bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B06: Studying cytarabine resistance through PDX models in acute myeloid leukemia
Authors: Farge Thomas 
Published: March 2017

Abstract
The major therapeutic barrier in acute myeloid leukemia (AML) is chemotherapy resistance. AML cells resistant to conventional chemotherapy targeting DNA synthesis are thought to be enriched in quiescent leukemic stem cells (LSCs). In order to better understand chemotherapy resistance in AML, we analyzed the response to cytarabine (AraC) through patient-derived xenograft (PDX) models with 20 primary AML patient specimens from two clinical sites and in the context of a French “Innovative models initiative” (IMODI) program. After confirming AML engraftment, highly immunodeficient NOD/LtSz-scid IL2Rγc null (NSG) mice were treated with AraC administered IP for 5 days as a single agent at 60 mg/kg daily, which correlates with human dosing. In all mice treated with this regimen, there was a significant but variable cytoreductive effect (4- to 46-fold reduction of tumor cell burden; 2- to 13-fold induction of apoptosis) at 3 days post-treatment. This in vivo AraC response in PDX models has been compared to clinicobiological data of their matched patients (including overall survival, FAB classification, and age at diagnosis). Furthermore, residual leukemic cells (RLCs), surviving after in vivo AraC treatment, have been characterized for their cell surface phenotype, stem cell frequency, cell cycle and metabolic status. Gene expression of RLCs from three different PDX models showed an enrichment of genes involved in inflammatory, immune and stress/ROS responses. When tested in three independent cohorts of AML patients (Verhaak et al. 2009; TGCA. 2011; Metzeler et al. 2011), the down-regulated gene signature is associated with an unfavorable prognosis in patients treated with intensive chemotherapy. Altogether, these results suggest a novel model of AraC chemotherapy resistance uncovering the control of the oxidative and mitochondrial energy metabolism in vivo and the relevance of PDX models for clinical investigations and new preclinical drug assessment. Further studies of the role of immune and stromal microenvironment will be assessed in this model to extend our findings in a more relevant setting.
Citation Format: Thomas Farge{Authors}. Studying cytarabine resistance through PDX models in acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B06.
Abstract B22: Establishment of Patient-Derived Xenograft (PDX) Models of Ovarian Cancer
Authors: Liang Li , Mercado-Uribe Imelda , Niu Na , Jiang Yi , Cheng Wenjun , Broaddus Russell , Bast Robert , Mills Gordon , Sood Anil K. , Liu Jinsong 
Published: March 2017

Abstract
Ovarian cancer is the most lethal gynecological malignancy. The majority of ovarian cancer patients are diagnosed at an advanced stage of disease, and the lack of good early screening and diagnostic tests is one of the reasons for the low overall survival rate. Moreover, there is no good marker to predict patients' response to chemotherapy. Patient-derived xenografts (PDXs) have become the most promising preclinical model for gynecologic malignances. We have successfully established 22 PDX models derived from ovarian cancer patients' surgical specimens implanted into severe combined immunodeficient (SCID) mice, non-obese diabetic (NOD)-SCID or Nude mice. The majority of the PDX models were generated from patients' samples diagnosed with high-grade serous carcinoma including 3 with BRCA1/2 mutations, as well as less common types of ovarian cancers such as low-grade serous, endometrioid, mucinous carcinomas, and carcinosarcoma. PDXs have been established from solid masses as well as from ascites. We have optimized protocol for establishing ovarian PDXs including implantation and collection methods, tumor type (solid versus ascites), and type of mouse strains used. Using SCID mice, our success rate exceeded 80% and recent data indicated that the success rate in NOD/SCID mice was higher. The link between the pathology and PDX core, the “triage protocol” and ongoing PARP inhibitor trials will provide an important array of PDXs including pre- and post-treatment PDXs for exploration for biomarkers as well as for co-clinical trials to validate the utility of rational drug combinations. All models were validated using short tandem repeats (STR) and compared to the H&E and immunohistochemistry stains from the matching patient's tissue. We also examined the expression of B7-H4, a novel member of the B7 family immune checkpoint regulators, in 9 patient-derived xenografts (PDXs) of high-grade ovarian serous carcinoma. Our data showed that B7-H4 proteins were expressed in 8 of 9 PDX models of high-grade serous carcinoma, suggesting that PDXs may be useful for studying immunotherapy.
Citation Format: Li Liang, Imelda Mercado-Uribe, Na Niu, Yi Jiang, Wenjun Cheng, Russell Broaddus, Robert Bast, Gordon Mills, Anil K. Sood, Jinsong Liu. Establishment of Patient-Derived Xenograft (PDX) Models of Ovarian Cancer. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B22.
Abstract B23: Neuroblastoma patient-derived orthotopic xenografts: Clinically relevant models for drug testing
Authors: Bexell Daniel , Braekeveldt Noémie , Mohlin Sofie , Wigerup Caroline , Gisselsson David , Tadeo Irene , Berbegall Ana P. , Navarro Sam , Noguera Rosa , Påhlman Sven 
Published: March 2017

Abstract
Background: We previously established neuroblastoma patient-derived orthotopic xenografts (PDXs) by implanting patient neuroblastoma fragments into immunodeficient NSG mice. SNP array analysis confirmed that PDXs maintain patient-specific chromosomal aberrations 1p del, MYCN amp and 17q gain. Immunohistochemistry showed that PDXs retain neuroblastoma markers and a highly infiltrative growth pattern. Importantly, we found spontaneous distant metastasis to lungs, liver and bone marrow. In vitro cultures established from the PDXs express neuroblastoma markers and retain their tumorigenic and metastatic ability in vivo after orthotopic injection.
Methods and Results: Given the important role of the tumor stroma for tumor progression and treatment response, we examined PDX stroma by immunohistochemistry. PDXs were highly vascularized with mouse endothelial cells and two PDX models also formed tumor vasculature by co-engrafted human tumor endothelial cells. Tumors contained pericytes, cancer-associated fibroblasts, macrophages and extracellular components resembling the patient disease. PDXs established in athymic nude mice additionally developed intratumoral lymphatic vessels and contained mouse-derived CD45+ lymphoid cells. Thus, PDXs reflect important tumor microenvironment hallmarks for high-stage neuroblastoma. Furthermore, we demonstrate the feasibility of using short-term in vitro cultured PDX-derived cells as a drug-testing model, and show that the HIF2A oncogene is transcriptionally regulated at hypoxia via the PI3K/mTORC2 pathway in these cells. The results establish the PI3K and mTORC2 pathways as potential therapeutic targets of aggressive neuroblastoma.
Conclusion: Neuroblastoma orthotopic PDXs reflect clinical aspects of high-risk disease including spontaneous metastasis, copy number changes and microenvironmental hallmarks. Neuroblastoma PDXs are relevant models for in vitro and in vivo preclinical drug testing.
Citation Format: Daniel Bexell, Noémie Braekeveldt, Sofie Mohlin, Caroline Wigerup, David Gisselsson, Irene Tadeo, Ana P. Berbegall, Sam Navarro, Rosa Noguera, Sven Påhlman. Neuroblastoma patient-derived orthotopic xenografts: Clinically relevant models for drug testing. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B23.
Abstract B29: Effects of prenatal exposure to cancer treatment: The development of a placental murine xenograft model
Authors: Verheecke Magali , Devlies Wout , Hermans Els , Amant Frédéric 
Published: March 2017

Abstract
The aim of this study was to develop a suitable murine xenograft model to examine the possible effect of drugs or chemotherapeutic agents on the placental tissue.
Methods: The test population consisted of 4 examination groups of six immunodefficient nude mice. After the mice were ovariectomised and hormonal stimulated (17b estradiol and progesterone pellets), placental tissue derived from first and third trimester pregnancies was engrafted subcutaneously bilateral in the interscapular fat pad. hCG (human chorionic gonadotrophin) secretion was measured in serum and urine by an enzyme-linked immunosorbent assay (ELISA). To examine the viability and preservation of the placental tissue, factors for proliferation (hCG, Ki67), apoptosis (cleaved caspase-3) and murine angiogenesis (CD31) were evaluated by immunohistochemistry (IHC). The expression level of genes relevant for the angiogenesis (IGF-1, PGF, IGF-2), inflammation (eNOS) and proliferation (Flk-1, Flt-1) was compared by using reverse transcription- quantitative real-time polymerase chain reaction (RT-qPCR).
Results: Comparing the placental tissue before and after engraftment, we found preserved structure and histological features. Also, the PCR analysis showed preserved genetic characteristics of the primary engrafted placental tissue. hCG secretion, evaluated by ELISA in the urine and blood, was present for 3 weeks.
Conclusion: We created a murine xenograft model with proven stability and preserved structure of the engrafted placental tissue for 3 weeks. This established murine xenograft model will be useful to examine the effect of cancer treatment; moreover, it could serve as a model for other fetal toxicity studies.
Citation Format: Magali Verheecke, Wout Devlies, Els Hermans, Frédéric Amant. Effects of prenatal exposure to cancer treatment: The development of a placental murine xenograft model. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B29.
Abstract B44: When murine tumors are thought to be human: A drawback of patient derived xenografts.
Authors: Menéndez Camino , Salvador Beatriz , Muñoz Manuel , Baños Natalia , Sarno Francesca , López-Casas Pedro P , Hidalgo Manuel 
Published: March 2017

Abstract
The use of preclinical models is essential in every aspect of translational cancer research, from the biologic understanding of the disease to the development of new treatments. Patient Derived Xenograft (PDX) models are increasingly used in translational cancer research due to their advantages over other preclinical models. However, although it has been widely demonstrate that these kind of models are predictive of clinical outcome, there are also some drawbacks when working with them.
Analyzing our PDX model collection, we have observed that there is a small percentage of cases in which a murine tumor is developed instead of the original human one by a process that has been called horizontal oncogenesis. This process was already observed and described in the early 80´s, however, it is still not well understood and the molecular mechanisms by which it happens remain unknown.
In order to determine the origin of the different murine tumors observed in our mice, we performed immunohistochemistry characterization of our altered models and found two different types of murine tumors: murine fibrosarcomas, which were observed in Colorectal and Pancreatic Ductal Adenocarcinoma PDX models; and murine lymphomas, that were observed mainly in Lung PDX models when they were implanted in Nod-scid mice. We also found a case in which a human lymphoproliferation grew in the animals instead of the sample from the small cell lung cancer obtained from the patient.
As these murine tumors grow in the same place where the human donor tumor was implanted, it is important to have a quick and effective method to identify them before performing any study with these altered models. In this regard, we have implemented a simple technique based on PCR analysis with primers that recognize K-Ras. We have designed an estrategy in which we can obtain amplicons of different sizes depending on their human or murine origin.
Although we still have to analize some of our PDX models, using this methodology we have confirmed that murine tumors appear in a very low percentage of cases (less than 5% to date). However, even with this low incidence we consider that is essential to identify those murine tumors as soon as possible in order to avoid wasting time, money and resources.
Citation Format: Camino Menéndez, Beatriz Salvador, Manuel Muñoz, Natalia Baños, Francesca Sarno, Pedro P López-Casas, Manuel Hidalgo. When murine tumors are thought to be human: A drawback of patient derived xenografts.. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B44.
Abstract IA02: Introduction to the EuroPDX Consortium
Authors: Roman-Roman Sergio 
Published: March 2017

Abstract
Started in early 2013, EurOPDX gathers 16 academic institutions throughout Europe including 6 Comprehensive Cancer Centres. Each institution is part of a hospital or is collaborating with a neighboring one. EurOPDX includes world-renowned experts at the forefront of research in basic, preclinical, translational and clinical oncology across multiple pathologies, and displays a wide range of expertise in technological platforms. The virtual PDX collection of the consortium consists of more than 1,500 subcutaneous and orthotopic models for more of 30 different pathologies. Our objective is to improve the predictability of preclinical data by (i) improving characterization of the models, (ii) implementing new PDX models to strengthen the representativeness of the collection, and humanized PDX models, (iii) harmonizing working practice, (iv) Integrating complementary models (e.g. ex vivo 2D and 3D assays) in innovative drug development pipelines, and (v) leveraging deep molecular and pharmacogenomic profiling data of the collection of models to discover predictive biomarkers, new targets, and new strategies to overcome drug resistance. In this lecture I will illustrate the value of the consortium with a few examples of collaborative projects involving academic labs but also industrial partners. In particular, I will discuss the current strategies to setting-up the logistics for the performance of multicenter (and sometimes multipathologies) preclinical and co-clinical trials in a collection of fully characterized PDX models.
Citation Format: Sergio Roman-Roman. Introduction to the EuroPDX Consortium. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA02.
Abstract IA04: Lgr5 stem cell-based organoids in human disease
Authors: Clevers Hans 
Published: March 2017

Abstract
The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We originally defined Lgr5 as a Wnt target gene, transcribed in colon cancer cells. Two knock-in alleles revealed exclusive expression of Lgr5 in cycling, columnar cells at the crypt base. Using lineage tracing experiments in adult mice, we found that these Lgr5+ve crypt base columnar cells (CBC) generated all epithelial lineages throughout life, implying that they represent the stem cell of the small intestine and colon. Lgr5 was subsequently found to represent an exquisitely specific and almost ‘generic’ marker for stem cells, including in hair follicles, kidney, liver, mammary gland, inner ear tongue and stomach epithelium.
Single sorted Lgr5+ve stem cells can initiate ever-expanding crypt-villus organoids, or so called ‘mini-guts’ in 3D culture. The technology is based on the observation that Lgr5 is the receptor for a potent stem cell growth factor, R-spondin. Similar 3D cultures systems have been developed for the Lgr5+ve stem cells of human stomach, liver, pancreas, prostate and kidney. Using CRISPR/Cas9 technology, genes can be efficiently modified in organoids of various origins.
Citation Format: Hans Clevers. Lgr5 stem cell-based organoids in human disease. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA04.
Abstract IA05: PDX in colorectal cancer and carcinoma of the anal canal
Authors: Dangles-Marie Virginie 
Published: March 2017

Abstract
Through 2 examples of digestive tumors, (colorectal cancer, “CRC”, and anal squamous cell carcinoma, “ASCC”), we will present the development and use of patient-derived tumor xenografts.
Colorectal cancer remains a major cause of mortality worldwide and CRC patient death is generally attributable to metastasis development. By contrast, ASCC is a rare tumor (&lt; 5% of all lower gastrointestinal tract malignancies in Europe) but with increasing incidence and mutilating surgery for patients with chemoradiotherapy-resistant tumors. Consequently, these both digestive tumors require new therapeutic approaches and relevant preclinical models to identify and test new drugs/combinations. In this context, we develop and characterize patient-derived CRC and ASCC xenografts.
We will illustrate the capacity of these PDXs to recapitulate the intratumoral clonal heterogeneity, gene expression profile, key molecular alterations, histology and drug response of the patient tumors through passages in mice. In addition to these now well-known features depicted in a large number of tumor types, we will discuss about practical situations (orthotopic engraftment, impact of mouse host, criteria for measuring drug efficacy). Finally, we will report alternative methods as ex vivo tumor spheres we have developed.
Citation Format: Virginie Dangles-Marie. PDX in colorectal cancer and carcinoma of the anal canal. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA05.
Abstract IA09: Expression profiling of colorectal cancer PDX models for disease stratification and tumor-stroma interaction analysis
Authors: Medico Enzo 
Published: March 2017

Abstract
Tumor-stroma interactions have long been implicated in neoplastic aggressiveness and resistance to treatment. In PDX models, after engraftment, the stromal components are contributed by the mouse host. As a consequence, transcripts expressed by cancer cells can be distinguished from stromal transcripts by their species of origin. We therefore exploited species-specific expression profiling of colorectal cancer (CRC) PDXs to evaluate the involvement of stromal components in recently defined CRC transcriptional subtypes. We found that stroma-derived transcripts profoundly affect the overall tumor transcriptome, and that a previously defined poor prognosis subtype is actually endowed with abundant stroma. To stratify CRC based on cancer cell-intrinsic transcriptional features, we performed class discovery on a human-specific gene expression dataset of 515 CRC PDXs, and identified five CRC intrinsic subtypes (CRIS). CRIS classification successfully categorized independent sets of primary and metastatic CRC tumors, with limited overlap on existing transcriptional classes and unprecedented predictive and prognostic performances. In a complementary approach, we focused on stroma-specific transcripts to define expression signatures reflecting the abundance in human CRC samples of fibroblasts, leukocytes and endothelial cells. Stromal scores were found to correlate with poor CRC prognosis and resistance of rectal cancer to preoperative radiotherapy, highlighting the microenvironment as a variable and dynamic component of CRC, with diagnostic and therapeutic potential.
Citation Format: Enzo Medico. Expression profiling of colorectal cancer PDX models for disease stratification and tumor-stroma interaction analysis. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA09.
Abstract A10: A distinct gene module for T cell dysfunction uncoupled from T cell activation and controlled by metallothioneins
Authors: Singer Meromit , Wang Chao , Cong Le , Marjanovic Nemanja D. , Kowalczyk Monika S. , Zhang Huiyuan , Nyman Jackson , Sakuishi Kaori , Kurtulus Sema , Gennert David , Xia Junrong , Kwon John YH , Nevin James , Herbst Rebecca H. , Yanai Itai , Rozenblatt-Rosen Orit , Kuchroo Vijay K. , Regev Aviv , Anderson Ana C. 
Published: March 2017

Abstract
Reversing the dysfunctional (also known as “exhausted”) T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and for only some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we leveraged mouse models to analyze RNA profiles of CD8+ tumor-infiltrating lymphocytes (TILs) at various functional states. In a comparative study we identified metallothioneins, regulators of zinc metabolism, as drivers of T cell dysfunction and used genetic perturbation to identify, for the first time, a distinct gene module for T cell dysfunction that is uncoupled from T cell activation and associated with a CD8+ Treg signature. An analysis of TILs at single-cell resolution revealed that our dysfunction module negatively correlates with activation signatures also at the single-cell level, indicating that our uncoupled signatures for T cell dysfunction and activation can represent cell-intrinsic states. Clustering of the single-cells revealed a previously uncharacterized subpopulation of CD8+ TILs that was strongly enriched for our novel dysfunction signature, but not for activation signatures. This subpopulation was depleted of cells from a metallothionein KO mouse model in which T cell dysfunction was not observed, implying that we have indeed identified a phenotypically dysfunctional subpopulation. Using CRISPR/Cas9 genome editing we validate that Gata-3, a transcription factor expressed specifically in our identified subpopulation, is a driver of the dysfunctional phenotype in CD8+ TILs. Our results open novel avenues for specifically targeting the dysfunctional T cell state while leaving T cell activation programs intact.
Citation Format: Meromit Singer, Chao Wang, Le Cong, Nemanja D. Marjanovic, Monika S. Kowalczyk, Huiyuan Zhang, Jackson Nyman, Kaori Sakuishi, Sema Kurtulus, David Gennert, Junrong Xia, John YH Kwon, James Nevin, Rebecca H. Herbst, Itai Yanai, Orit Rozenblatt-Rosen, Vijay K. Kuchroo, Aviv Regev, Ana C. Anderson. A distinct gene module for T cell dysfunction uncoupled from T cell activation and controlled by metallothioneins. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A10.