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https://www.readbyqxmd.com/read/29458007/a-genomically-characterized-collection-of-high-grade-serous-ovarian-cancer-xenografts-for-preclinical-testing
#1
Paulina Cybulska, Jocelyn M Stewart, Azin Sayad, Carl Virtanen, Patricia A Shaw, Blaise Clarke, Natalie Stickle, Marcus Q Bernardini, Benjamin G Neel
High-grade serous ovarian cancer (HGSC) is the leading cause of morbidity and mortality from gynecologic malignancy. Overall survival remains low, due to the nearly ubiquitous emergence of platinum-resistance and the paucity of effective next-line treatments. Current cell culture-based models show limited similarity to HGSC and are therefore unreliable predictive models for pre-clinical evaluation of investigational drugs. This deficiency could help explain the low overall rate of successful drug development and the decades of largely unchanged approaches to HGSC treatment...
February 16, 2018: American Journal of Pathology
https://www.readbyqxmd.com/read/29453361/heterogeneity-and-mutation-in-kras-and-associated-oncogenes-evaluating-the-potential-for-the-evolution-of-resistance-to-targeting-of-kras-g12c
#2
Vincent L Cannataro, Stephen G Gaffney, Carly Stender, Zi-Ming Zhao, Mark Philips, Andrew E Greenstein, Jeffrey P Townsend
Activating mutations in RAS genes are associated with approximately 20% of all human cancers. New targeted therapies show preclinical promise in inhibiting the KRAS G12C variant. However, concerns exist regarding the effectiveness of such therapies in vivo given the possibilities of existing intratumor heterogeneity or de novo mutation leading to treatment resistance. We performed deep sequencing of 27 KRAS G12-positive lung tumors to determine the prevalence of other oncogenic mutations within KRAS or within commonly mutated downstream genes that could confer resistance at the time of treatment...
February 16, 2018: Oncogene
https://www.readbyqxmd.com/read/29453314/ar-expression-in-breast-cancer-ctcs-associates-with-bone-metastases
#3
Nicola Aceto, Aditya Bardia, Ben S Wittner, Maria C Donaldson, Ryan O'Keefe, Amanda Engstrom, Francesca Bersani, Yu Zheng, Valentine Comaills, Kira Niederhoffer, Huili Zhu, Olivia MacKenzie, Toshi Shioda, Dennis Sgroi, Ravi Kapur, David T Ting, Beverly Moy, Sridhar Ramaswamy, Mehmet Toner, Daniel A Haber, Shyamala Maheswaran
Molecular drivers underlying bone metastases in human cancer are not well understood, in part due to constraints in bone tissue sampling. Here, RNA sequencing (RNA-seq) was performed of circulating tumor cells (CTCs) isolated from blood samples of women with metastatic estrogen receptor (ER)+ breast cancer, comparing cases with progression in bone versus visceral organs. Among the activated cellular pathways in CTCs from bone-predominant breast cancer is androgen receptor (AR) signaling. AR gene expression is evident, as is its constitutively active splice variant AR-v7...
February 16, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29453291/lsd1-inhibition-exerts-its-anti-leukemic-effect-by-recommissioning-pu-1-and-c-ebp%C3%AE-dependent-enhancers-in-aml
#4
Monica Cusan, Sheng F Cai, Helai P Mohammad, Andrei Krivtsov, Alan Chramiec, Evangelia Loizou, Matthew D Witkin, Kimberly N Smitheman, Daniel G Tenen, Min Ye, Britta Will, Ulrich Steidl, Ryan G Kruger, Ross L Levine, Hugh Y Rienhoff, Richard P Koche, Scott A Armstrong
Epigenetic regulators are recurrently mutated and aberrantly expressed in acute myeloid leukemia (AML). Targeted therapies designed to inhibit these chromatin-modifying enzymes, such as the histone demethylase lysine specific demethylase 1 (LSD1) and the histone methyltransferase DOT1L, have been developed as novel treatment modalities for these often refractory diseases. A common feature of many of these targeted agents is their ability to induce myeloid differentiation, suggesting that multiple paths toward a myeloid gene expression program can be engaged to relieve the differentiation blockade that is uniformly seen in AML...
February 16, 2018: Blood
https://www.readbyqxmd.com/read/29453226/modeling-the-human-bone-marrow-niche-in-mice-from-host-bone-marrow-engraftment-to-bioengineering-approaches
#5
REVIEW
Ander Abarrategi, Syed A Mian, Diana Passaro, Kevin Rouault-Pierre, William Grey, Dominique Bonnet
Xenotransplantation of patient-derived samples in mouse models has been instrumental in depicting the role of hematopoietic stem and progenitor cells in the establishment as well as progression of hematological malignancies. The foundations for this field of research have been based on the development of immunodeficient mouse models, which provide normal and malignant human hematopoietic cells with a supportive microenvironment. Immunosuppressed and genetically modified mice expressing human growth factors were key milestones in patient-derived xenograft (PDX) models, highlighting the importance of developing humanized microenvironments...
February 16, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29452092/microrna-630-inhibitor-sensitizes-chemoresistant-ovarian-cancer-to-chemotherapy-by-enhancing-apoptosis
#6
Kyung Jin Eoh, So Hyun Lee, Hee Jung Kim, Jung-Yun Lee, Sunghoon Kim, Sang Wun Kim, Young Tae Kim, Eun Ji Nam
MicroRNA-630 (miR-630) has been implicated in the development and progression of multiple cancers. The current study aimed to investigate the role of miR-630 in chemoresistant epithelial ovarian cancer. MiR-630 expression levels were detected in ovarian cancer cell line SKOV3 and paclitaxel-resistant SKOV3 (SKOV3-TR) via microarray and qRT-PCR. MiR-630 inhibitors and negative controls were transfected into SKOV3 and SKOV3-TR cells. Wound healing, invasion, chemosensitivity, and cell apoptosis assays were performed to determine proliferation and migration rates...
February 13, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29449529/gambogenic-acid-inhibits-fibroblast-growth-factor-receptor-signaling-pathway-in-erlotinib-resistant-non-small-cell-lung-cancer-and-suppresses-patient-derived-xenograft-growth
#7
Linfeng Xu, Xiaoxiao Meng, Naihan Xu, Wenwei Fu, Hongsheng Tan, Li Zhang, Qianjun Zhou, Jianan Qian, Shiwei Tu, Xueting Li, Yuanzhi Lao, Hongxi Xu
Erlotinib resistance causes a high degree of lethality in non-small-cell lung cancer (NSCLC) patients. The high expression and activation of several receptor tyrosine kinases, such as JAK/STAT3, c-Met, and EGFR, play important roles in drug resistance. The development of tyrosine kinase inhibitors is urgently required in the clinic. Our previous study found that Gambogenic acid (GNA), a small molecule derived from the traditional Chinese medicine herb gamboge, induced cell death in several NSCLC cell lines through JAK/STAT3 inhibition...
February 15, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29449437/dynamic-clonal-progression-in-xenografts-of-acute-lymphoblastic-leukemia-with-intrachromosomal-amplification-of-chromosome-21
#8
Paul B Sinclair, Helen H Blair, Sarra L Ryan, Lars Buechler, Joanna Cheng, Jake Clayton, Rebecca Hanna, Shaun Hollern, Zoe Hawking, Matthew Bashton, Claire J Schwab, Lisa Jones, Lisa J Russell, Helen Marr, Peter Carey, Christina Halsey, Olaf Heidenreich, Anthony V Moorman, Christine J Harrison
Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of childhood precursor B-cell acute lymphoblastic leukemia. There are no cell lines with iAMP21 and these abnormalities are too complex to faithfully engineer in animal models. As a resource for future functional and pre-clinical studies, we have created xenografts from intrachromosomal amplification of chromosome 21 leukemia patient blasts and characterised them by in-vivo and ex-vivo luminescent imaging, FLOW immunophenotyping, and histological and ultrastructural analysis of bone marrow and the central nervous system...
February 15, 2018: Haematologica
https://www.readbyqxmd.com/read/29445127/cripto-1-contributes-to-stemness-in-hepatocellular-carcinoma-by-stabilizing-dishevelled-3-and-activating-wnt-%C3%AE-catenin-pathway
#9
Regina Cheuk-Lam Lo, Carmen Oi-Ning Leung, Kristy Kwan-Shuen Chan, Daniel Wai-Hung Ho, Chun-Ming Wong, Terence Kin-Wah Lee, Irene Oi-Lin Ng
Identification and characterization of functional molecular targets conferring stemness properties in hepatocellular carcinoma (HCC) offers crucial insights to overcome the major hurdles of tumor recurrence, metastasis and chemoresistance in clinical management. In the current study, we investigated the significance of Cripto-1 in contributing to HCC stemness. Cripto-1 was upregulated in the sorafenib-resistant clones derived from HCC cell lines and patient-derived xenograft that we previously developed, suggesting an association between Cripto-1 and stemness...
February 14, 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29440294/in-vitro-and-in-vivo-activity-of-imgn853-an-antibody-drug-conjugate-targeting-folate-receptor-alpha-linked-to-dm4-in-biologically-aggressive-endometrial-cancers
#10
Gary Altwerger, Elena Bonazzoli, Stefania Bellone, Tomomi Egawa-Takata, Gulden Menderes, Francesca Pettinella, Anna Bianchi, Francesco Riccio, Jacqueline Feinberg, Luca Zammataro, Chanhee Han, Ghanshyam Yadav, Katherine Dugan, Ashley Morneault, Jose F Ponte, Natalia Buza, Pei Hui, Serena Wong, Babak Litkouhi, Elena Ratner, Dan-Arin Silasi, Gloria S Huang, Masoud Azodi, Peter E Schwartz, Alessandro D Santin
Grade 3 endometrioid and uterine serous carcinomas (USC) account for the vast majority of endometrial cancer deaths. The purpose of this study was to determine folic acid receptor alpha (FR⍺) expression in these biologically aggressive (Type II) endometrial cancers,and evaluate FR⍺ as a targetable receptor for IMGN853 (Mirvetuximab soravtansine). The expression of FR⍺ was evaluated by immunohistochemistry (IHC) and flow cytometry in 90 endometrioid and USC samples. The in vitro cytotoxic activity and bystander effect were studied in primary uterine cancer cell lines expressing differential levels of FR⍺...
February 13, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29440177/ponatinib-shows-potent-antitumor-activity-in-small-cell-carcinoma-of-the-ovary-hypercalcemic-type-sccoht-through-multi-kinase-inhibition
#11
Jessica D Lang, William P D Hendricks, Krystal A Orlando, Hongwei Yin, Jeffrey Kiefer, Pilar Ramos, Ritin Sharma, Patrick Pirrotte, Elizabeth A Raupach, Chris Sereduk, Nanyun Tang, Winnie S Liang, Megan Washington, Salvatore J Facista, Victoria L Zismann, Emily M Cousins, Michael B Major, Yemin Wang, Anthony N Karnezis, Aleksandar Sekulic, Ralf Hass, Barbara C Vanderhyden, Praveen Nair, Bernard E Weissman, David G Huntsman, Jeffrey M Trent
PURPOSE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT. EXPERIMENTAL DESIGN: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib...
February 9, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29440173/canine-research-to-benefit-humans-and-dogs-alike
#12
(no author information available yet)
The Jackson Laboratory recently launched the Tallwood Canine Cancer Research Initiative, in which tumor samples from dogs will be collected to create patient-derived xenografts in mice. These models, and their accompanying genome sequences, can then be shared with researchers around the world. The initiative's goal is to learn more about the biology of human cancers through comparative genomic analyses.
February 13, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29440171/crosstalk-signaling-between-her3-and-hpv16-e6-and-e7-mediates-resistance-to-pi3k-inhibitors-in-head-and-neck-cancer
#13
Toni M Brand, Stefan Hartmann, Neil E Bhola, Hua Li, Yan Zang, Rachel A O'Keefe, Max V Ranall, Sourav Bandyopadhyay, Margaret Soucheray, Nevan J Krogan, Carolyn Kemp, Umamaheswar Duvvuri, Theresa LaVallee, Daniel E Johnson, Michelle A Ozbun, Julie E Bauman, Jennifer R Grandis
Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the phosphatidylinositol 3-kinase (PI3K) pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC...
February 12, 2018: Cancer Research
https://www.readbyqxmd.com/read/29440145/the-fact-inhibitor-cbl0137-synergizes-with-cisplatin-in-small-cell-lung-cancer-by-increasing-notch1-expression-and-targeting-tumor-initiating-cells
#14
Sarmishtha De, Daniel J Lindner, Claire Coleman, Gary Wildey, Afshin Dowlati, George R Stark
Traditional treatments of small cell lung cancer (SCLC) with cisplatin, a standard of care therapy, spare the tumor-initiating cells (TIC) that mediate drug resistance. Here we report a novel therapeutic strategy that preferentially targets TIC in SCLC in which cisplatin is combined with CBL0137, an inhibitor of the histone chaperone facilitates chromatin transcription (FACT), which is highly expressed in TIC. Combination of cisplatin and CBL0137 killed patient-derived and murine SCLC cell lines synergistically...
February 13, 2018: Cancer Research
https://www.readbyqxmd.com/read/29437792/mechanistic-exploration-of-cancer-stem-cell-marker-voltage-dependent-calcium-channel-%C3%AE-2%C3%AE-1-subunit-mediated-chemotherapy-resistance-in-small-cell-lung-cancer
#15
Jiangyong Yu, Shuhang Wang, Wei Zhao, Jianchun Duan, Zhijie Wang, Hanxiao Chen, Yanhua Tian, Di Wang, Jun Zhao, Tongtong An, Hua Bai, Meina Wu, Jie Wang
PURPOSE: Chemo-resistance in small cell lung cancer (SCLC) is reportedly attributed to the existence of resistant cancer stem cells (CSCs). Studies involving CSC-specific markers and related mechanisms in SCLC remain limited. The current study explored the role of the voltage-dependent calcium channel α2δ1 subunit as a CSC marker in chemo-resistant SCLC, and explored the potential mechanisms of α2δ1-mediated chemo-resistance and strategies of overcoming the resistance. EXPERIMENTAL DESIGN: α2δ1 positive cells were identified and isolated from SCLC cell lines and patient derived xenografts (PDXs) models, and CSC-like properties were subsequently verified...
February 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29437789/targeted-bite-expression-by-an-oncolytic-vector-augments-therapeutic-efficacy-against-solid-tumors
#16
Tobias Speck, Johannes Pw Heidbuechel, Rūta Veinalde, Dirk Jaeger, Christof von Kalle, Claudia R Ball, Guy Ungerechts, Christine E Engeland
PURPOSE: Immunotherapy with bispecific T cell engagers has achieved striking success against hematological malignancies, but efficacy against solid tumors has been limited. We hypothesized that oncolytic measles viruses encoding bispecific T cell engagers (MV-BiTEs) represent a safe and effective treatment against solid tumors through local BiTE expression, direct tumor cell lysis and in situ tumor vaccination. EXPERIMENTAL DESIGN: To test this hypothesis, we generated MV-BiTEs from the Edmonston B vaccine strain to target two model antigens...
February 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29436393/therapeutically-targeting-tumor-microenvironment-mediated-drug-resistance-in-estrogen-receptor-positive-breast-cancer
#17
Kevin Shee, Wei Yang, John W Hinds, Riley A Hampsch, Frederick S Varn, Nicole A Traphagen, Kishan Patel, Chao Cheng, Nicole P Jenkins, Arminja N Kettenbach, Eugene Demidenko, Philip Owens, Anthony C Faber, Todd R Golub, Ravid Straussman, Todd W Miller
Drug resistance to approved systemic therapies in estrogen receptor-positive (ER+) breast cancer remains common. We hypothesized that factors present in the human tumor microenvironment (TME) drive drug resistance. Screening of a library of recombinant secreted microenvironmental proteins revealed fibroblast growth factor 2 (FGF2) as a potent mediator of resistance to anti-estrogens, mTORC1 inhibition, and phosphatidylinositol 3-kinase inhibition in ER+ breast cancer. Phosphoproteomic analyses identified ERK1/2 as a major output of FGF2 signaling via FGF receptors (FGFRs), with consequent up-regulation of Cyclin D1 and down-regulation of Bim as mediators of drug resistance...
February 7, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29435104/niclosamide-suppresses-acute-myeloid-leukemia-cell-proliferation-through-inhibition-of-creb-dependent-signaling-pathways
#18
Hee-Don Chae, Nick Cox, Gary V Dahl, Norman J Lacayo, Kara L Davis, Samanta Capolicchio, Mark Smith, Kathleen M Sakamoto
CREB (cAMP Response Element Binding protein) is a transcription factor that is overexpressed in primary acute myeloid leukemia (AML) cells and associated with a decreased event-free survival and increased risk of relapse. We recently reported a small molecule inhibitor of CREB, XX-650-23, which inhibits CREB activity in AML cells. Structure-activity relationship analysis for chemical compounds with structures similar to XX-650-23 led to the identification of the anthelminthic drug niclosamide as a potent anti-leukemic agent that suppresses cell viability of AML cell lines and primary AML cells without a significant decrease in colony forming activity of normal bone marrow cells...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29433585/characterization-and-validation-of-potential-therapeutic-targets-based-on-the-molecular-signature-of-patient-derived-xenografts-in-gastric-cancer
#19
Zuhua Chen, Wenwen Huang, Tiantian Tian, Wanchun Zang, Jingyuan Wang, Zhentao Liu, Zhongwu Li, Yumei Lai, Zhi Jiang, Jing Gao, Lin Shen
BACKGROUND: Patient-derived xenograft (PDX) models with definite molecular signature are attractive preclinical models for development of novel targeted drugs. Here, we profiled and explored potential therapeutic targets based on characterized PDX models for advanced gastric cancer (AGC). METHODS: The genomic variation and molecular profile of 50 PDX models from AGC patients were analyzed by targeted next-generation sequencing, in situ hybridization, and immunohistochemistry...
February 13, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29433538/microrna-193a-stimulates-pancreatic-cancer-cell-repopulation-and-metastasis-through-modulating-tgf-%C3%AE-2-tgf-%C3%AE-riii-signalings
#20
Chi Fang, Chen-Yun Dai, Zhu Mei, Ming-Jie Jiang, Dian-Na Gu, Qian Huang, Ling Tian
BACKGROUND: Pancreatic cancer characterizes high recurrence and poor prognosis. In clinical practice, radiotherapy is widely used for pancreatic cancer treatment. However, the outcome remains undesirable due to tumor repopulation and following recurrence and metastasis after radiation. So, it is highly needed to explore the underlying molecular mechanisms and accordingly develop therapeutic strategies. Our previous studies revealed that dying cells from chemoradiation could stimulate repopulation of surviving pancreatic cancer cells...
February 13, 2018: Journal of Experimental & Clinical Cancer Research: CR
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