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patient derived xenograft cancer

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
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
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
Diane Ojo, Xiaozeng Lin, Ying Wu, Jessica Cockburn, Anita Bane, Damu Tang
We report that BMI1 promotes tamoxifen resistance in estrogen receptor (ER)-positive breast cancer (BC). BMI1 overexpression conferred MCF7 and TD47 cells resistance to tamoxifen; BMI1 knockdown sensitized the process. In MCF7-derived tamoxifen resistant cells, BMI1 expression was upregulated and BMI1 knockdown reduced the resistance. BMI1 is an oncogene; its oncogenic activity is attributed to BMI1-stimulated E3 ubiquitin ligase activity, a process that requires BMI1's ring finger (RF) domain. However, a BMI1 mutant without RF conferred tamoxifen resistance...
April 4, 2018: Cancer Letters
Lvfen Gao, Ming Chen, Yuan Ouyang, Ruobin Li, Xian Zhang, Xuesong Gao, Xiaoyu Wang, Shaoqiang Lin
AIMS: Ovarian cancer (OC) has the highest mortality rate of all gynecological cancers. Currently, the first-line OC treatment consists of cytoreductive surgery and platinum-based chemotherapy. However, most patients develop chemoresistance after the first-line treatment limits the success of treatment. Therefore, there is an urgent need to identify effective therapeutic agents. MAIN METHODS: Cell viabilities were detected by MTS assay; Annexin V-FITC/PI assay and western blotting assay were performed to analyze the apoptotic cells in vitro; An immunofluorescence assay was performed to analyze the TUNEL+ apoptotic cells in vivo; Patient-derived xenografts were established to test the in vivo antitumor effects; The key proteins of p53, caspase-mediated apoptotic pathway and Akt/mTOR pathway were detected by Western blotting...
April 3, 2018: Life Sciences
Suk Hyung Lee, Wenhuo Hu, Justin T Matulay, Mark V Silva, Tomasz B Owczarek, Kwanghee Kim, Chee Wai Chua, LaMont J Barlow, Cyriac Kandoth, Alanna B Williams, Sarah K Bergren, Eugene J Pietzak, Christopher B Anderson, Mitchell C Benson, Jonathan A Coleman, Barry S Taylor, Cory Abate-Shen, James M McKiernan, Hikmat Al-Ahmadie, David B Solit, Michael M Shen
Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture...
April 5, 2018: Cell
Kei Kawaguchi, Kentaro Miyake, Qinghong Han, Shukuan Li, Yuying Tan, Kentaro Igarashi, Thinzar M Lwin, Takashi Higuchi, Tasuku Kiyuna, Masuyo Miyake, Hiromichi Oshiro, Michael Bouvet, Michiaki Unno, Robert M Hoffman
Pancreatic cancer is a recalcitrant disease. Gemcitabine (GEM) is the most widely-used first-line therapy for pancreatic cancer, but most patients eventually fail. Transformative therapy is necessary to significantly improve the outcome of pancreatic cancer patients. Our and other's previous work has demonstrated tumors have an elevated requirement for methionine and are susceptible to methionine restriction. The present study used a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer to determine the efficacy of recombinant methioninase (rMETase) to effect methionine restriction and thereby overcome GEM-resistance...
April 6, 2018: Cell Cycle
Ganjun Yu, Yanfeng Wu, Wenying Wang, Jia Xu, Xiaoping Lv, Xuetao Cao, Tao Wan
PD-1 blockade has demonstrated impressive clinical outcomes in colorectal cancers that have high microsatellite instability. However, the therapeutic efficacy for patients with tumors with low microsatellite instability or stable microsatellites needs further improvement. Here, we have demonstrated that low-dose decitabine could increase the expression of immune-related genes such as major histocompatibility complex genes and cytokine-related genes as well as the number of lymphocytes at the tumor site in CT26 colorectal cancer-bearing mice...
April 5, 2018: Cellular & Molecular Immunology
Zhiwei Hu, Rulong Shen, Amanda Campbell, Elizabeth L McMichael, Lianbo Yu, Bhuvaneswari Ramaswamy, Cheryl A London, Tian Xu, William E Carson
Triple-negative breast cancer (TNBC) is a leading cause of breast cancer death and is often associated with BRCA1 and BRCA2 mutation. Due to the lack of validated target molecules, no targeted therapy for TNBC is approved. Tissue factor (TF) is a common yet specific surface target receptor for cancer cells, tumor vascular endothelial cells and cancer stem cells in several types of solid cancers including breast cancer. Here we report evidence supporting the idea that TF is a surface target in TNBC. We used in vitro cancer lines and in vivo tumor xenografts in mice, all with BRCA1 or BRCA2 mutations, derived from patients' tumors...
April 5, 2018: Cancer Immunology Research
Roberta Noberini, Daniela Osti, Claudia Miccolo, Cristina Richichi, Michela Lupia, Giacomo Corleone, Sung-Pil Hong, Piergiuseppe Colombo, Bianca Pollo, Lorenzo Fornasari, Giancarlo Pruneri, Luca Magnani, Ugo Cavallaro, Susanna Chiocca, Saverio Minucci, Giuliana Pelicci, Tiziana Bonaldi
Histone post-translational modifications (PTMs) generate a complex combinatorial code that regulates gene expression and nuclear functions, and whose deregulation has been documented in different types of cancers. Therefore, the availability of relevant culture models that can be manipulated and that retain the epigenetic features of the tissue of origin is absolutely crucial for studying the epigenetic mechanisms underlying cancer and testing epigenetic drugs. In this study, we took advantage of quantitative mass spectrometry to comprehensively profile histone PTMs in patient tumor tissues, primary cultures and cell lines from three representative tumor models, breast cancer, glioblastoma and ovarian cancer, revealing an extensive and systematic rewiring of histone marks in cell culture conditions, which includes a decrease of H3K27me2/me3, H3K79me1/me2 and H3K9ac/K14ac, and an increase of H3K36me1/me2...
March 29, 2018: Nucleic Acids Research
Ke Gong, Gao Guo, David E Gerber, Boning Gao, Michael Peyton, Chun Huang, John D Minna, Kimmo J Hatanpaa, Kemp Kernstine, Ling Cai, Yang Xie, Hong Zhu, Farjana Fattah, Shanrong Zhang, Masaya Takahashi, Bipasha Mukherjee, Sandeep Burma, Jonathan Dowell, Kathryn Dao, Vassiliki A Papadimitrakopoulou, Victor Olivas, Trever G Bivona, Dawen Zhao, Amyn A Habib
Although aberrant Epidermal Growth Factor Receptor (EGFR) signaling is widespread in cancer, EGFR inhibition is effective only in a subset of NSCLC (non-small cell lung cancer) with EGFR activating mutations. A majority of NSCLCs express EGFR wild type (EGFRwt) and do not respond to EGFR inhibition. Tumor necrosis factor (TNF) is a major mediator of inflammation-induced cancer. We find that a rapid increase in TNF level is a universal adaptive response to EGFR inhibition in NSCLC regardless of EGFR status. EGFR signaling actively suppresses TNF mRNA levels by inducing expression of miR-21 resulting in decreased TNF mRNA stability...
April 3, 2018: Journal of Clinical Investigation
Silvia Vega-Rubín-de-Celis, Zhongju Zou, Álvaro F Fernández, Bo Ci, Min Kim, Guanghua Xiao, Yang Xie, Beth Levine
Allelic loss of the autophagy gene, beclin 1/BECN1 , increases the risk of patients developing aggressive, including human epidermal growth factor receptor 2 (HER2)-positive, breast cancers; however, it is not known whether autophagy induction may be beneficial in preventing HER2-positive breast tumor growth. We explored the regulation of autophagy in breast cancer cells by HER2 in vitro and the effects of genetic and pharmacological strategies to increase autophagy on HER2-driven breast cancer growth in vivo...
April 2, 2018: Proceedings of the National Academy of Sciences of the United States of America
Alexander Drilon, Romel Somwar, Biju P Mangatt, Henrik Edgren, Patrice Desmeules, Anja Ruusulehto, Roger S Smith, Lukas Delasos, Morana Vojnic, Andrew J Plodkowski, Joshua Sabari, Kenneth Ng, Joseph Montecalvo, Jason Chang, Huichun Tai, William W Lockwood, Victor Martinez, Gregory J Riely, Charles M Rudin, Mark G Kris, Maria E Arcila, Christopher Matheny, Ryma Benayed, Natasha Rekhtman, Marc Ladanyi, Gopinath Ganji
NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMAs) of the lung. The oncoprotein binds ERBB3-ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 monoclonal antibody therapy (GSK2849330) in an exceptional responder with an NRG1-rearranged IMA on a phase 1 trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four NRG1-rearranged IMA patients (including the index patient post-GSK2849330)...
April 2, 2018: Cancer Discovery
Haisen Yin, Risheng Que, Chunying Liu, Weidan Ji, Bin Sun, Xuejing Lin, Qin Zhang, Xinying Zhao, Zhangxiao Peng, Xiaofeng Zhang, Haihua Qian, Lei Chen, Yonggang Yao, Changqing Su
Hepatocellular carcinoma (HCC) is the second leading cause of cancer related death which needs novel drugs to improve patient outcome. Survivin overexpresses in HCC and contributes to HCC malignant progression. In this study, we established a Survivin-targeted drug screening platform, a cell model HepG2-Sur5P-EGFP-Sur3U stably transfected with lentivirus carrying an EGFP expression cassette, in which the EGFP expression was regulated by the upstream Survivin promoter and downstream Survivin 3'-UTR. By using this platform, we screened and easily identified one of matrine derivatives, WM-127, from hundreds of matrine derivatives...
March 30, 2018: Cancer Letters
Sofia Karkampouna, Danny van der Helm, Peter C Gray, Lanpeng Chen, Irena Klima, Jöel Grosjean, Mark C Burgmans, Arantza Farina-Sarasqueta, Ewa B Snaar-Jagalska, Deborah M Stroka, Luigi Terracciano, Bart van Hoek, Alexander F Schaapherder, Susan Osanto, George N Thalmann, Hein W Verspaget, Minneke J Coenraad, Marianna Kruithof-de Julio
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Despite increasing treatment options for this disease, prognosis remains poor. CRIPTO (TDGF1) protein is expressed at high levels in several human tumours and promotes oncogenic phenotype. Its expression has been correlated to poor prognosis in HCC. In this study, we aimed to elucidate the basis for the effects of CRIPTO in HCC. We investigated CRIPTO expression levels in three cohorts of clinical cirrhotic and HCC specimens...
March 31, 2018: Journal of Pathology
James D Byrne, Mohammad R N Jajja, Adrian T O'Neill, Allison N Schorzman, Amanda W Keeler, J Christopher Luft, William C Zamboni, Joseph M DeSimone, Jen Jen Yeh
PURPOSE: Effective treatment of patients with locally advanced pancreatic cancer is a significant unmet clinical need. One major hurdle that exists is inadequate drug delivery due to the desmoplastic stroma and poor vascularization that is characteristic of pancreatic cancer. The local iontophoretic delivery of chemotherapies provides a novel way of improving treatment. With the growing practice of highly toxic combination therapies in the treatment of pancreatic cancer, the use of iontophoresis for local delivery can potentiate the anti-cancer effects of these therapies while sparing unwanted toxicity...
March 30, 2018: Cancer Chemotherapy and Pharmacology
Kirstin A Zettlitz, Wen-Ting K Tsai, Scott M Knowles, Naoko Kobayashi, Timothy R Donahue, Robert E Reiter, Anna M Wu
Pancreatic cancer has a high mortality rate due to late diagnosis and the tendency to invade surrounding tissues and metastasize at an early stage. A molecular imaging agent that enables both pre-surgery antigen-specific positron emission tomography (immunoPET) and intra-operative near-infrared fluorescent (NIRF)-guidance could benefit diagnosis, staging and surgical resection of pancreatic cancer, which remains the only curative treatment. Methods: A dually labeled probe was developed based on A2 cys-diabody (A2cDb) targeting the cell surface antigen prostate stem cell antigen (PSCA) that is expressed in a majority of pancreatic cancers...
March 30, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Yue Zhao, Timothy Wai Ho Shuen, Tan Boon Toh, Xue Ying Chan, Min Liu, Sue Yee Tan, Yong Fan, Hechuan Yang, Shridhar Ganpathi Lyer, Glenn Kunnath Bonney, Eva Loh, Kenneth Tou En Chang, Thiam Chye Tan, Weiwei Zhai, Jerry Kok Yen Chan, Edward Kai-Hua Chow, Cheng Ean Chee, Guan Huei Lee, Yock Young Dan, Pierce Kah-Hoe Chow, Han Chong Toh, Seng Gee Lim, Qingfeng Chen
OBJECTIVE: As the current therapeutic strategies for human hepatocellular carcinoma (HCC) have been proven to have limited effectiveness, immunotherapy becomes a compelling way to tackle the disease. We aim to provide humanised mouse (humice) models for the understanding of the interaction between human cancer and immune system, particularly for human-specific drug testing. DESIGN: Patient-derived xenograft tumours are established with type I human leucocyte antigen matched human immune system in NOD- scid Il2rg-/- (NSG) mice...
March 30, 2018: Gut
Atsushi Suetsugu, Masahito Shimizu, Shigetoyo Saji, Hisataka Moriwaki, Robert M Hoffman
The tumor microenvironment (TME) contains stromal cells in a complex interaction with cancer cells. This relationship has become better understood with the use of fluorescent proteins for in vivo imaging, originally developed by our laboratories. Spectrally-distinct fluorescent proteins can used for color-coded imaging of the complex interaction of the tumor microenvironment in the living state using cancer cells expressing a fluorescent protein of one color and host mice expressing another-color fluorescent protein...
April 2018: Anticancer Research
Philipp Manegold, Keane K Y Lai, Yongfeng Wu, Jia-Ling Teo, Heinz-Josef Lenz, Yuri S Genyk, Stephen J Pandol, Kaijin Wu, David P Lin, Yibu Chen, Cu Nguyen, Yi Zhao, Michael Kahn
BACKGROUND: Although canonical Wnt signaling is known to promote tumorigenesis in pancreatic ductal adenocarcinoma (PDAC), a cancer driven principally by mutant K-Ras , the detailed molecular mechanisms by which the Wnt effector β-catenin regulates such tumorigenesis are largely unknown. We have previously demonstrated that β-catenin's differential usage of the Kat3 transcriptional coactivator cyclic AMP-response element binding protein-binding protein (CBP) over its highly homologous coactivator p300 increases self-renewal and suppresses differentiation in other types of cancer...
March 29, 2018: Cancers
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