bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A41: Patient-Derived Fluorescent Orthotopic Xenografts (PDOX™) models for personalized anti-metastatic cancer therapy and drug discovery
Authors: Hoffman Robert M. 
Published: May 2015

Abstract
The original patient-derived xenografts (PDX) was developed in Rygaard's laboratory (Acta Pathol Microbiol Scand 77: 758-760, 1969), who was the first to use nude mice for cancer research, in this case implanting human patient tumors subcutaneously. A number of other laboratories around the world followed with their own subcutaneous nude mouse models of patient tumors as well as cancer cell lines in nude mice. Two decades ago, our laboratory developed the first orthotopic patient tumor models in nude mice for colon cancer (Proc Natl Acad Sci USA 88: 9345-9349, 1991), pancreatic cancer (Proc Natl Acad Sci USA 89: 5645-5649, 1992), for ovarian cancer (Anticancer Research 13, 283-286, 1993) and for breast cancer (Anticancer Res. 13, 901 904, 1993). These were major advancements since this was the first time metastasis could occur in PDX since the patent tumors were implanted orthotopically. We have termed these models patient-derived orthotopic xenografts (PDOX™). We have now developed technology to make the orthotopic patient tumor models genetically fluorescent by passaging patient tumors through transgenic mice ubiquitously expressing fluorescent proteins (J Cell Biol 113, 2290-2295, 2012) in order to label the PDOX™ stroma. The labeled stroma is stable upon passage to non-transgenic mice for rapid screening of effective agents. PDOX™, enable rapid screening of anti-metastatic agents for patients with highly recalcitrant tumors, a major advance in individualized cancer therapy.
Citation Format: Robert M. Hoffman. Patient-Derived Fluorescent Orthotopic Xenografts (PDOX™) models for personalized anti-metastatic cancer therapy and drug discovery. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A41.
Abstract B01: A portable imaging system for fluorescence-guided surgery on a human colon cancer patient-derived orthotopic xenograft (PDOX™) nude mouse model
Authors: Hiroshima Yukihiko , Maawy Ali , Kaushal Sharmeela , Zhang Yong , Uehara Fuminari , Miwa Shinji , Yano Shuya , Sato Sho , Murakami Takashi , Momiyama Masashi , Chishima Takashi , Tanaka Kuniya , Bouvet Michael , Endo Itaru , Hoffman Robert M. 
Published: May 2015

Abstract
In this study, we determined the effectiveness of fluorescence-guided surgery (FGS) using a fluorophore-conjugated anti-carcinoembryonic antigen (CEA) antibody on a colon-cancer patient-derived orthotopic xenografts (PDOX™) nude mouse model. The patient tumor was established in NOD/SCID mice and passed orthotopically in nude mice to make PDOX™ models. Eight weeks after orthotopic implantation in nude mice, a monoclonal anti-CEA antibody conjugated with Alexa 488 was delivered to the PDOX™ models as a single intravenous dose 24 hours before laparotomy. The tumor was completely resected under fluorescence guidance using a hand-held portable fluorescence imaging system. Frozen section microscopy of the resected specimen demonstrated that the anti-CEA antibody selectively labeled cancer cells in the colon cancer PDOX™. Histologic evaluation of the resected specimen demonstrated that cancer cells were not present in the margins. The results of the present report predict that FGS using a fluorophore-conjugated anti-CEA antibody and hand-held portable imaging system should improve intraoperative staging and efficacy of resection for colorectal cancer in the clinic.
Citation Format: Yukihiko Hiroshima, Ali Maawy, Sharmeela Kaushal, Yong Zhang, Fuminari Uehara, Shinji Miwa, Shuya Yano, Sho Sato, Takashi Murakami, Masashi Momiyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. A portable imaging system for fluorescence-guided surgery on a human colon cancer patient-derived orthotopic xenograft (PDOX™) nude mouse model. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B01.
Abstract B02: Modeling of early to invasive stages of pancreatic cancer progression with an iPSC-like line from human pancreatic ductal adenocarcinoma
Authors: Kim Jungsun , Hoffman John P. , Reichert Maximilian , Rhim Andrew , Stanger Ben Z. , Gumbs Andrew , Zaret Kenneth S. 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has one of the worst prognoses of any human malignancy. When human PDAC cells are injected into immunodeficient animals, they create tumors of the late stage from which they were derived. We hypothesized that if human PDAC cells were converted to pluripotency and then allowed to differentiate back into pancreatic tissue, they might undergo early stages of cancer. Although most induced pluripotent stem cell (iPSC) lines were not of the expected cancer genotype, one PDAC line, 10–22 cells, when injected into immunodeficient mice, generates pancreatic intraepithelial neoplasia (PanIN) precursors to PDAC that progress to the invasive stage. The PanIN-like cells secrete or release proteins from many genes that are known to be expressed in human pancreatic cancer progression and that predicted an HNF4a network in intermediate-stage lesions. Recent studies show that the PanIN cells progress to metastases at longer time. The cells are being engineered so that tumor progression, and regression in response to drugs, can be monitored in vivo. Thus, rare events allow iPSC technology to provide a live human cell model of early pancreatic cancer and insights into disease progression.
Citation Format: Jungsun Kim, John P. Hoffman, Maximilian Reichert, Andrew Rhim, Ben Z. Stanger, Andrew Gumbs, Kenneth S. Zaret. Modeling of early to invasive stages of pancreatic cancer progression with an iPSC-like line from human pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B02.
Abstract B09: Aspirin inhibits cyclooxygenase 2-mediated prostaglandin production and tumorigenesisin a preclinical model of tuberous sclerosis complex
Authors: Li Chenggang , Lee Po-Shun , Sun Yang , Gu Xiaoxiao , Zhang Erik , Wu Chin-Lee , Parkhitko Andrey , Aurrichio Neil , Morrison Tasha , Blenis John , Xu Kai-Feng , Henske Elizabeth Petri , Levy Bruce , Kwiatkowski David , Yu Jane 
Published: May 2015

Abstract
Lymphangioleiomyomatosis (LAM) is a female predominant progressive and neoplastic disorder that leads to lung destruction and respiratory failure primarily in women. LAM is typically due to TSC2 mutations resulting in mTORC1 activation in proliferative smooth muscle-like cells in the lung. The female predominance of LAM suggests that estradiol contributes to disease development.
Metabolomic profiling identified estradiol-enhanced prostaglandin biosynthesis signature in Tsc2-deficient cells, both in vitro and in vivo. Estradiol increased the expression of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostaglandin biosynthesis, which was increased at baseline in TSC2-deficient cells, and was not affected by rapamycin treatment, but decreased by Torin 1 treatment and Rictor knockdown, associated with reduction of levels phospho-Akt (S473). Prostaglandin production was also increased in TSC2-deficient cells. In preclinical models, Celecoxib or aspirin treatment suppressed tumor progression. LAM patients had significantly higher serum prostaglandin levels than healthy women. 15-epi-lipoxin-A4 was identified in exhaled breath condensate from LAM subjects and was increased by aspirin treatment, indicative of functional COX-2 expression in the LAM airway. Targeting COX-2 and prostaglandin pathways may have therapeutic value in LAM and TSC-related diseases, and possibly in other conditions associated with mTOR-hyperactivation.
Citation Format: Chenggang Li, Po-Shun Lee, Yang Sun, Xiaoxiao Gu, Erik Zhang, Chin-Lee Wu, Andrey Parkhitko, Neil Aurrichio, Tasha Morrison, John Blenis, Kai-Feng Xu, Elizabeth Petri Henske, Bruce Levy, David Kwiatkowski, Jane Yu. Aspirin inhibits cyclooxygenase 2-mediated prostaglandin production and tumorigenesisin a preclinical model of tuberous sclerosis complex. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B09.
Abstract B27: Characterization of tumor-host interactions that promote liver metastasis of colorectal cancer
Authors: Pena Maria Marjorette O. , Zhang Yu , Davis Celestia 
Published: May 2015

Abstract
The leading cause of death from colorectal cancer is metastasis. The five year survival rate drops from 95% when the disease is at the localized stage to approximately 12% when metastasis has occurred. Because of its asymptomatic progression, metastasis is often detected at the final stage when little can be done, and little is now regarding the mechanisms that direct the early steps when intervention can potentially have an impact on its progression. In order to elucidate the mechanisms, we developed a mouse model of CRC metastasis to the liver, the frequent target organ of metastasis by cecum implantation of CT26 mouse colon adenocarcinoma cells into immunocompetent host Balb/cByJ mice. This model can recapitulate disease progression from the growth of the primary tumor to establishment of metastatic lesions within a defined time frame. Using this model, we isolated isogenic cell lines that gave rise to a high frequency of spontaneous metastasis to the liver. Implantation of the most highly metastatic CT26-FL3 cell line gave rise to liver metastasis in 90% of host mice, ten-fold higher than the parental CT26 cell line, in as early as 10 days. Initial characterization revealed that these cells expressed elevated levels of genes whose products promoted invasion, migration, and mobilization of bone marrow derived cells (BMDCs) to the pre-metastatic liver. We determined the genetic signatures of the CT26 and CT26-FL3 cells and that of the pre-metastatic and metastatic liver environment by microarray analyses to identify genes that might mediate the crosstalk between the primary tumor and target organ to promote progression of liver metastasis. The results identified genes encoding proteins that might act as potent effectors of the immune response that are induced in the early stage of metastasis. We characterize these proteins and assess their potential as viable biomarkers for early diagnosis of metastatic disease or as targets to deter metastatic progression. Our mouse model, therefore, can be an important platform to characterize metastatic cells and to elucidate tumor-host interactions and mechanisms that drive liver metastasis of CRC. In addition, it can be a valuable tool for pre-clinical evaluation of therapies targeted against metastatic CRC.
Citation Format: Maria Marjorette O. Pena, Yu Zhang, Celestia Davis. Characterization of tumor-host interactions that promote liver metastasis of colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B27.
Abstract B32: The Survivin-deltaEx3 isoform drives microvascular proliferation and malignant progression in proneural gliomas
Authors: Rao Ganesh , Doucette Tiffany , Yang Yuhui , Fuller Greg , Rao Arvind 
Published: May 2015

Abstract
Introduction: Survivin expression correlates with poor prognosis in high-grade glioma. The influence of Survivin isoforms on outcome is poorly understood. We analyzed the dominant anti-apoptotic transcript variants of Survivin using expression data and modeled them in vivo.
Methods: TCGA mRNA expression data was used to study Survivin in low- and high-grade gliomas including proneural(PN) and mesenchymal(Mes) subtypes. We expressed the anti-apoptotic isoforms of Survivin (transcript variants 1 and 2) in vivo using the RCAS/Ntv-a system.
Results: In low-grade glioma, increased expression of Survivin occurred in 22/167(13.2%) cases, and was associated with shortened survival (log rank test, p=0.005). In high-grade gliomas, increased expression occurred in 258/547(47%) cases. Variant 1 was expressed in 215/258(83%) cases, and variant 2 was expressed in 26/258(10%) cases. Median survival was 451 days and 382 days for variant 1 and 2 expressors respectively. Survivin was preferentially expressed in PN relative to Mes gliomas(chi squared, p&lt;0.0001). In PN gliomas, Survivin was expressed in 94/141(67%) cases which had shorter progression free survival(log rank test, p=0.04). Median survival in PN gliomas was 447 days for Variant 1 expressors and 394 days for Variant 2 expressors. In mice, ectopic expression of variant 1 yielded tumors in 28/30(93%) of mice and only 7/28(25%) were high-grade. Ectopic expression of Variant 2 yielded tumors in 27/28(96%) of mice and the majority (22/27,(81%)) were high grade(chi squared, p&lt;0.0001). CD31 expression (to quantify angiogenesis) was significantly higher in Variant 2-derived tumors than Variant 1(t test, p&lt;0.0001). Tumor free survival was shorter in mice with variant-2 derived tumors(log rank test, p=0.01)
Conclusions: Survivin expression in low-grade gliomas is associated with poor survival and is more common in PN gliomas. Poorer survival correlates with Survivin Variant 2, relative to the common isoform. In a PN murine glioma model, variant 2 promotes malignant progression, angiogenesis and shortens tumor-free survival.
Note: This abstract was not presented at the conference.
Citation Format: Ganesh Rao, Tiffany Doucette, Yuhui Yang, Greg Fuller, Arvind Rao. The Survivin-deltaEx3 isoform drives microvascular proliferation and malignant progression in proneural gliomas. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B32.
Abstract B34: High-throughput synthetic lethal interaction screening in model organisms as a strategy for the identification of novel therapeutic targets in cancer
Authors: Srivas Rohith , Shen John Paul , Li Jian Feng , Licon Katherine , Wang Ze Zhong , Bojoquez-Gomez Ana , Xu Lucy , Gross Andrew , Bean Gordon , Sobol Robert , Ideker Trey 
Published: May 2015

Abstract
Loss of tumor suppressor activity is a near universal feature of cancer. Synthetic lethality, in which combined perturbation of two genes results in cell death, has been proposed as a strategy to identify drug targets that specifically attack cancers deficient in a tumor suppressor (TS) gene. To develop a catalog of such combinations, we screened for synthetic-lethal interactions among all yeast orthologs of known TS and druggable genes, resulting in quantitative growth rates for 130,000 pairwise genetic mutants. Similar interaction profiles were highly predictive of TS genes in the same pathway, identifying a novel role for NDNL2/NSE3 in the G1/S checkpoint. TS/drug combinations likely to induce cancer cell death were prioritized using multiple criteria, including conservation across divergent species. Among the top hits were putative interactions involving either BRCA1 or XRCC3 with histone deacetylases, as well as Rad17 with CHK1/2. These were confirmed using small molecule inhibitors and short-pin RNA silencing in human cancer cell lines. This work provides a resource of &gt;300 deeply conserved interactions among tumor suppressors and matched drug targets.
Citation Format: Rohith Srivas, John Paul Shen, Jian Feng Li, Katherine Licon, Ze Zhong Wang, Ana Bojoquez-Gomez, Lucy Xu, Andrew Gross, Gordon Bean, Robert Sobol, Trey Ideker. High-throughput synthetic lethal interaction screening in model organisms as a strategy for the identification of novel therapeutic targets in cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B34.
Abstract B46: Adult stem cell quiescence as a tumor suppressor mechanism in squamous tumors
Authors: White Andrew C. , Khuu Joan , Dang Christine , Tran Kathy , Liu Anqi , Lowry Bill 
Published: May 2015

Abstract
Adult stem cells cycle between periods of quiescence and activation with varied periodicities. In many organs, adult stem cells are also uniquely poised to serve as cancer cells of origin. It is unclear, however, whether tumorigenesis is influenced by the activation state of the adult stem cell. Since hair follicle stem cells (HFSCs) act as cancer cells of origin for cutaneous squamous cell carcinoma (SCC) and undergo defined cycles of quiescence and activation, we sought to determine if SCC initiation was dependent on stem cell activity. These data show that HFSCs are unable to initiate tumors during the quiescent phase of the hair cycle, indicating that the mechanisms that keep HFSCs dormant are dominant to gain of oncogenes (Ras) or loss of tumor suppressors (p53). Instead, prolonged oncogenic stimuli only exert their effects when HFSC quiescence mechanisms are removed by normal HFSC activation. Thus, stem cell quiescence is a novel form of tumor suppression in hair follicle stem cells. Furthermore, Pten activity is necessary for quiescence based tumor suppression, since Pten deletion alleviates this stem cell specific ability. The loss of Pten in this context differentially regulates a number of signaling pathways, all of which led to phenotype progression without induction of a typical anagen cycle. This model suggests a mechanism with potentially broad implications, in which adult stem cells that contain mutations sufficient to initiate cancer could lay dormant for long periods of time without presentation of disease.
Citation Format: Andrew C. White, Joan Khuu, Christine Dang, Kathy Tran, Anqi Liu, Bill Lowry. Adult stem cell quiescence as a tumor suppressor mechanism in squamous tumors. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B46.
Abstract IA1: Modeling pancreatic cancer biology and medicine
Authors: Tuveson David A. 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDA) tumors characteristically contain an abundant desmoplastic stroma that impedes drug delivery and promotes drug resistance. We have found through genetic, cellular and pharmacological approaches that a variety of cell intrinsic and extrinsic pathways promote pancreatic cancer progression and drug resistance, and methods to modulate such processes will be discussed here. These observations were made first in genetically engineered mouse models of PDA, and have prompted multiple translational efforts to seek patient benefit. Finally, methods to accelerate the discovery to translation process using primary tissue organoids will be introduced.
Citation Format: David A. Tuveson. Modeling pancreatic cancer biology and medicine. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr IA1.
Abstract IA19: Canine cancer genetics: What dogs can tell us about ourselves
Authors: Ostrander Elaine A. 
Published: May 2015

Abstract
The 165 domestic US dogs breeds display tremendous morphologic variation, making them an appealing model for the identification of genetic regulators of vertebrate shape and development and disease susceptibility. We have genotyped over 1000 dogs representing 85 domestic breeds to generate a reference dataset on over 60,000 informative SNPs per dog. This, combined with morphometric data has allowed us to map and sequence loci that control various features of breed-specific traits related to shape and size. In addition to helping us understand the genetics of morphologic variation, the underlying loci have also helped us understand the genetics of growth regulation. We now have a clearer sense of how variation is created in body size, leg length, head shape and other features that define various breeds of dog because of such studies. The domestic dog is also a robust model for studying the genetics of disease susceptibility as some breeds harbor an elevated risk, particularly for types of cancer, in spite of a relatively simple genetic architecture that is common to all dogs. One example of breed-specific disease propensity is squamous cell carcinoma of the digit (SCCoD), a locally aggressive cancer that frequently causes lytic bone lesions and multiple toe recurrence. SCCoD is uncommon in most dog breeds, but occurs in Schnauzers, Briards, and Standard Poodles, who are at about a 10-fold increased risk. Another cancer of interest to humans and dogs is transitional cell carcinoma of the bladder, which we observe at increased risk in Scottish Terriers (22 fold increased risk), West Highland White Terriers and Shelties. A final example is histiocytic carcinoma, which is common to Flat Coated Retrievers and Bernese Mountain dogs. Advances in genomic technologies, together with valued clinical collaborations, have allowed us to undertake studies aimed at understanding the genetic susceptibility of each. Key to advancing these studies has been the availability of dense SNP chips and the ever-increasing amount of data on a variety of dog breeds. We will report on our progress on each.
Citation Format: Elaine A. Ostrander. Canine cancer genetics: What dogs can tell us about ourselves. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr IA19.
Abstract IA2: Developing therapeutics using the zebrafish
Authors: Zon Leonard I. 
Published: May 2015

Abstract
The zebrafish is a wonderful disease model, and it is now possible to develop new therapies to treat human disease. A screen for blood stem cells in the developing aorta led to the discovery of PGE2 as a regulator of stem cell engraftment. After studies with mouse and human hematopoietic cells, a clinical trial proceeded to test PGE2 in cord blood transplantation. In 12 leukemic patients receiving 2 cord blood units, one treated with dmPGE2, 10 patients engrafted with the treated cord blood. The neutrophils and platelets recovered more quickly than the untreated cord blood. Another chemical, leflunomide, was found in zebrafish to block neural crest development. Leflunomide also suppressed neural crest gene transcription in human melanomas, and reduced the rate of human tumor formation in mouse xenografts. The effect was stronger in combination with a BRAF inhibitor known to block cell proliferation. This has led to a clinical trial in which 43 patients will be treated for metastaic melanoma. To date, three patients have been treated. In another example, a chemical suppressor screen was done on the rps29 mutant that resembles Diamond Blackfan anemia. Calmodulin antagonists rescue the defect in hematopoiesis. These antagonists also rescue the hematopoietic block found in human CD34 cells treated with an shRNA to rps19. This suggests that calmodulin antagonists could be used to treat patient with Diamond Blackfan anemia. The zebrafish offers an excellent opportunity to find new therapeutics.
Citation Format: Leonard I. Zon. Developing therapeutics using the zebrafish. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr IA2.