bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1463: Engraftment of patient derived xenografts on mice with a humanized immune system
Authors: Wulf-Goldenberg Annika , Stecklum Maria , Eckert Klaus , Behrens Diana , Fichtner Iduna , Hoffmann Jens 
Published: August 2015

Abstract
The stimulation of the endogenous antitumor immunity has the potential to achieve clinically significant tumor regression. The recent clinical success with antibodies interfering with immune checkpoints on T-cells (PD1 and CTLA-4) has motivated oncology research world wide to focuses on new immunotherapy approaches. Further immune regulatory molecules are currently in target validation and together with cancer vaccines, therapeutic antibodies, immunoconjugates, and tumor reactive T-cells (CARTs) they all might contribute to an improved cancer therapy in the next years.
The identification and validation of new targets for antitumor immune therapy is still a challenge for the preclinical research as the classical syngeneic tumor models are of limited translational value and the patient-derived human tumor xenograft models (PDX) are growing on immunodeficient animals.
In first studies using human mononuclear cells (MNC) we demonstrated the engraftment of human T cells on immunodeficient mice. The transplanted human mononuclear cells (MNC) differentiated in T cell as measured by CD3, CD4 and CD8 expression. The inoculation and tumor growth of SW480 colon cancer cells on humanized mice was possible concurrent with accumulation of human T cells in the tumor.
Our aim was the further improvement of this test system and the demonstration of a functional reconstitution of a human immune system by engrafting human hematopoietic stem cells in immunodeficient mice.
Humanized mice were transplanted with patient derived melanoma fragments without evidence for rejection correlated with an increase of human T cells in the peripheral blood. Drug sensitivity testing with various immunoconjugates will follow.
Our humanized mouse models will enable a more appropriate preclinical assessment of immune-based therapeutic antitumor strategies especially when combining the humanized mouse with patient-derived tumor xenografts.
Citation Format: Annika Wulf-Goldenberg, Maria Stecklum, Klaus Eckert, Diana Behrens, Iduna Fichtner, Jens Hoffmann. Engraftment of patient derived xenografts on mice with a humanized immune system. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1463. doi:10.1158/1538-7445.AM2015-1463
Abstract 1464: Patient-derived tumor xenograft are susceptible to formation of B-cell lymphoma after initial transplantation of human carcinoma to immunodeficient mice
Authors: Bondarenko Gennadiy , Ugolkov Andrey , Kulesza Piotr , Rohan Stephen M. , Dubrovskyi Oleksii , Gursel Demirkan , Mathews Jeremy V. , O'Halloran Thomas V. , Wei Jian-Jun , Mazar Andrew P. 
Published: August 2015

Abstract
Patient-derived xenograft (PDX) tumor models have emerged as new and effective models for developing novel anticancer therapies and personalized use of chemotherapeutic drugs. The PDX approach is based on the transplantation of primary or metastatic human tumors into highly immunodeficient NOD scid gamma (NSG) mice followed by continuous propagation of the established engrafment in mice. Clinicians can evaluate the effects of cancer drugs on their patients’ personalized tumor grafts enabling them to select the best treatment for the cancer patient. Here, we report that PDX tumors engrafted in NSG mice are susceptible to formation of B-cell lymphomas. We xenografted primary or metastatic human tumor fragments into NSG mice and found that tumors generated from patients’ samples of breast (1 out 3 cases), colon (2 out of 6 cases), pancreatic (1 out of 3 cases), bladder (1 out of 2 cases) and renal (1 out of 2 cases) cancer were histologically similar to lymphoid neoplasm. Moreover, we found that the first passage (F1) of some breast and pancreatic cancer PDX tumors could grow as a lymphoid neoplasm in one mouse and as an adenocarcinoma in another mouse after initial transplantation of the pieces from the same human tumor graft (F0). Whereas subcutaneous PDX tumors resembling primary human carcinoma histology were slow growing and non-metastatic, we found that subcutaneous PDX lymphoid neoplasms were fast growing and formed large metastatic lesions in lymph nodes, liver, lungs and spleen of the mouse. Immunohistochemical staining confirmed that lymphoma cells express human leucocyte common antigen CD45 and B-cell antigen CD19/20. By using Epstein-Barr Virus-encoded RNA (EBER) in situ hybridization, we found that PDX lymphoma cells were EBER-positive. Because B-cells are typically present in any solid malignant tumor, B-cell PDX lymphomas may evolve in a wide range of PDX tumor models. Our results suggest that histolopathological evaluation and lymphoid marker testing should be performed as part of the initial model characterization in order to exclude B-cell lymphomas during the development of PDX tumor model from solid human carcinoma.
Citation Format: Gennadiy Bondarenko, Andrey Ugolkov, Piotr Kulesza, Stephen M. Rohan, Oleksii Dubrovskyi, Demirkan Gursel, Jeremy V. Mathews, Thomas V. O'Halloran, Jian-Jun Wei, Andrew P. Mazar. Patient-derived tumor xenograft are susceptible to formation of B-cell lymphoma after initial transplantation of human carcinoma to immunodeficient mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1464. doi:10.1158/1538-7445.AM2015-1464
Abstract 1475: Therapeutic responses in a novel patient-derived xenograft mouse model for rare acinar cell pancreatic carcinoma
Authors: Marlow Laura A. , Mathias Adam C. , Dawson Louis K. , Durham William F. , Meshaw Kenneth A. , Mullin Robert J. , Synnott Aidan J. , Paz-Fumagalli Ricardo , Krishna Murli , Von Hoff Daniel , Small Daniel L. , Colon-Otero Gerardo , Copland John A. 
Published: August 2015

Abstract
Acinar cell carcinoma of the pancreas (ACC) is an uncommon malignancy, accounting for less than 1% of all pancreatic neoplasms. Because of its rarity, only a few retrospective studies are available to help guide management. We previously reported the case of a patient with metastatic ACC who achieved prolonged survival with doxorubicin as a result of personalized treatment designed in part on the basis of molecular and in-vitro data collected on analysis of the tumor and primary cells in culture developed from the liver metastasis. We now report the characterization of a patient derived xenograft (PDX) mouse model originating from this patient's ACC liver metastasis tissue. Antitumor activity of multiple drugs (5-FU, irinotecan, oxaliplatin, gemcitabine, bevacizumab, erlotinib, doxorubicin and imatinib) used as single agent therapy is demonstrated. Of the targeted and cytotoxic therapies used, oxaliplatin produced a dramatic and prolonged response to therapy even after withdrawal of treatment. Bevacizumab produced a significant response, as well. Serum lipase and tissue amylase levels correlated with the antitumor response to therapy. Thus, we have developed and characterized an ACC PDX model that may be used in drug discovery for the treatment of this rare cancer for which no standard of care exists.
Note: This abstract was not presented at the meeting.
Citation Format: Laura A. Marlow, Adam C. Mathias, Louis K. Dawson, William F. Durham, Kenneth A. Meshaw, Robert J. Mullin, Aidan J. Synnott, Ricardo Paz-Fumagalli, Murli Krishna, Daniel Von Hoff, Daniel L. Small, Gerardo Colon-Otero, John A. Copland. Therapeutic responses in a novel patient-derived xenograft mouse model for rare acinar cell pancreatic carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1475. doi:10.1158/1538-7445.AM2015-1475
Abstract 1476: Effect of target therapies in liver cancer PDX tumor models: Response, resistance and predictive biomarkers
Authors: Yu Tengfei , Yan Ying , Du Wei , Hua Liang , Yang Xuqin , Tan Tingting , Gu Jiali , Jiang Jingjing , Ye Xin K. , Gu Zhenyu 
Published: August 2015

Abstract
Liver cancer is one of the leading causes of cancer mortality worldwide. Hepatocelluar carcinoma (HCC) is the most common form of liver cancer, followed by intrahepatic cholangiocarcinoma (IHCC). HCC has dismal clinical outcome, whereas the prognosis is even worse for IHCC as it is more difficult to diagnose and to treat comparing to HCC. Surgical resection and local ablation remain the top choices of therapy for early liver cancer while chemoembolization-TACE is commonly used to treat intermediate HCC. Sorafenib is the only FDA approved target therapy for advanced HCC and its clinical utility in IHCC is still being examined in clinical trials. On-going clinical trials are also testing therapeutic modalities against oncogenic pathways including RTK signaling pathways, PI3K/Ras pathways and the angiogenesis pathway.
PDX tumor models recapitulate the clinical complexity of the original human cancers. At GenenDesign, we have established over 800 PDX tumor models and conducted extensive drug response tests in a mouse trial format. GenenDesign liver cancer PDX tumor panel comprises of 36 HCC and over 10 IHCC models. Our in-house mouse trials in liver PDX tumor models include treatment with sorafenib as well as XL184, a multi-kinase inhibitor currently being evaluated in clinical trials. In addition, crizotinib (a cMET inhibitor) and AZD4547 (an FGFR inhibitor) as mono-therapies as well as in combination with sorafenib are also tested in search of therapeutic signals. From these studies, we have identified both drug sensitive and de novo drug resistant models. Through long-term treatment, acquired resistance models and reversible resistance models are also established.
Currently, GD liver cancer PDX tumors are being analyzed by genetic and genomic profiling (hot-spot mutational analysis, exome-seq, RNA-seq, SNP array and gene expression array). Bioinformatics analysis is on-going to identify genomic signatures with the potential as predictive biomarkers for sorafenib and other targeted therapies in liver cancer. Together with genomic profiling, signal search in PDX mouse trials promise to be effective in generating preclinical datasets to facilitate clinical trial designs.
Citation Format: Tengfei Yu, Ying Yan, Wei Du, Liang Hua, Xuqin Yang, Tingting Tan, Jiali Gu, Jingjing Jiang, Xin K. Ye, Zhenyu Gu. Effect of target therapies in liver cancer PDX tumor models: Response, resistance and predictive biomarkers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1476. doi:10.1158/1538-7445.AM2015-1476
Abstract 1478: Development of novel Mi-HTX in vivo platform by reconstituting autologous immune components in patient tumor-derived xenografts
Authors: Thiyagarajan Saravanan , Radhakrishnan Padhma , Radhakrishna Vinod D , Pinto Dency D , Majumder Biswanath 
Published: August 2015

Abstract
Developing a clinically relevant in vivo platform for testing novel anti cancer therapeutics is hindered by lack of preservation of several critical components of tumor microenvironments. While syngenic mice model is being used traditionally for understanding action of immunomodulator compounds one major drawback of this model is it does not represent human specific targets therefore exhibit poor translational potential. Patient tumor derived xenograft (PDX) is increasingly appreciated as a surrogate of patient tumors for functional screening of anticancer drugs. However, these models also display limitation of stably maintaining active phenotypes of intra-tumor or tumor infiltrating immune cells in a dynamical setting where mice immune system is also compromised. Recently developed ex vivo CANScript platform (presenting in AACR-2015 Annual meeting) shows promises in realization of a preserved patient immune network in short term culture but have inherent constraints of determining PK/PD correlations. To overcome this limitation and meet the growing need of testing immunomodulator drugs in an immunologically relevant in vivo model here we engineer a novel human tumor xenograft platform called Mi-HTX where patient immune network was reconstituted by implanting suitably primed peripheral blood mononuclear cells from same donor. The data shows the preferential recruitment of several key immune cells (CD8, macrophage and TRegs). The PK/PD/Efficacy correlation of human anti-CTLA-4 in Mi-HTX platform shows the potential application of this model for systematically evaluating immunomodulator drugs.
Citation Format: Saravanan Thiyagarajan, Padhma Radhakrishnan, Vinod D Radhakrishna, Dency D Pinto, Biswanath Majumder. Development of novel Mi-HTX in vivo platform by reconstituting autologous immune components in patient tumor-derived xenografts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1478. doi:10.1158/1538-7445.AM2015-1478
Abstract 1479: Investigation of the permeation and retention of biocompatible low-retention superparamagnetic iron oxide nanoclusters in tumors with magnetic resonance imaging
Authors: Wei Yushuang , Shan Liang , Wang Paul , Zhou Qibing 
Published: August 2015

Abstract
Superparamagnetic iron oxide (SPIO) nanoclusters assembled with poly-L-lysine (PLL) and hydroxyl starch show a unique bioclearance property with low retention in the liver and spleen and effective renal excretion. In the orthotopic liver tumor model, the assembled low retention biocompatible SPIO nanoclusters exhibit a high contrast enhancing capability in T2-weighted magnetic resonance imaging (MRI) at a low dose. For the orthotopic liver tumor, the T2-weighted MRI with SPIO nanoclusters is a negative imaging method to reduce the signal intensity of the normal liver tissue, whereas the potential of the retention and permeability of SPIO nanoclusters in tumors was not fully assessed. The latter becomes critically important for diagnosis and prognosis of pancreatic and prostate tumors in the non-reticuloendothelial system. Two approaches of tumor targeting were investigated and compared in this study including the passive targeting via the EPR effect of nanoparticles and the active targeting by the tumor-specific ligands such as TAT, iRGD and pH sensitive peptides. The accumulation of SPIO nanoclusters in tumors was assessed in the subcutaneous pancreatic and prostate tumor models with MRI over times, iron levels and pathological assessment. Our results showed that the retention and permeation of SPIO nanoclusters varied with multiple factors of tumors. For example, well developed tumors with large necrosis core tended to have a high level of SPIO accumulation. In contrast, the early stage solid tumor had minimal retention of SPIOs. Similar effects have been observed in both passive and active tumor targeting by SPIO nanoclusters. Moreover, the accumulation of SPIOs in tumor was achieved over a longer time period over 24 to 48 h with long retention as compared with those in the normal liver, lung, and spleen tissue (between 30 min to 3 h) with rapid clearance. Our data suggested that with well-designed tumor targeting, the biocompatible low-retention SPIO nanoclusters could be an effective MRI contrast agent for MRI of pancreatic and prostate tumors.
Citation Format: Yushuang Wei, Liang Shan, Paul Wang, Qibing Zhou. Investigation of the permeation and retention of biocompatible low-retention superparamagnetic iron oxide nanoclusters in tumors with magnetic resonance imaging. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1479. doi:10.1158/1538-7445.AM2015-1479
Abstract 149: Overexpression of the long non-coding RNA PVT1 and its role in cervical carcinogenesis
Authors: Iden Marissa , Fye Samantha , Ramchandran Ramani , Rader Janet S. 
Published: August 2015

Abstract
Although it is becoming increasingly clear that long non-coding RNAs (lncRNAs) are intricately involved in numerous cancer types, the mechanisms by which they influence carcinogenesis remain poorly understood. The plasmacytoma variant translocation 1 gene (PVT1) is a lncRNA that has been designated as an oncogene due to its contribution to the phenotype of multiple cancers. Further, our lab has recently demonstrated that human papillomavirus (HPV) integration, a hallmark of invasive cervical cancer (ICC), into the PVT1 locus occurs in multiple cervical tumors. The present study was designed to investigate the role of PVT1 in cervical carcinogenesis. PVT1 expression was measured by quantitative PCR (qPCR) in 41 ICC samples, 20 normal cervix samples, and four cervical cell lines (SiHa, HeLa, DoTc2, and E6/E7-transformed ectocervical epithelial cells). Further, we used siRNA-targeted knockdown in conjunction with functional assays to examine PVT1's effects on cervical cancer cell proliferation, migration and invasion, apoptosis, and cisplatin-resistance. Our results demonstrate that PVT1 expression is significantly increased in ICC tissue versus normal cervix. PVT1 knockdown in cervical cancer cell lines resulted in significantly decreased cell proliferation, migration and invasion. Further, apoptosis and cisplatin cytotoxicity were significantly increased in PVT1 siRNA-transfected cells. Collectively, our data suggest that PVT1 may play a crucial role in cervical carcinogenesis. Future work will focus on determining the mechanism(s) by which this lncRNA exerts its multiple effects on cancer-related processes.
Citation Format: Marissa Iden, Samantha Fye, Ramani Ramchandran, Janet S. Rader. Overexpression of the long non-coding RNA PVT1 and its role in cervical carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 149. doi:10.1158/1538-7445.AM2015-149
Abstract 1500: Syndecan-1 targeted mesoporous silica-coated gold nanorods act as theranostic agents for in vivo detection of orthotopic pancreatic tumors using multispectral optoacoustic tomography
Authors: Khanal Anil , Kimbrough Charles W. , Garbett Nichola C. , Burlison Joseph A. , Grizzle William E. , McNally Lacey R. 
Published: August 2015

Abstract
Detection of pancreatic cancer is especially challenging in comparison to many cancers due to severe limitations of both contrast agent delivery to pancreatic tumors and limitations of traditional imaging techniques such as poor resolution and low depth penetration. Theranostic nanoparticles encompassing both therapeutic and diagnostic capabilities can overcome limitations associated with conventional cancer diagnosis and therapy. In this study, we compared mesoporous silica coated gold nanorods (MS-GNR) and polyacrylic acid coated gold nanorods (PAA-GNR) targeted to tumor cells via Syndecan-1 ligand for detection of orthotopic pancreatic cancer in vivo. Because one of the major difficulties for translation of theranostic nanoparticles to the clinic is an inability track performance of nanoparticles in vivo, especially at depths required of orthotopic tumors, we will overcome this impediment by utilizing multispectral optoacoustic tomography (MSOT). Multispectral optoacoustic tomography provides high optical contrast images at a microscale resolution and reasonable penetration depth by combining the advantages of optical (high sensitivity) and ultrasound (increased depth of penetration). Our results indicate that the Syndecan-1 MS-GNR were superior to Syndecan-1 PAA-GNR, untargeted MS-GNR, or untargeted PAA-GNR as contrast agents to identify pancreatic cancer in vivo via MSOT. The Syndecan-1 MS-GNR particles also resulted in reduced off-target accumulation compared to Syndecan-1 PAA-GNR. This study is among the first to evaluate biodistribution of ligand-targeted nanoparticles in the context of orthotopic pancreatic cancer using multispectral optoacoustic tomography. The MS GNR can be utilized as theranostic platform due to ability of mesoporous silica to encapsulate drug and easy surface modification with cancer recognizing motif peptide.
Citation Format: Anil Khanal, Charles W. Kimbrough, Nichola C. Garbett, Joseph A. Burlison, William E. Grizzle, Lacey R. McNally. Syndecan-1 targeted mesoporous silica-coated gold nanorods act as theranostic agents for in vivo detection of orthotopic pancreatic tumors using multispectral optoacoustic tomography. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1500. doi:10.1158/1538-7445.AM2015-1500
Abstract 1502: DCLK1 labeling a unique pancreatic cellular lineage contributes to intraductal papillary mucinous neoplasm development
Authors: Qiu Wanglong , Su Gloria 
Published: August 2015

Abstract
BACKGROUND & AIMS: Recently DCLK1 has been controversial as a biomarker of progenitor cells in both intestinal tract and pancreas. Pancreatic intraductal papillary mucinous neoplasm (IPMN), in contrast to pancreatic intraepithelial neoplasia (PanIN), has been relatively less investigated. Here, we explored whether DCLK1-expressing cells were involved in the genesis of pancreatic IPMNs using mouse models. METHODS: We compared the incidence of DCLK1-positive cells in pancreatic tissue samples derived from mouse models for IPMNs, PanINs, acinar to ductal metaplasia (ADM), and human IPMN samples by immunohistochemistry. And how the DCLK1+ cells engage ADM and IPMNs and its origin were investigated by in vitro culture and in vivo lineage tracing. RESULTS: The DCLK1+ cells were identified exclusively in the pancreatic tissues with activated oncogene compared to wild-type. Mouse lineage tracing experiments showed that DCLK1+ cells might originate from a cell lineage distinct from pancreatic PDX1 (+) progenitors. The pancreatic DCLK1+ cells shared the features of tuft cells but absence of IPMN tumor biomarkers. DCLK1+ cells presented in the acinar clusters prior to formation of metaplastic ductal cells, and enriched in the “IPMN niches”. Oncogenic signaling pathways such as SHH and DLL4 were activated or upregulated in the tumor cells but not the DCLK1+ cells of IPMNs. DCLK1 was also expressed in a subpopulation of tumor cells in 20% of human IPMN patients. CONCLUSIONS: DCLK1 labels a unique pancreatic cellular lineage in mouse. The clustering of DCLK1+ cells is an early event in oncogene-induced tumorigenesis. Pancreatic DCLK1+ cells may contribute to the initiation of ADM and its progression to IPMNs.
Key words: Pancreatic IPMN; ADM; DCLK1; SOX9.
Citation Format: Wanglong Qiu, Gloria Su. DCLK1 labeling a unique pancreatic cellular lineage contributes to intraductal papillary mucinous neoplasm development. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1502. doi:10.1158/1538-7445.AM2015-1502