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https://www.readbyqxmd.com/read/29050333/characterization-of-cadd522-a-small-molecule-that-inhibits-runx2-dna-binding-and-exhibits-antitumor-activity
#1
Myoung Sook Kim, Ramkishore Gernapudi, Eun Yong Choi, Rena G Lapidus, Antonino Passaniti
The RUNX2 transcription factor promotes breast cancer growth and metastasis through interactions with a variety of cofactors that activate or repress target genes. Using a direct drug discovery approach we identified CADD522 as a small molecule that inhibits the DNA binding of the runt box domain protein, RUNX2. The current study defines the effect of CADD522 on breast cancer growth and metastasis, and addresses the mechanisms by which it exerts its anti-tumor activity. CADD522 treatment resulted in significant growth inhibition, clonogenic survival, tumorsphere formation, and invasion of breast cancer cells...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29046702/in-vivo-validation-of-metastasis-regulating-microrna-766-in-human-triple-negative-breast-cancer-cells
#2
Keunhee Oh, Dong-Sup Lee
Breast cancer is the second most common cancer and the most frequent cancer in women worldwide. Recent improvements in early detection and effective adjuvant chemotherapies have improved the survival of breast cancer patients. Even with initial disease remission, one-third of all breast cancer patients will relapse with distant metastasis. Breast cancer metastasis is largely an incurable disease and the main cause of death among breast cancer patients. Cancer metastasis is comprised of complex processes that are usually not controllable by intervention of a single molecular target...
September 2017: Laboratory Animal Research
https://www.readbyqxmd.com/read/29042771/styrene-maleic-acid-encapsulated-rl71-micelles-suppress-tumor-growth-in-a-murine-xenograft-model-of-triple-negative-breast-cancer
#3
Orleans Martey, Mhairi Nimick, Sebastien Taurin, Vignesh Sundararajan, Khaled Greish, Rhonda J Rosengren
Patients with triple negative breast cancer have a poor prognosis due in part to the lack of targeted therapies. In the search for novel drugs, our laboratory has developed a second-generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidine-4-one (RL71), that exhibits potent in vitro cytotoxicity. To improve the clinical potential of this drug, we have encapsulated it in styrene maleic acid (SMA) micelles. SMA-RL71 showed improved biodistribution, and drug accumulation in the tumor increased 16-fold compared to control...
2017: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/29039610/establishment-of-a-human-primary-pancreatic-cancer-mouse-model-to-examine-and-investigate-gemcitabine-resistance
#4
Ya-Jing Zhang, Chen-Lei Wen, Yu-Xin Qin, Xiao-Mei Tang, Min-Min Shi, Bo-Yong Shen, Yuan Fang
Pancreatic cancer is one of the most fatal types of cancer and is associated with a dismal prognosis. Gemcitabine-based chemotherapy is clinically used for the treatment of advanced pancreatic cancer. However, many forms of pancreatic cancer have acquired resistance to gemcitabine. In order to prevent patients from suffering from the side effects of chemotherapy and to have the chance to receive more effective intervention, assessment of whether the patient pancreatic cancer cells are resistant to gemcitabine before clinical practice is crucial...
October 12, 2017: Oncology Reports
https://www.readbyqxmd.com/read/29035366/cytoplasmic-p53-couples-oncogene-driven-glucose-metabolism-to-apoptosis-and-is-a-therapeutic-target-in-glioblastoma
#5
Wilson X Mai, Laura Gosa, Veerle W Daniels, Lisa Ta, Jonathan E Tsang, Brian Higgins, W Blake Gilmore, Nicholas A Bayley, Mitra Dehghan Harati, Jason T Lee, William H Yong, Harley I Kornblum, Steven J Bensinger, Paul S Mischel, P Nagesh Rao, Peter M Clark, Timothy F Cloughesy, Anthony Letai, David A Nathanson
Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models...
October 9, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29033371/a-small-molecule-inhibitor-of-the-%C3%AE-catenin-tcf4-interaction-suppresses-colorectal-cancer-growth-in-vitro-and-in-vivo
#6
Seung Ho Shin, Do Young Lim, Kanamata Reddy, Margarita Malakhova, Fangfang Liu, Ting Wang, Mengqiu Song, Hanyong Chen, Ki Beom Bae, Joohyun Ryu, Kangdong Liu, Mee-Hyun Lee, Ann M Bode, Zigang Dong
Colorectal cancer is associated with aberrant activation of the Wnt pathway. β-Catenin plays essential roles in the Wnt pathway by interacting with T-cell factor 4 (TCF4) to transcribe oncogenes. We synthesized a small molecule, referred to as HI-B1, and evaluated signaling changes and biological consequences induced by the compound. HI-B1 inhibited β-catenin/TCF4 luciferase activity and preferentially caused apoptosis of cancer cells in which the survival is dependent on β-catenin. The formation of the β-catenin/TCF4 complex was disrupted by HI-B1 due to the direct interaction of HI-B1 with β-catenin...
September 27, 2017: EBioMedicine
https://www.readbyqxmd.com/read/29030058/mdm2-antagonists-counteract-drug-induced-dna-damage
#7
Anna E Vilgelm, Priscilla Cobb, Kiran Malikayil, David Flaherty, C Andrew Johnson, Dayanidhi Raman, Nabil Saleh, Brian Higgins, Brandon A Vara, Jeffrey N Johnston, Douglas B Johnson, Mark C Kelley, Sheau-Chiann Chen, Gregory D Ayers, Ann Richmond
Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage...
September 19, 2017: EBioMedicine
https://www.readbyqxmd.com/read/29027990/il6-blockade-potentiates-the-anti-tumor-effects-of-%C3%AE-secretase-inhibitors-in-notch3-expressing-breast-cancer
#8
Dong Wang, Jiahui Xu, Bingjie Liu, Xueyan He, Lei Zhou, Xin Hu, Feng Qiao, Anli Zhang, Xiaojun Xu, Huafeng Zhang, Max S Wicha, Lixing Zhang, Zhi-Ming Shao, Suling Liu
Notch pathways have important roles in carcinogenesis including pathways involving the Notch1 and Notch2 oncogenes. Pan-Notch inhibitors, such as gamma secretase inhibitors (GSIs), have been used in the clinical trials, but the outcomes of these trials have been insufficient and have yielded unclear. In the present study, we demonstrated that GSIs, such as MK-0752 and RO4929097, inhibit breast tumor growth, but increase the breast cancer stem cell (BCSC) population in Notch3-expressing breast cancer cells, in a process that is coupled with IL6 induction and is blocked by the IL6R antagonist Tocilizumab (TCZ)...
October 13, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29025772/impaired-hla-class-i-antigen-processing-and-presentation-as-a-mechanism-of-acquired-resistance-to-immune-checkpoint-inhibitors-in-lung-cancer
#9
Scott Gettinger, Jungmin Choi, Katherine Hastings, Anna Truini, Ila Datar, Ryan Sowell, Anna Wurtz, Weilai Dong, Guoping Cai, Mary Ann Melnick, Victor Y Du, Joseph Schlessinger, Sarah B Goldberg, Anne Chiang, Miguel F Sanmamed, Ignacio Melero, Jackeline Agorreta, Luis M Montuenga, Richard Lifton, Soldano Ferrone, Paula Kavathas, David L Rimm, Susan M Kaech, Kurt A Schalper, Roy S Herbst, Katerina Politi
Mechanisms of acquired resistance to immune checkpoint inhibitors (ICIs) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell surface HLA class I expression in the tumor and a matched patient-derived xenograft (PDX)...
October 12, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29021381/activation-of-fak-and-src-mediates-acquired-sorafenib-resistance-in-a549-human-lung-adenocarcinoma-xenografts
#10
Qingyu S Zhou, Xiaofang Guo, Riya Choksi
Despite encouraging clinical results with sorafenib monotherapy in patients with KRAS-mutant non-small cell lung cancer (NSCLC), the overall survival benefit of this drug is limited by the inevitable development of acquired resistance. The exact mechanism underlying acquired sorafenib resistance in KRAS-mutant NSCLC is unclear. In this study, the mechanism of acquired sorafenib resistance was explored using a biologically relevant xenograft model, which was established by using the A549 human lung adenocarcinoma cell line and an in-vivo derived sorafenib-resistant A549 subline (A549/SRFres)...
October 11, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29017050/neuroblastoma-metastases-leveraging-the-avian-neural-crest
#11
Tina Zheng, Marie Ménard, William A Weiss
Neuroblastoma, an embryonal cancer of neural crest origin, shows metastases frequently at diagnosis. In this issue of Cancer Cell, Delloye-Bourgeois and colleagues demonstrate that neuroblastoma cell lines and patient-derived xenografts engraft and adopt a metastatic program in chick embryos. They identify Sema3C as a candidate switch that regulates metastatic spread.
October 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29016929/trivalent-car-t-cells-overcome-interpatient-antigenic-variability-in-glioblastoma
#12
Kevin Bielamowicz, Kristen Fousek, Tiara T Byrd, Hebatalla Samaha, Malini Mukherjee, Nikita Aware, Meng-Fen Wu, Jordan S Orange, Pavel Sumazin, Tsz-Kwong Man, Sujith K Joseph, Meenakshi Hegde, Nabil Ahmed
Background: Glioblastoma (GBM) is the most common primary malignant brain cancer, and is currently incurable. Chimeric Antigen Receptor (CAR) T-cells have shown promise in GBM treatment. While we have shown that combinatorial targeting of two glioma antigens offsets antigen escape and enhances T-cell effector functions, the inter-patient variability in surface antigen expression between patients hinders the clinical impact of targeting two antigen pairs. This study addresses targeting 3 antigens using a single CAR T-cell product for broader application...
September 16, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/29016926/activation-of-wee1-confers-resistance-to-pi3k-inhibition-in-glioblastoma
#13
Shaofang Wu, Shuzhen Wang, Feng Gao, Luyuan Li, Siyuan Zheng, W K Alfred Yung, Dimpy Koul
Background: Oncogenic activation of phosphatidylinositol-3 kinase (PI3K) signaling plays a pivotal role in the development of glioblastoma (GBM). However, pharmacological inhibition of PI3K has so far not been therapeutically successful due to adaptive resistance through a rapid rewiring of cancer cell signaling. Here we identified that WEE1 is activated after transient exposure to PI3K inhibition and confers resistance to PI3K inhibition in GBM. Methods: Patient-derived glioma-initiating cells and established GBM cells were treated with PI3K inhibitor or WEE1 inhibitor alone or in combination, and cell proliferation was evaluated by CellTiter-Blue assay...
July 7, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28993429/tgf-%C3%AE-1-secreted-by-tregs-in-lymph-nodes-promotes-breast-cancer-malignancy-via-up-regulation-of-il-17rb
#14
Shih-Chia Huang, Pei-Chi Wei, Wendy W Hwang-Verslues, Wen-Hung Kuo, Yung-Ming Jeng, Chun-Mei Hu, Jin-Yuh Shew, Chiun-Sheng Huang, King-Jen Chang, Eva Y-Hp Lee, Wen-Hwa Lee
Lymph node (LN) metastasis is commonly associated with systemic distant organ metastasis in human breast cancer and is an important prognostic predictor for survival of breast cancer patients. However, whether tumor-draining LNs (TDLNs) play a significant role in modulating the malignancy of cancer cells for distant metastasis remains controversial. Using a syngeneic mouse mammary tumor model, we found that breast tumor cells derived from TDLN have higher malignancy and removal of TDLNs significantly reduced distant metastasis...
October 9, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28991298/exosomal-delivery-of-berry-anthocyanidins-for-the-management-of-ovarian-cancer
#15
Farrukh Aqil, Jeyaprakash Jeyabalan, Ashish K Agrawal, Al-Hassan Kyakulaga, Radha Munagala, Lynn Parker, Ramesh C Gupta
Despite optimal diagnosis and early therapeutic interventions, the prognosis for ovarian cancer patients remains dismal because the efficacy of chemotherapy is limited by the development of resistance and off-site toxicity. Berry bioactives indicate preventive and therapeutic activities against various cancer types. Here, we examined the antiproliferative activity of berry anthocyanidins (Anthos) against drug-sensitive (A2780) and drug-resistant (A2780/CP70, OVCA432 and OVCA433) ovarian cancer cells. These drug-resistant ovarian cancer cell lines overexpress p-glycoproteins (PgP) and show >100-fold resistance to the chemotherapeutic drug cisplatin compared to A2780...
October 9, 2017: Food & Function
https://www.readbyqxmd.com/read/28991255/patient-derived-xenografts-undergo-mouse-specific-tumor-evolution
#16
Uri Ben-David, Gavin Ha, Yuen-Yi Tseng, Noah F Greenwald, Coyin Oh, Juliann Shih, James M McFarland, Bang Wong, Jesse S Boehm, Rameen Beroukhim, Todd R Golub
Patient-derived xenografts (PDXs) have become a prominent cancer model system, as they are presumed to faithfully represent the genomic features of primary tumors. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We observed rapid accumulation of CNAs during PDX passaging, often due to selection of preexisting minor clones. CNA acquisition in PDXs was correlated with the tissue-specific levels of aneuploidy and genetic heterogeneity observed in primary tumors...
October 9, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28986890/xenograft-as-in-vivo-experimental-model
#17
Manuela Porru, Luca Pompili, Carla Caruso, Carlo Leonetti
The identification of experimental models that recapitulate human cancers designed to predict patient clinical response to therapies is a major break in oncology. Cancer stem cells (CSCs) represent a small tumor cell population responsible for drug resistance, where their effective killing may lead to identifying better treatment options. While the CSCs hypothesis highlights the need for a specific tumor target, patient-derived xenografts (PDXs) should also be considered for drug development as they better represent tumor heterogeneity and the environment in which a tumor develops...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28986391/altered-hydroxymethylation-is-seen-at-regulatory-regions-in-pancreatic-cancer-and-regulates-oncogenic-pathways
#18
Sanchari Bhattacharyya, Kith Pradhan, Nathaniel Campbell, Jozef Mazdo, Aparna Vasantkumar, Shahina Maqbool, Tushar D Bhagat, Sonal Gupta, Masako Suzuki, Yiting Yu, John M Greally, Ulrich Steidl, James Bradner, Meelad Dawlaty, Lucy Godley, Anirban Maitra, Amit Verma
Transcriptional deregulation of oncogenic pathways is a hallmark of cancer and can be due to epigenetic alterations. 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification that has not been studied in pancreatic cancer. Genome-wide analysis of 5-hmC-enriched loci with hmC-seal was conducted in a cohort of low-passage pancreatic cancer cell lines, primary patient-derived xenografts, and pancreatic controls and revealed strikingly altered patterns in neoplastic tissues. Differentially hydroxymethylated regions preferentially affected known regulatory regions of the genome, specifically overlapping with known H3K4me1 enhancers...
October 6, 2017: Genome Research
https://www.readbyqxmd.com/read/28982921/patient-derived-mouse-models-of-cancer-patient-derived-orthotopic-xenografts-pdox
#19
(no author information available yet)
No abstract text is available yet for this article.
October 2017: Anticancer Research
https://www.readbyqxmd.com/read/28981962/the-bmp-antagonist-noggin-is-produced-by-osteoblasts-in-response-to-the-presence-of-prostate-cancer-cells
#20
Huda F AlShaibi, Farid Ahmed, Clive Buckle, Ann Cm Fowles, Jalaluddin Awlia, Marco G Cecchini, Colby L Eaton
BACKGROUND: Bone metastasis is a key event responsible for morbidity in prostate cancer patients. Interactions between prostate cancer cells and the bone microenvironment facilitate survival of tumour cells and alter bone turnover, a process that is thought to enhance the growth of metastases in this site. This study aimed to test the hypothesis that the presence of tumours cells increases TGFβ signaling in bone and that this regulates the proliferation and differentiation of osteoblastic lineage cells in metastatic sites...
October 5, 2017: Biotechnology and Applied Biochemistry
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