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https://www.readbyqxmd.com/read/29690909/targeting-chemotherapy-resistant-leukemia-by-combining-dnt-cellular-therapy-with-conventional-chemotherapy
#1
Branson Chen, Jong Bok Lee, Hyeonjeong Kang, Mark D Minden, Li Zhang
BACKGROUND: While conventional chemotherapy is effective at eliminating the bulk of leukemic cells, chemotherapy resistance in acute myeloid leukemia (AML) is a prevalent problem that hinders conventional therapies and contributes to disease relapse, and ultimately patient death. We have recently shown that allogeneic double negative T cells (DNTs) are able to target the majority of primary AML blasts in vitro and in patient-derived xenograft models. However, some primary AML blast samples are resistant to DNT cell therapy...
April 24, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29688859/patient-derived-xenograft-models-in-musculoskeletal-malignancies
#2
REVIEW
Wan Lu, Tu Chao, Chen Ruiqi, Su Juan, Li Zhihong
Successful oncological drug development for bone and soft tissue sarcoma is grossly stagnating. A major obstacle in this process is the lack of appropriate animal models recapitulating the complexity and heterogeneity of musculoskeletal malignancies, resulting in poor efficiency in translating the findings of basic research to clinical applications. In recent years, patient-derived xenograft (PDX) models generated by directly engrafting patient-derived tumor fragments into immunocompromised mice have recaptured the attention of many researchers due to their properties of retaining the principle histopathology, biological behaviors, and molecular and genetic characteristics of the original tumor, showing promising future in both basic and clinical studies of bone and soft tissue sarcoma...
April 23, 2018: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29686424/mechanisms-and-clinical-activity-of-an-egfr-and-her2-exon-20-selective-kinase-inhibitor-in-non-small-cell-lung-cancer
#3
Jacqulyne P Robichaux, Yasir Y Elamin, Zhi Tan, Brett W Carter, Shuxing Zhang, Shengwu Liu, Shuai Li, Ting Chen, Alissa Poteete, Adriana Estrada-Bernal, Anh T Le, Anna Truini, Monique B Nilsson, Huiying Sun, Emily Roarty, Sarah B Goldberg, Julie R Brahmer, Mehmet Altan, Charles Lu, Vassiliki Papadimitrakopoulou, Katerina Politi, Robert C Doebele, Kwok-Kin Wong, John V Heymach
Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors...
April 23, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29686388/discordant-inheritance-of-chromosomal-and-extrachromosomal-dna-elements-contributes-to-dynamic-disease-evolution-in-glioblastoma
#4
Ana C deCarvalho, Hoon Kim, Laila M Poisson, Mary E Winn, Claudius Mueller, David Cherba, Julie Koeman, Sahil Seth, Alexei Protopopov, Michelle Felicella, Siyuan Zheng, Asha Multani, Yongying Jiang, Jianhua Zhang, Do-Hyun Nam, Emanuel F Petricoin, Lynda Chin, Tom Mikkelsen, Roel G W Verhaak
To understand how genomic heterogeneity of glioblastoma (GBM) contributes to poor therapy response, we performed DNA and RNA sequencing on GBM samples and the neurospheres and orthotopic xenograft models derived from them. We used the resulting dataset to show that somatic driver alterations including single-nucleotide variants, focal DNA alterations and oncogene amplification on extrachromosomal DNA (ecDNA) elements were in majority propagated from tumor to model systems. In several instances, ecDNAs and chromosomal alterations demonstrated divergent inheritance patterns and clonal selection dynamics during cell culture and xenografting...
April 23, 2018: Nature Genetics
https://www.readbyqxmd.com/read/29685880/integrative-kinome-profiling-identifies-mtorc1-2-inhibition-as-treatment-strategy-in-ovarian-clear-cell-carcinoma
#5
Joseph J Caumanns, Katrien Berns, G Bea A Wisman, Rudolf S N Fehrmann, Tushar Tomar, Harry Klip, Gert Jan Meersma, E Marielle Hijmans, Annemiek Gennissen, Evelien W Duiker, Desiree Weening, Hiroaki Itamochi, Roelof Jc Kluin, An K L Reyners, Michael J Birrer, Helga B Salvesen, Ignace Vergote, Els Van Nieuwenhuysen, James D Brenton, Elena I Braicu, Jolanta Kupryjanczyk, Beata Spiewankiewicz, Lorenza Mittempergher, Rene Bernards, Ate G J van der Zee, Steven de Jong
PURPOSE: Advanced stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA. In this study, we aimed to identify currently unknown mutated kinases in OCCC patients and test druggability of downstream affected pathways in OCCC models. EXPERIMENTAL DESIGN: In a large set of OCCC patients (n=124), the human kinome (518 kinases) and additional cancer related genes were sequenced and copy number alterations were determined...
April 23, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29684420/novel-cancer-gene-variants-and-gene-fusions-of-triple-negative-breast-cancers-tnbcs-reveal-their-molecular-diversity-conserved-in-the-patient-derived-xenograft-pdx-model
#6
Jaeyun Jung, Kiwon Jang, Jung Min Ju, Eunji Lee, Jong Won Lee, Hee Jung Kim, Jisun Kim, Sae Byul Lee, Beom Seok Ko, Byung Ho Son, Hee Jin Lee, Gyungyup Gong, Sei Yeon Ahn, Jung Kyoon Choi, Shree Ram Singh, Suhwan Chang
Despite the improved 5-year survival rate of breast cancer, triple-negative breast cancer (TNBC) remains a challenge due to lack of effective targeted therapy and higher recurrence and metastasis than other subtypes. To identify novel druggable targets and to understand its unique biology, we tried to implement 24 patient-derived xenografts (PDXs) of TNBC. The overall success rate of PDX implantation was 45%, much higher than estrogen receptor (ER)-positive cases. Immunohistochemical analysis revealed conserved ER/PR/Her2 negativity (with two exceptions) between the original and PDX tumors...
April 20, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29684110/mechanistic-insights-into-anticancer-properties-of-oligomeric-proanthocyanidins-from-grape-seeds-in-colorectal-cancer
#7
Preethi Ravindranathan, Divya Pasham, Uthra Balaji, Jacob Cardenas, Jinghua Gu, Shusuke Toden, Ajay Goel
Although the anticancer properties of oligomeric proanthocyanidins (OPCs) from grape seeds have been well recognized, the molecular mechanisms by which they exert anticancer effects are poorly understood. In this study, through comprehensive RNA-sequencing-based gene expression profiling in multiple colorectal cancer cell lines, we for the first time illuminate the genome-wide effects of OPCs from grape seeds in colorectal cancer. Our data revealed that OPCs affect several key cancer-associated genes. In particular, genes involved in cell cycle and DNA replication were most significantly and consistently altered by OPCs across multiple cell lines...
April 19, 2018: Carcinogenesis
https://www.readbyqxmd.com/read/29683208/a-novel-tricarbonylmethane-agent-cmc2-24-reduces-human-pancreatic-tumor-growth-in-mice-by-targeting-ras
#8
Naveen A Mallangada, Joselin M Vargas, Swaroopa Thomas, Matthew G DiGiovanni, Brandon M Vaeth, Matthew D Nemesure, Ruixue Wang, Joseph F LaComb, Jennie L Williams, Lorne M Golub, Francis Johnson, Gerardo G Mackenzie
Pancreatic Cancer (PC) is a deadly disease in need of new therapeutic options. We recently developed a novel tricarbonylmethane agent (CMC2.24) as a therapeutic agent for PC, and evaluated its efficacy in preclinical models of PC. CMC2.24 inhibited the growth of various human PC cell lines in a concentration and time-dependent manner. Normal human pancreatic epithelial cells were resistant to CMC2.24, indicating selectivity. CMC2.24 reduced the growth of subcutaneous and orthotopic PC xenografts in mice by up to 65% (p < 0...
April 23, 2018: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/29682179/antiapoptotic-bcl-2-proteins-determine-sorafenib-regorafenib-resistance-and-bh3-mimetic-efficacy-in-hepatocellular-carcinoma
#9
Anna Tutusaus, Milica Stefanovic, Loreto Boix, Blanca Cucarull, Aynara Zamora, Laura Blasco, Pablo García de Frutos, Maria Reig, Jose C Fernandez-Checa, Montserrat Marí, Anna Colell, Jordi Bruix, Albert Morales
Sorafenib, systemic treatment for advanced hepatocellular carcinoma (HCC), and regorafenib, novel second line treatment after sorafenib failure, have efficacy limited by evasive mechanisms of acquired-drug resistance. BCL-2 proteins participate in the response to tyrosine kinase inhibitors; however, their role in HCC therapy with sorafenib/regorafenib remains uncertain. BH3-mimetic ABT-263 (navitoclax) enhanced sorafenib activity, inducing cell death via a mitochondrial caspase-dependent mechanism, after BCL-xL/BCL-2 inhibition...
March 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29675102/synergistic-antitumor-effects-of-cmet-inhibitor-in-combination-with-anti-vegf-in-colorectal-cancer-patient-derived-xenograft-models
#10
Xiangheng Chen, Zhonghai Guan, Jun Lu, Haohao Wang, Zhongkun Zuo, Fei Ye, Jiangsheng Huang, Lisong Teng
cMet signaling pathway is involved in the resistance to anti-VEGF therapy and cMet overexpression is associated with tumor progression and poor prognosis. In this study, the expression of cMet in 146 Chinese colorectal cancer (CRC) patients was examined by immunohistochemistry staining. Our data demonstrated that cMet overexpression rate was 42.5% (62/146) and cMet overexpression was closely correlated with distant metastasis of CRC. Using CRC patient-derived xenograft (PDX) mouse models we investigated antitumor activity of a novel selective cMet inhibitor volitinib alone or in combination with anti-VEGF inhibitor apatinib in vivo ...
2018: Journal of Cancer
https://www.readbyqxmd.com/read/29672049/discovery-of-n-2-4-amino-cyclohexyl-9-cyclopentyl-n-6-4-morpholin-4-ylmethyl-phenyl-9-h-purine-2-6-diamine-as-a-potent-flt3-kinase-inhibitor-for-acute-myeloid-leukemia-with-flt3-mutations
#11
Tomas Gucky, Eva Řezníčková, Tereza Radosova Muchova, Radek Jorda, Zuzana Klejova, Veronika Malinkova, Karel Berka, Vaclav Bazgier, Haresh Ajani, Martin Lepsik, Vladimir Divoky, Vladimir Krystof
FLT3 tyrosine kinase is a potential drug target in acute myeloid leukemia (AML) because patients with FLT3-ITD mutations respond poorly to standard cytotoxic agents and there is a clear link between the disease and the oncogenic properties of FLT3. We present novel 2,6,9-trisubstituted purine derivatives with potent FLT3 inhibitory activity. The lead compound 7d displays nanomolar activity in biochemical assays and selectively blocks proliferation of AML cell lines harboring FLT3-ITD mutations, whereas other transformed and normal human cells are several orders of magnitude less sensitive...
April 19, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29669759/multi-kinase-inhibitor-ct-707-targets-liver-cancer-by-interrupting-the-hypoxia-activated-igf-1r-yap-axis
#12
Hong Zhu, Dan-Dan Wang, Tao Yuan, Fang-Jie Yan, Chen-Ming Zeng, Xiao-Yang Dai, Zi-Bo Chen, Ying Chen, Tianyi Zhou, Guang-Han Fan, Meidan Ying, Ji Cao, Peihua Luo, Xi-Jie Liu, Yuandong Hu, Yong Peng, Qiaojun He, Bo Yang
Given that YAP signaling acts as a critical survival input for hypoxic cancer cells in hepatocellular carcinoma (HCC), disruption of YAP function and the maintenance of hypoxia is an attractive way to treat HCC. Utilizing a cell-based YAP-TEAD luciferase reporter assay and functional analyses, we identified CT-707, a China-FDA approved multi-kinase inhibitor under clinical trial with remarkable inhibitory activity against YAP function. CT-707 exhibited prominent cytotoxicity under hypoxia on HCC cells, which was attributable to the inhibition of YAP signaling...
April 18, 2018: Cancer Research
https://www.readbyqxmd.com/read/29666304/strategic-therapeutic-targeting-to-overcome-venetoclax-resistance-in-aggressive-b-cell-lymphomas
#13
Lan V Pham, Shengjian Huang, Hui Zhang, Jun Zhang, Taylor Bell, Shouhao Zhou, Elizabeth Pogue, Zhiyong Ding, Laura Lam, Jason R Westin, R Eric Davis, Ken H Young, L Jeffrey Medeiros, Richard J Ford, Krystle Nomie, Liang Zhang, Michael Wang
PURPOSE: B-cell lymphoma-2 (BCL-2), an anti-apoptotic protein often dysregulated in B-cell lymphomas, promotes cell survival and provides protection from stress. A recent Phase I first-in-human study of the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma showed an overall response rate of 44%. These promising clinical results prompted our examination of the biological effects and mechanism of action underlying venetoclax activity in aggressive B-cell lymphoma, including mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL)...
April 17, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29666301/fratricide-of-nk-cells-in-daratumumab-therapy-for-multiple-myeloma-overcome-by-ex-vivo-expanded-autologous-nk-cells
#14
Yufeng Wang, Yibo Zhang, Tiffany Hughes, Jianying Zhang, Michael A Caligiuri, Don M Benson, Jianhua Yu
PURPOSE: Daratumumab and its use in combination with other agents is becoming a new standard of care for treatment of multiple myeloma (MM). We mechanistically studied how daratumumab acts on NK cells. EXPERIMENTAL DESIGN: Quantities of NK cells in peripheral blood (PB) and/or bone marrow (BM) of MM patients or healthy donors were examined by flow cytometry. NK cell apoptosis and the associated mechanism were assessed by flow cytometry and immunoblotting. Patients' NK cells were expanded in vitro using feeder cells...
April 17, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29666142/tumor-xenograft-modeling-identifies-tcf4-itf2-loss-associated-with-breast-cancer-chemoresistance
#15
Gorka Ruiz de Garibay, Francesca Mateo, Agostina Stradella, Rafael Valdés-Mas, Luis Palomero, Jordi Serra-Musach, Diana A Puente, Ander Díaz-Navarro, Gardenia Vargas-Parra, Eva Tornero, Idoia Morilla, Lourdes Farré, María Martinez-Iniesta, Carmen Herranz, Emmet McCormack, August Vidal, Anna Petit, Teresa Soler, Conxi Lázaro, Xose S Puente, Alberto Villanueva, Miguel Angel Pujana
Understanding the mechanisms of cancer therapeutic resistance is fundamental to improving cancer care. There is clear benefit from chemotherapy in different breast cancer settings; however, knowledge of the mutations and genes that mediate resistance is incomplete. In this study, by modeling chemoresistance in patient-derived xenografts (PDXs), we show that adaptation to therapy is genetically complex and identify loss of transcription factor 4 (TCF4) associated with this process. A triple-negative BRCA1 -mutated PDX was used to study the genetics of chemoresistance...
April 13, 2018: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/29664709/non-clinical-efficacy-and-safety-studies-on-g1xcgd-a-lentiviral-vector-for-ex-vivo-gene-therapy-of-x-linked-chronic-granulomatous-disease
#16
Christian Brendel, Michael Rothe, Giorgia Santilli, Sabine Charrier, Stefan Stein, Hana Kunkel, Daniela Abriss, Uta Müller-Kuller, Bobby Gaspar, Ute Modlich, Anne Galy, Axel Schambach, Adrian J Thrasher, Manuel Grez
Chronic granulomatous disease (CGD) is a debilitating primary immunodeficiency affecting phagocyte function due to the absence of nicotinamide dinucleotide phosphate (NADPH) oxidase activity. The vast majority of CGD patients in the Western world have mutations within the X-linked CYBB gene encoding for gp91phox (NOX2), the redox center of the NADPH oxidase complex (XCGD). Current treatments of XCGD are not entirely satisfactory, and prior attempts at autologous gene therapy using gammaretrovirus vectors did not provide long-term curative effects...
April 17, 2018: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29662203/potent-antitumor-efficacy-of-anti-gd2-car-t-cells-in-h3-k27m-diffuse-midline-gliomas
#17
Christopher W Mount, Robbie G Majzner, Shree Sundaresh, Evan P Arnold, Meena Kadapakkam, Samuel Haile, Louai Labanieh, Esther Hulleman, Pamelyn J Woo, Skyler P Rietberg, Hannes Vogel, Michelle Monje, Crystal L Mackall
Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10 , and recent results suggest benefit in central nervous system malignancies11-13 . Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2...
April 16, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29661776/targeting-the-leukemia-antigen-pr1-with-immunotherapy-for-the-treatment-of-multiple-myeloma
#18
Gheath Alatrash, Alexander A Perakis, Celine Kerros, Haley L Peters, Pariya Sukhumalchandra, Mao Zhang, Haroon Jakher, Madhushree Zope, Rebecca S Patenia, Anna Sergeeva, Shuhua Yi, Ken H Young, Anne V Philips, Amanda C Herrmann, Haven R Garber, Na Qiao, Jinsheng Weng, Lisa S St John, Sijie Lu, Karen Clise-Dwyer, Elizabeth A Mittendorf, Qing Ma, Jeffrey J Molldrem
PURPOSE: PR1 is a human leukocyte antigen (HLA)-A2 nonameric peptide derived from neutrophil elastase (NE) and proteinase 3 (P3). We have previously shown that PR1 is cross-presented by solid tumors, leukemia, and antigen presenting cells, including B cells. We have also shown that cross-presentation of PR1 by solid tumors renders them susceptible to killing by PR1-targeting immunotherapies. Since multiple myeloma (MM) is derived from B cells, we investigated whether MM is also capable of PR1 cross-presentation and subsequently capable of being targeted using PR1 immunotherapies...
April 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29661755/a-cd123-targeting-antibody-drug-conjugate-imgn632-designed-to-eradicate-aml-while-sparing-normal-bone-marrow-cells
#19
Yelena Kovtun, Gregory E Jones, Sharlene Adams, Lauren Harvey, Charlene A Audette, Alan Wilhelm, Chen Bai, Lingyun Rui, Rassol Laleau, Fenghua Liu, Olga Ab, Yulius Setiady, Nicholas C Yoder, Victor S Goldmacher, Ravi V J Chari, Jan Pinkas, Thomas Chittenden
The outlook for patients with refractory/relapsed acute myeloid leukemia (AML) remains poor, with conventional chemotherapeutic treatments often associated with unacceptable toxicities, including severe infections due to profound myelosuppression. Thus there exists an urgent need for more effective agents to treat AML that confer high therapeutic indices and favorable tolerability profiles. Because of its high expression on leukemic blast and stem cells compared with normal hematopoietic stem cells and progenitors, CD123 has emerged as a rational candidate for molecularly targeted therapeutic approaches in this disease...
April 24, 2018: Blood Advances
https://www.readbyqxmd.com/read/29659677/targeting-the-human-epidermal-growth-factor-receptor-2-her2-oncogene-in-colorectal-cancer
#20
S Siena, A Sartore-Bianchi, S Marsoni, H I Hurwitz, S J McCall, F Penault-Llorca, S Srock, A Bardelli, L Trusolino
BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. Using functional and genomic analyses of patient-derived xenografts, we previously showed that a subset (approximately 5%) of metastatic colorectal cancer (CRC) tumors are driven by amplification or mutation of HER2. MATERIALS AND METHODS: This paper reviews the role of HER2 as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target in CRC, considering the specifics of HER2 testing in this tumor type...
April 6, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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