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Yukihiko Hiroshima, Ali Maawy, Yong Zhang, Nan Zhang, Takashi Murakami, Takashi Chishima, Kuniya Tanaka, Yasushi Ichikawa, Michael Bouvet, Itaru Endo, Robert M Hoffman
Patient-derived xenograft (PDX) mouse models of cancer are emerging as an important component of personalized precision cancer therapy. However, most models currently offered to patients contain their tumors subcutaneously-transplanted in immunodeficient mice, which rarely metastasize. In contrast, orthotopic-transplant patient-derived models, termed patient-derived orthotopic xenografts (PDOX), usually metastasize as in the patient. We have demonstrated in the present report why orthotopic models are so important for the patient, since primary and metastatic tumors developed in an orthotopic model can have differential chemosensitivity, not detectable in standard subcutaneous tumor models...
September 28, 2016: Oncotarget
Anthony Gonçalves, François Bertucci, Arnaud Guille, Severine Garnier, José Adelaide, Nadine Carbuccia, Oliver Cabaud, Pascal Finetti, Serge Brunelle, Gilles Piana, Jeanne Tomassin-Piana, Maria Paciencia, Eric Lambaudie, Cornel Popovici, Renaud Sabatier, Carole Tarpin, Magali Provansal, Jean-Marc Extra, François Eisinger, Hagay Sobol, Patrice Viens, Marc Lopez, Christophe Ginestier, Emmanuelle Charafe-Jauffret, Max Chaffanet, Daniel Birnbaum
BACKGROUND: Routine feasibility and clinical impact of genomics-based tumor profiling in advanced breast cancer (aBC) remains to be determined. We conducted a pilot study to evaluate whether precision medicine could be prospectively implemented for aBC patients in a single center and to examine whether patient-derived tumor xenografts (PDX) could be obtained in this population. RESULTS: Thirty-four aBC patients were included. Actionable targets were found in 28 patients (82%)...
October 18, 2016: Oncotarget
Jianfeng Lu, Donna McEachern, Shunqiang Li, Matthew J Ellis, Shaomeng Wang
Endocrine therapy has been highly effective for the treatment of estrogen-receptor positive breast cancer, but endocrine resistance develops in a significant proportion of patients. In an effort to develop novel therapeutic strategies for the treatment of endocrine resistant breast cancer, we have evaluated a potent and specific MDM2-p53 interaction inhibitor, MI-77301, which has been advanced into clinical development, for its therapeutic potential and mechanism of action in vitro and in vivo in WHIM9 and WHIM18 patient-derived xenograft (PDX) models...
October 7, 2016: Molecular Cancer Therapeutics
Tushar Tomar, Steven de Jong, Nicolette G Alkema, Rieks L Hoekman, Gert Jan Meersma, Harry G Klip, Ate Gj van der Zee, G Bea A Wisman
BACKGROUND: In high-grade serous ovarian cancer (HGSOC), intrinsic and/or acquired resistance against platinum-containing chemotherapy is a major obstacle for successful treatment. A low frequency of somatic mutations but frequent epigenetic alterations, including DNA methylation in HGSOC tumors, presents the cancer epigenome as a relevant target for innovative therapy. Patient-derived xenografts (PDXs) supposedly are good preclinical models for identifying novel drug targets. However, the representativeness of global methylation status of HGSOC PDXs compared to their original tumors has not been evaluated so far...
October 20, 2016: Genome Medicine
Zhu Zeng, Rui Yu, Fanglei Zuo, Bo Zhang, Deju Peng, Huiqin Ma, Shangwu Chen
Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, is an excellent therapeutic peptide drug for type 2 diabetes due to longer lasting biological activity compared to GLP-1. This study explored the feasibility of using probiotic Lactobacillus paracasei as an oral vector for recombinant exendin-4 peptide delivery, an alternative to costly chemical synthesis and inconvenient administration by injection. L. paracasei transformed with a plasmid encoding the exendin-4 gene (L. paracasei L14/pMG76e-exendin-4) with a constitutive promotor was successfully constructed and showed efficient secretion of exendin-4...
2016: PloS One
Agnieszka Mika, Heidi E Day, Alexander Martinez, Nicole L Rumian, Benjamin N Greenwood, Maciej Chichlowski, Brian M Berg, Monika Fleshner
Manipulating gut microbes may improve mental health. Prebiotics are indigestible compounds that increase the growth and activity of health- promoting microorganisms, yet few studies have examined how prebiotics affect CNS function. Using an acute inescapable stressor known to produce learned helplessness behaviors such as failure to escape and exaggerated fear, we tested whether early life supplementation of a blend of two prebiotics, galactooligosaccharide (GOS) and polydextrose (PDX), and the glycoprotein lactoferrin (LAC) would attenuate behavioral and biological responses to stress later in life...
October 20, 2016: European Journal of Neuroscience
Alice Iezzi, Elisa Caiola, Massimo Broggini
The Phosphatidyl inositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and c-Met signaling pathways are often deregulated in cancer. The two pathways are interconnected and at least c-Met has been implicated in drug resistance. The aim of the study was to assess in ovarian cancer preclinical models, the efficacy and tolerability of a dual PI3K mTOR inhibitor (PF-05212384 or gedatolisib) and a c-Met inhibitor (crizotinib) either as single agents or in combination. In vitro, both PF-05212384 and crizotinib showed a concentration dependent activity in the two ovarian cancer cell lines...
October 2016: Translational Oncology
Dennis Wang, Nhu-An Pham, Jiefei Tong, Shingo Sakashita, Ghassan Allo, Lucia Kim, Naoki Yanagawa, Vibha Raghavan, Yuhong Wei, Christine To, Quang M Trinh, Maud H W Starmans, Michelle A Chan-Seng-Yue, Dianne Chadwick, Lei Li, Chang-Qi Zhu, Ni Liu, Ming Li, Sharon Lee, Vladimir Ignatchenko, Dan Strumpf, Paul Taylor, Nadeem Moghal, Geoffrey Liu, Paul C Boutros, Thomas Kislinger, Melania Pintilie, Igor Jurisica, Frances A Shepherd, John D McPherson, Lakshmi Muthuswamy, Michael F Moran, Ming-Sound Tsao
Availability of lung cancer models that closely mimic human tumors remains a significant gap in cancer research, as tumor cell lines and mouse models may not recapitulate the spectrum of lung cancer heterogeneity seen in patients. We aimed to establish a patient-derived tumor xenograft (PDX) resource from surgically resected non-small cell lung cancer (NSCLC). Fresh tumor tissue from surgical resection was implanted and grown in the subcutaneous pocket of non-obese severe combined immune deficient (NOD SCID) gamma mice...
October 17, 2016: International Journal of Cancer. Journal International du Cancer
Lei You, Xiaoxia Ren, Yongxing Du, Wenjing Zhao, Ming Cui, Ge Chen, Yupei Zhao
Pathogenesis of pancreatic ductal adenocarcinoma (PDAC) is thought to develop through the progression of precursor lesions, known as pancreatic intraepithelial neoplasias (PanIN). In the present study, we showed that c-Fos promoted proliferation, cell cycle and migration in pancreatic cancer cells. Caerulein was used to accelerate the pathogenesis of Pdx-cre; KrasG12D mice. During PanIN formation and development of PDAC, the expression of ERK and c-Fos increased concomitantly. When ERK activity was inhibited by U0126, the expression of c-Fos also decreased...
October 13, 2016: Oncology Reports
Bing-Ying Xie, Ai-Wen Wu
BACKGROUND: Colorectal cancer (CRC) is a heterogeneous disease; current research relies on cancer cell lines and animal cancer models, which may not precisely imitate inner human tumors and guide clinical medicine. The purpose of our study was to explore and further improve the process of producing three-dimensional (3D) organoid model and impel the development of personalized therapy. METHODS: We subcutaneously injected surgically resected CRC tissues from a patient into BALB/c-nu mice to build patient-derived xenografts (PDXs)...
2016: Chinese Medical Journal
Julian A Harrison, J Andrew Aquilina
The compositions of paradoxin and taipoxin (PDx and TPx, respectively) were investigated using size exclusion chromatography (SEC) and nano-electrospray ionization mass spectrometry (nano-ESI-MS). The elution profiles from size exclusion chromatography of the venoms from Oxyuranus microlepidotus and Oxyuranus scutellatus were similar. Fractions corresponding to the trimeric toxins were treated with guanidinium hydrochloride and the individual subunits were separated by HPLC. In this report we present the size exclusion chromatography profiles for these toxins, and the nano-ESI mass spectra of the subunits after separation by HPLC: the first such comparative study of these toxins at the protein level...
December 2016: Data in Brief
P Zarzosa, N Navarro, I Giralt, C Molist, A Almazán-Moga, I Vidal, A Soriano, M F Segura, R Hladun, A Villanueva, S Gallego, J Roma
The use of preclinical models is essential in translational cancer research and especially important in pediatric cancer given the low incidence of each particular type of cancer. Cell line cultures have led to significant advances in cancer biology. However, cell lines have adapted to growth in artificial culture conditions, thereby undergoing genetic and phenotypic changes which may hinder the translational application. Tumor grafts developed in mice from patient tumor tissues, generally known as patient-derived xenografts (PDXs), are interesting alternative approaches to reproducing the biology of the original tumor...
October 7, 2016: Clinical & Translational Oncology
Diego Soares Carvalho, Marilia Melo Diniz, André Abour Haidar, Maria de Fátima Cavanal, Eduardo da Silva Alves, Angelo Rafael Carpinelli, Frida Zaladek Gil, Aparecida Emiko Hirata
Maternal hyperglycemia can result in defects in glucose metabolism and pancreatic β-cell function in offspring. The purpose of this study was to evaluate the impact of maternal diabetes mellitus on pancreatic islets, muscle and adipose tissue of the offspring, with or without oral l-Arginine supplementation. The induction of diabetes was performed using streptozotocin (60mg/kg). Animals were studied at 3 months of age and treatment (sucrose or l-Arginine) was administered from weaning. We observed that l-Arg improved insulin sensitivity in the offspring of diabetic mothers (DA), reflected by higher insulin-induced phosphorylation of Akt in muscle and adipose tissue...
October 4, 2016: European Journal of Pharmacology
Hongjuan Zhao, Rosalie Nolley, Andy M W Chan, Erinn B Rankin, Donna M Peehl
MET plays an important role in the development and progression of papillary renal cell carcinoma (pRCC). Evaluation of efficacy of MET inhibitors against pRCC has been hampered by limited preclinical models depicting MET abnormalities. We established a new patient-derived xenograft (PDX) model of pRCC carrying an activating mutation of MET and tested the ability of cabozantinib, an inhibitor of receptor tyrosine kinases including MET, to inhibit tumor growth and metastasis. Precision-cut, thin tissue slices from a pRCC specimen obtained by nephrectomy were implanted under the renal capsule of RAG2(-/-)γC(-/-) mice to establish first generation TSG-RCC-030...
August 11, 2016: Cancer Biology & Therapy
Ming-Sound Tsao, Licun Wu, Ghassan Allo, Thomas John, Ming Li, Tetsuzo Tagawa, Isabelle Opitz, Masaki Anraku, Zhihong Yun, Melania Pintilie, Geoffrey Liu, Bethany Pitcher, Ron Feld, Michael R Johnston, Marc de Perrot
PURPOSE: Malignant pleural mesothelioma (MPM) is a rare but aggressive disease with few therapeutic options. The tumor stromal interface is important in MPM, but this is lost in cell lines, the main model used for preclinical studies. We sought to characterise MPM patient derived xenografts (PDX) to determine their suitability as pre-clinical models and whether tumors that engraft reflect a more aggressive biological phenotype. EXPERIMENTAL DESIGN: Fresh tumors were harvested from extrapleural pneumonectomy (EPP), decortication or biopsy samples of 50 MPM patients, and implanted subcutaneously into immunodeficient mice and serially passaged for up to five generations...
September 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Rachel Eyre, Denis G Alférez, Kath Spence, Mohamed Kamal, Frances L Shaw, Bruno M Simões, Angélica Santiago-Gómez, Aida Sarmiento-Castro, Maria Bramley, Mohammed Absar, Zahida Saad, Sumohan Chatterjee, Cliona Kirwan, Ashu Gandhi, Anne C Armstrong, Andrew M Wardley, Ciara S O'Brien, Gillian Farnie, Sacha J Howell, Robert B Clarke
Breast cancer specific mortality results from tumour cell dissemination and metastatic colonisation. Identification of the cells and processes responsible for metastasis will enable better prevention and control of metastatic disease, thus reducing relapse and mortality. To better understand these processes, we prospectively collected 307 patient-derived breast cancer samples (n = 195 early breast cancers (EBC) and n = 112 metastatic samples (MBC)). We assessed colony-forming activity in vitro by growing isolated cells in both primary (formation) and secondary (self-renewal) mammosphere culture, and tumour initiating activity in vivo through subcutaneous transplantation of fragments or cells into mice...
September 28, 2016: Journal of Mammary Gland Biology and Neoplasia
B H Lok, Y Feng, E E Gardner, G K Yu, Y K Ru, N Riaz, E deStanchina, S N Powell, Y J Shen, J T Poirier, C M Rudin
No abstract text is available yet for this article.
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
S Lefort, A Thuleau, Y Kieffer, P Sirven, I Bieche, E Marangoni, A Vincent-Salomon, F Mechta-Grigoriou
The CXCR4 receptor and its ligand CXCL12 (also named stromal cell-derived factor 1, SDF1) have a critical role in chemotaxis and homing, key steps in cancer metastasis. Although myofibroblasts expressing CXCL12 are associated with the presence of axillary metastases in HER2 breast cancers (BC), the therapeutic interest of targeting CXCR4/CXCL12 axis in the different BC subtypes remains unclear. Here, we investigate this question by testing antitumor activity of CXCR4 inhibitors in patient-derived xenografts (PDX), which faithfully reproduce human tumor properties...
September 26, 2016: Oncogene
Ana S Leal, Michael B Sporn, Patricia A Pioli, Karen T Liby
Because the 5-year survival rate for pancreatic cancer remains under 10%, new drugs are needed for the prevention and treatment of this devastating disease. Patients with chronic pancreatitis have a 12-fold higher risk of developing pancreatic cancer. LSL-Kras(G12D/+);Pdx-1-Cre (KC) mice replicate the genetics, symptoms and histopathology found in human pancreatic cancer. Immune cells infiltrate into the pancreas of these mice and produce inflammatory cytokines that promote tumor growth. KC mice are particularly sensitive to the effects of lipopolysaccharide (LPS), as only 48% of KC mice survived an LPS challenge while 100% of wildtype (WT) mice survived...
September 22, 2016: Carcinogenesis
Jason R Pitarresi, Xin Liu, Sudarshana M Sharma, Maria C Cuitiño, Raleigh D Kladney, Thomas A Mace, Sydney Donohue, Sunayana G Nayak, Chunjing Qu, James Lee, Sarah A Woelke, Stefan Trela, Kyle LaPak, Lianbo Yu, Joseph McElroy, Thomas J Rosol, Reena Shakya, Thomas Ludwig, Gregory B Lesinski, Soledad A Fernandez, Stephen F Konieczny, Gustavo Leone, Jinghai Wu, Michael C Ostrowski
Preclinical studies have suggested that the pancreatic tumor microenvironment both inhibits and promotes tumor development and growth. Here we establish the role of stromal fibroblasts during acinar-to-ductal metaplasia (ADM), an initiating event in pancreatic cancer formation. The transcription factor V-Ets avian erythroblastosis virus E26 oncogene homolog 2 (ETS2) was elevated in smooth muscle actin-positive fibroblasts in the stroma of pancreatic ductal adenocarcinoma (PDAC) patient tissue samples relative to normal pancreatic controls...
September 2016: Neoplasia: An International Journal for Oncology Research
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