T. , Green Michael , Fairclough Michael , Ramirez Irene Barinaga-Rementeria , He Shuning , Snaar-Jagalska B.Ewa , Hollywood Katherine A. , Dunn Warwick , Spaink Herman P. , Lorigan Paul , Claude Emmanuelle , Williams Kaye , Hurlstone Adam , McMahon Adam 
Published: August 2018

Abstract
Lipids play diverse roles in the body, including cell structure, cell signalling, and energy production; all of which are altered in cancer. Lipid metabolism is therefore a potential therapeutic target, and here has been investigated using a transgenic zebrafish model. This study combines transcriptome and lipidomic analyses for the first time, with in-vivo positron emission tomography (PET) and ex-vivo desorption electrospray ionisation-mass spectrometry (DESI-MS), to investigate lipid metabolism changes in melanoma. Most lipids are made of fatty acids, and the methods by which tumours acquire fatty acids can be altered compared to normal tissue. Here, the PET tracer [18F]-FTHA (a fatty acid analogue) has been used to demonstrate free fatty acid uptake in melanoma tumours in-vivo. Additionally, the excellent spatial resolution of mass spectrometry imaging has been utilised by imaging the FTHA ex-vivo by DESI-MS, allowing more precise spatial correlation with the histology, and revealing the heterogeneous nature of this fatty acid uptake. These imaging data complement the findings of the transcriptome analyses which show upregulation of genes associated with fatty acid uptake. Integrating transcriptome and lipidome data analyses revealed dysregulation of glycerophospholipid pathways, and was supported by DESI-MS data, which revealed heterogeneous changes in lipid metabolism.
Citation Format: Fiona Henderson, Hannah Johnston, Emrys Jones, Duncan Foster, Raghavendar T. Nagaraju, Michael Green, Michael Fairclough, Irene Barinaga-Rementeria Ramirez, Shuning He, B.Ewa Snaar-Jagalska, Katherine A. Hollywood, Warwick Dunn, Herman P. Spaink, Paul Lorigan, Emmanuelle Claude, Kaye Williams, Adam Hurlstone, Adam McMahon. Multi-modality imaging to interrogate lipidome changes during melanoma progression in zebrafish [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 4109.
Abstract 4137: Inhibition of protein synthesis with polyamine depletion in high-risk neuroblastoma
Authors: Flynn Andrea T. , Liu Kangning , Vu Annette , Hogarty Michael D. 
Published: August 2018

Abstract
The MYC family of oncogenes coordinately deregulate cellular programs that link cell cycle progression with the requisite biomass and energy creation. Neuroblastoma is a MYC-driven, commonly lethal pediatric tumor, with a high proportion of tumors containing MYCN amplification. Polyamine synthesis is a pathway downstream of MYC, with polyamines functioning, in part, to support protein synthesis. ODC1 encodes ornithine decarboxylase, the rate-limiting enzyme in polyamine synthesis, and we found that ODC1 is co-amplified with MYCN in a subset of high-risk neuroblastomas (~8%). Difluoromethylornithine (DFMO) is an irreversible inhibitor or ornithine decarboxylase and is an approved agent for the treatment of Trypanosomiasis. We have previously shown that DFMO inhibits tumor progression and synergizes with chemotherapy in murine mouse models of neuroblastoma, and we postulate that inhibition of protein synthesis is a predominant mechanism of anti-tumor activity. The effects of polyamine depletion on specific components of protein translational machinery have yet to be defined. Here, we show inhibition of global protein synthesis of up to 90% after treatment with various concentrations of DFMO in vitro, with a larger decrease in protein synthesis generally correlating with the presence of MYCN amplification. We found that colony formation is inhibited at DFMO exposures as low as 150 to 500 μM DFMO, which are achievable concentrations in adults based on previous clinical trials. We also show via isoelectric focusing that treatment of neuroblastoma cells in vitro with DFMO leads to a marked decrease in the proportion of hypusinated, or active, eIF5A (an elongation factor important in translation of polyproline stretches and possibly broader influence on translation initiation). To interrogate influences of polyamine depletion on the cap-dependent translation eIF4F complex, we evaluated for changes in the phosphorylation of 4E-BP1 in DFMO treatment conditions, though no changes in phosphorylation were seen compared to controls. Studies to further elucidate the protein synthetic components affected by polyamine depletion are ongoing, as are studies to assess for selective effects of DFMO on polyproline-containing proteins via eIF5A. Further elucidation of the mechanisms of DFMO activity will identify opportunities for drug synergy and provide a responder hypothesis to test in upcoming pivotal Phase 2 and 3 clinical trial of DFMO in the treatment of neuroblastoma.
Citation Format: Andrea T. Flynn, Kangning Liu, Annette Vu, Michael D. Hogarty. Inhibition of protein synthesis with polyamine depletion in high-risk neuroblastoma [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 4137.
Abstract 4146: N6Methyladenosine RNA demethylase ALKBH5 as a novel therapeutic target for osteosarcoma
Authors: Yadav Pooja , Subbarayalu Panneerdoss , Abdelfattah Nourhan , Eedunuri Vijay K. , Chen Yidong , Rao Manjeet K. 
Published: August 2018

Abstract
Osteosarcoma (OS) is the most prevalent primary bone malignancy that affects children and young adults. Despite several years of research, survival outcome of OS patients has not improved in last three decades. OS is treated with multi-modal chemotherapy, which is highly toxic and does not work well for metastatic and chemo-resistant tumors. Currently there is no FDA approved drug that can serve as an alternative to chemotherapy, warranting an urgent need to find more efficacious and targeted therapeutics for OS. Here, we report that RNA demethylase AlkB Homolog 5 (ALKBH5) may serve as a novel therapeutic adjuvant for treating OS. N6 Methyladenosine (m6 A) is the most common internal mRNA modification, which is modulated by the multi-component RNA methyltransferase complex, RNA demethylase (ALKBH5) and m6A readers . We show that ALKBH5 is amplified in sarcomas and its expression is highly elevated in osteosarcoma patients. We demonstrate that silencing of ALKBH5 inhibits the OS growth and migration without affecting the viability of normal human fetal osteoblast cells. Our results reveal that ALKBH5 depletion impairs the cell cycle progression and induces apoptosis in OS cells. Interestingly, we demonstrate that reduction in ALKBH5 levels suppresses the DNA damage repair capacity of osteosarcoma cells rendering them sensitive to DNA damaging agent like Doxorubicin. Using DR-GFP reporter-based homologous recombination (HR) assay, we show that ALKBH5 depletion leads to reduced HR-mediated DNA repair capacity of osteosarcoma cells. Supporting this, we observed significantly reduced expression of several genes that are known to play critical roles in cell cycle progression and DNA damage repair. In summary, this study shows that ALKBH5 is a critical regulator of OS growth and chemosensitivity. Approaches aimed at silencing ALKBH5 can be potentially used to inhibit osteosarcoma growth and progression as well as sensitize osteosarcoma cells to DNA damaging agents.
Citation Format: Pooja Yadav, Panneerdoss Subbarayalu, Nourhan Abdelfattah, Vijay K. Eedunuri, Yidong Chen, Manjeet K. Rao. N6Methyladenosine RNA demethylase ALKBH5 as a novel therapeutic target for osteosarcoma [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 4146.
Abstract 4176: Abrogation of desmoglein 2-mediated c-met activation as a novel therapeutic strategy for reducing anaplastic thyroid cancer metastasis
Authors: Lee Dong G. , Min Jeong-Ki 
Published: August 2018

Abstract
Anaplastic thyroid cancer (ATC) is a fast growing and highly metastatic cancer with limited therapeutic options. Thus, targeted therapies need to be developed. This study aims to determine desmoglein 2 (Dsg2) expression in ATC and to elucidate its biological role and potential as a therapeutic target in ATC. Dsg2 expression was low or abnormal in ATC tissues. The ATC patients with reduced Dsg2 expression also had distant metastasis. Dsg2 depletion significantly increased cell migration and invasion, with relatively little effect on ATC cell proliferation in vitro, and increased distant metastasis in vivo. Dsg2 knockdown induced cell motility through the hepatocyte growth factor receptor (HGFR, c-Met)/Src/Rac1 signaling axis, with no alterations in the expression of EMT-related molecules. Further, specific targeting of c-Met significantly inhibited the motility of shDsg2-depleted ATC cells. Decreased membrane expression of Dsg2 increases the metastatic potential of ATC cells. Dsg2 plays an important role in migration and invasiveness in cell lines derived from ATC. Therapies targeting c-Met might be effective for ATC patients with decreased membrane expression of Dsg2. Thus, analysis of Dsg2 expression may provide a novel therapeutic strategy for ATC treatment.
Keywords Anaplastic Thyroid Cancer, Desmoglein 2, Metastasis, c-Met, Tivantinib
Citation Format: Dong G. Lee, Jeong-Ki Min. Abrogation of desmoglein 2-mediated c-met activation as a novel therapeutic strategy for reducing anaplastic thyroid cancer metastasis [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 4176.
Abstract 4181: Simultaneous inhibition of the Wnt/B-catenin and Ras pathways by KY1022 effectively suppresses tumor initiation and progression of colorectal cancer
Authors: Ro Eun Ji , Hwang Jeong-Ha , Cho Yong-Hee , Choi Kang-Yell 
Published: August 2018

Abstract
APC (80-90%) and K-Ras (40-50%) mutations frequently occur in human colorectal cancer (CRC) and these mutations cooperatively accelerate tumorigenesis including metastasis. In addition, both B-catenin and Ras levels are highly increased in CRC, especially in metastatic CRC (mCRC). Targeting these signaling pathways may therefore be an ideal strategy for treating mCRC; however, therapeutics targeting both of these pathways have not been developed because the mechanisms regulating these pathways are not well understood. Based on our recent identification of the B-catenin destruction complex-mediated Ras protein stability mechanism, we screened a small-molecule library to identify compounds that destabilize both B-catenin and Ras proteins via inhibition of the Wnt/B-catenin pathway. Among the effective small molecules destabilizing both B-catenin and Ras proteins via inhibition of the Wnt/β-catenin pathway, we characterized KY1022, a small molecule that most effectively inhibits EMT, an initial process of metastasis. As shown by in vitro and in vivo studies using APCMin/+/K-RasG12DLA2 mice, KY1022 effectively suppressed the development of mCRC at an early stage of tumorigenesis. Our results suggest that a small molecular approach degrading both B-catenin and Ras via inhibition of the Wnt/B-catenin signaling would be an ideal strategy for treatment of CRC including mCRC.
Citation Format: Eun Ji Ro, Jeong-Ha Hwang, Yong-Hee Cho, Kang-Yell Choi. Simultaneous inhibition of the Wnt/B-catenin and Ras pathways by KY1022 effectively suppresses tumor initiation and progression of 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 4181.
Abstract 4196: Aspirin inhibits metastasis in the intravascular phase through the blockade of COX-1-TXA2 pathway in platelets
Authors: Lucotti Serena , Cerutti Camilla , Soyer Magali , Gil-Bernabé Ana M. , Gomes Ana L. , Allen Philip D. , Smart Sean , Markelc Bostjan , Watson Karla , Armstrong Paul C. , Mitchell Jane A. , Warner Timothy D. , Ridley Anne J. , Muschel Ruth J. 
Published: August 2018

Abstract
Evidence from experimental studies and clinical trials has shown that aspirin reduces the incidence of distant metastases. Aspirin inhibits cyclooxygenase (COX)-1 and COX-2, triggering anti-thrombotic and anti-inflammatory effects, respectively. However, the mechanisms underlying the anti-metastatic effect of aspirin are still largely unknown.
By employing mouse models of experimental and spontaneous metastasis, we have shown that aspirin and a selective COX-1 inhibitor dramatically reduced metastatic lung nodules, an effect that was not replicated by selective inhibition of COX-2. Metastasis was impaired in COX-1 deficient mice as well, suggesting a pivotal role of microenvironmental COX-1 in the metastatic process. In particular, COX-1 activity was essential during the intravascular phase of pulmonary metastasis. Using a model of platelet depletion and re-infusion we identified platelet-derived thromboxane A2 (TXA2) as the main product of COX-1 responsible for its permissive effect on metastasis. The inhibition of the COX-1-TXA2 pathway in platelets decreased the aggregation of platelets on tumor cells and was associated with a reduction in endothelial activation, in tumor cell adhesion to the endothelium, in recruitment of metastasis-promoting monocytes/macrophages and in transendothelial migration. Thus, platelet-derived TXA2 orchestrates the generation of a favorable intravascular metastatic niche that promotes tumor cell seeding and metastasis.
Taken together, our data suggest that COX-1 inhibition in platelets by aspirin is sufficient to exert an anti-metastatic effect and shed a new light on COX-1-TXA2 signalling in the context of tumor cell dissemination. From this perspective, TXA2 might present a more selective therapeutic target for the prevention of metastasis.
Citation Format: Serena Lucotti, Camilla Cerutti, Magali Soyer, Ana M. Gil-Bernabé, Ana L. Gomes, Philip D. Allen, Sean Smart, Bostjan Markelc, Karla Watson, Paul C. Armstrong, Jane A. Mitchell, Timothy D. Warner, Anne J. Ridley, Ruth J. Muschel. Aspirin inhibits metastasis in the intravascular phase through the blockade of COX-1-TXA2 pathway in platelets [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 4196.