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https://www.readbyqxmd.com/read/28534511/stromal-derived-igf2-promotes-colon-cancer-progression-via-paracrine-and-autocrine-mechanisms
#1
C Unger, N Kramer, D Unterleuthner, M Scherzer, A Burian, A Rudisch, M Stadler, M Schlederer, D Lenhardt, A Riedl, S Walter, A Wernitznig, L Kenner, M Hengstschläger, J Schüler, W Sommergruber, H Dolznig
The insulin-like growth factor (IGF)2/IGF1 receptor (IGF1R) signaling axis has an important role in intestinal carcinogenesis and overexpression of IGF2 is an accepted risk factor for colorectal cancer (CRC) development. Genetic amplifications and loss of imprinting contribute to the upregulation of IGF2, but insufficiently explain the extent of IGF2 expression in a subset of patients. Here, we show that IGF2 was specifically induced in the tumor stroma of CRC and identified cancer-associated fibroblasts (CAFs) as the major source...
May 22, 2017: Oncogene
https://www.readbyqxmd.com/read/28534338/-application-and-development-of-patient-derived-tumor-xenograft-model-in-translational-medicine-of-tumor
#2
Zhenqiang Wang, Zhenggang Zhu
Development of novel drugs is an integral part of the translational medicine in the field of cancer research, and the construction and application of preclinical animal models play vital roles in drugs development. Patient-derived tumor xenograft models (PDX) have been shown to be more accurate in prediction of clinical outcomes of novel drugs and are being used for preclinical drug evaluation based on the fact that PDX models mostly retain the principal histologic and genetic characteristics of their donor tumor...
May 25, 2017: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
https://www.readbyqxmd.com/read/28533437/metformin-inhibits-cellular-proliferation-and-bioenergetics-in-colorectal-cancer-patient-derived-xenografts
#3
Nur-Afidah Mohamed Suhaimi, Wai Min Phyo, Hao Yun Yap, Sharon Heng Yee Choy, Xiaona Wei, Yukti Choudhury, Wai Jin Tan, Luke Anthony Peng Yee Tan, Roger Sik Yin Foo, Suzanne Hui San Tan, Zenia Tiang, Chin Fong Wong, Poh Koon Koh, Min-Han Tan
There is increasing pre-clinical evidence suggesting that metformin, an anti-diabetic drug, has anti-cancer properties against various malignancies including colorectal cancer (CRC). However, majority of evidence which were derived from cancer cell lines and xenografts are likely to overestimate the benefit of metformin since these models are inadequate and require supraphysiological levels of metformin. Here, we generated patient-derived xenografts (PDX) lines from 2 CRC patients to assess the properties of metformin and 5-fluorouracil (5-FU), the first-line drug treatment for CRC...
May 22, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28529557/a-single-center-experience-of-sorafenib-monotherapy-in-patients-with-advanced-intrahepatic-cholangiocarcinoma
#4
Ting-Ting Pan, Wei Wang, Wei-Dong Jia, Ge-Liang Xu
Patients with advanced intrahepatic cholangiocarcinoma (ICC) have a poor prognosis and the therapeutic options available for treating ICC are limited. Sorafenib, a multikinase inhibitor of vascular endothelial growth factor receptor 2 and 3, platelet derived growth factor receptor-β, B-Raf proto-oncogene, serine/threonine kinase and C-Raf proto-oncogene, serine/threonine kinase, is a novel reference standard for the treatment of advanced hepatocellular carcinoma. Sorafenib has previously been demonstrated to exhibit significant antitumor activity in various cholangiocarcinoma cell lines and in xenograft ICC models...
May 2017: Oncology Letters
https://www.readbyqxmd.com/read/28526733/discovery-and-optimization-of-hkt288-a-cadherin-6-targeting-adc-for-the-treatment-of-ovarian-and-renal-cancer
#5
Carl U Bialucha, Scott D Collins, Xiao Li, Parmita Saxena, Xiamei Zhang, Clemens Dürr, Bruno LaFont, Pierric Prieur, Yeonju Shim, Rebecca Mosher, David Lee, Lance Ostrom, Tiancen Hu, Sanela Bilic, Ivana Liric Rajlic, Vladimir Capka, Wei Jiang, Joel P Wagner, GiNell Elliott, Artur Veloso, Jessica C Piel, Meghan M Flaherty, Keith G Mansfield, Emily K Meseck, Tina Rubic-Schneider, Anne Serdakowski London, William R Tschantz, Markus Kurz, Duc Nguyen, Aaron Bourret, Matthew J Meyer, Jason E Faris, Mary J Janatpour, Vivien W Chan, Nicholas C Yoder, Kalli C Catcott, Molly A McShea, Xiuxia Sun, Hui Gao, Juliet Williams, Francesco Hofmann, Jeffrey A Engelman, Seth A Ettenberg, William R Sellers, Emma Lees
Despite an improving therapeutic landscape, significant challenges remain in treating the majority of advanced ovarian and renal cancer patients. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancer. HKT288 is an optimized CDH6-targeting DM4-based antibody drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal anti-tumor activity and highlights CDH6 as a novel antigen for biotherapeutic development...
May 19, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28526063/targeting-the-cxcr4-pathway-using-a-novel-anti-cxcr4-igg1-antibody-pf-06747143-in-chronic-lymphocytic-leukemia
#6
Manoj K Kashyap, Carlos I Amaya-Chanaga, Deepak Kumar, Brett Simmons, Nanni Huser, Yin Gu, Max Hallin, Kevin Lindquist, Rolla Yafawi, Michael Y Choi, Ale-Ali Amine, Laura Z Rassenti, Cathy Zhang, Shu-Hui Liu, Tod Smeal, Valeria R Fantin, Thomas J Kipps, Flavia Pernasetti, Januario E Castro
BACKGROUND: The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow...
May 19, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28524233/bortezomib-sensitizes-human-osteosarcoma-cells-to-adriamycin-induced-apoptosis-through-ros-dependent-activation-of-p-eif2%C3%AE-atf4-chop-axis
#7
Miao Xian, Handi Cao, Ji Cao, Xuejing Shao, Difeng Zhu, Ning Zhang, Ping Huang, Weixu Li, Bo Yang, Meidan Ying, Qiaojun He
Osteosarcoma is the most common bone cancer, and chemotherapy is currently indispensable for its treatment. Adriamycin has been claimed to be the most effective agent for osteosarcoma, however, the outcome of adriamycin chemotherapy remains unsatisfactory. Here, we reported a potent combination therapy that bortezomib, a proteasome inhibitor, enhances adriamycin-induced apoptosis to eliminate osteosarcoma cells and we revealed that the activation of p-eIF2α/ATF4/CHOP axis is the underlying associated mechanisms...
May 19, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28522750/inhibition-of-mitochondrial-matrix-chaperones-and-anti-apoptotic-bcl-2-family-proteins-empower-antitumor-therapeutic-responses
#8
Georg Karpel-Massler, Chiaki Tsuge Ishida, Elena Bianchetti, Chang Shu, Rolando Perez-Lorenzo, Basil Horst, Matei Banu, Kevin A Roth, Jeffrey N Bruce, Peter Canoll, Dario C Altieri, Markus D Siegelin
Rational therapeutic approaches based on synthetic lethality may improve cancer management. Based on a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and Obatoclax) or selective (ABT199, WEHI-539 and A1210477), along with the established mitochondrial matrix chaperone inhibitor Gamitrinib-TPP...
May 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28522602/can-microsatellite-status-of-colorectal-cancer-be-reliably-assessed-after-neoadjuvant-therapy
#9
Jennifer B Goldstein, William Wu, Ester Borras, Gita Masand, Amanda Cuddy, Maureen E Mork, Sarah Bannon, Patrick M Lynch, Miguel Rodriguez-Bigas, Melissa Taggart, Ji Wu, Paul Scheet, Scott Kopetz, Y Nancy You, Eduardo Vilar
Purpose: Determination of microsatellite instability (MSI) by PCR is the gold standard; however, immunohistochemistry (IHC) of mismatch repair (MMR) proteins is frequently performed instead. The reliability of these methods on post-neoadjuvant-therapy specimens is unknown.  We examined the effect of neoadjuvant therapy on MSI results by PCR and IHC. Experimental design: A total of 239 colorectal cancers resected after neoadjuvant therapy were assessed for MSI with PCR and IHC. PCR and IHC results for matched paired pre- and post-treatment specimens were compared...
May 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28522592/sensitization-of-egfr-wild-type-non-small-cell-lung-cancer-cells-to-egfr-tyrosine-kinase-inhibitor-erlotinib
#10
Judith Raimbourg, Marie-Pierre Joalland, Mathilde Cabart, Ludmilla de Plater, Fanny Bouquet, Ariel Savina, Didier Decaudin, Jaafar Bennouna, François M Vallette, Lisenn Lalier
The benefit of EGFR-TKI in non-small cell lung cancer has been demonstrated in mutant EGFR tumors as first-line treatment but the benefit in wild-type EGFR tumors is marginal as well as restricted to maintenance therapy in pretreated patients. This work aimed at questioning the effects of cisplatin initial treatment on the EGFR pathway in non-small cell lung cancer and the functional consequences in vitro and in in vivo animal models of Patient-Derived Xenografts (PDX). We establish here that cisplatin pretreatment specifically sensitizes wild-type EGFR expressing cells to erlotinib, contrary to what happens in mutant-EGFR cells and with a blocking EGFR antibody, both in vitro and in vivo The sensitization entails the activation of the kinase Src upstream of EGFR, thereafter transactivating EGFR through a ligand-independent activation...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28522590/notch-inhibitor-pf-03084014-inhibits-hepatocellular-carcinoma-growth-and-metastasis-via-suppression-of-cancer-stemness-due-to-reduced-activation-of-notch1-stat3
#11
Chuan Xing Wu, Aimin Xu, Cathy C Zhang, Peter Olson, Lin Chen, Terence K Lee, Tan To Cheung, Chung Mau Lo, Xiao Qi Wang
Aberrant activation of the Notch signaling pathway is implicated in many solid tumors, including hepatocellular carcinoma (HCC), indicating a potential use of Notch inhibitors for treatment. In this study, we investigated the antitumor and antimetastasis efficacy of the novel Notch inhibitor (γ-secretase inhibitor) PF-03084014 in HCC. HCC spherical cells (stem-like cancer cells), a sphere-derived orthotopic tumor model and one patient-derived xenograft (PDX) model were used in our experiment. We demonstrated that PF-03084014 inhibited the self-renewal and proliferation of cancer stem cells...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28522584/cooperative-targets-of-combined-mtor-hdac-inhibition-promote-myc-degradation
#12
John K Simmons, Aleksandra M Michalowski, Benjamin J Gamache, Wendy DuBois, Jyoti Patel, Ke Zhang, Joy Gary, Shuling Zhang, Snehal Gaikwad, Daniel Connors, Nicholas Watson, Elena Leon, Jin-Qiu Chen, W Michael Kuehl, Maxwell P Lee, Adriana Zingone, Ola Landgren, Peter Ordentlich, Jing Huang, Beverly A Mock
Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI<1) when treated with this drug combination compared to single agents.  In addition, a breast cancer patient-derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared to single agents...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28518151/disulfiram-copper-selectively-eradicates-aml-leukemia-stem-cells-in-vitro-and-in-vivo-by-simultaneous-induction-of-ros-jnk-and-inhibition-of-nf-%C3%AE%C2%BAb-and-nrf2
#13
Bing Xu, Shiyun Wang, Rongwei Li, Kai Chen, Lingli He, Manman Deng, Vinodh Kannappan, Jie Zha, Huijuan Dong, Weiguang Wang
Acute myeloid leukemia (AML) is a heterogeneous malignancy. Despite the advances in past decades, the clinical outcomes of AML patients remain poor. Leukemia stem cells (LSCs) is the major cause of the recurrence of AML even after aggressive treatment making, promoting development of LSC-targeted agents is an urgent clinical need. Although the antitumor activity of disulfiram (DS), an approved anti-alcoholism drug, has been demonstrated in multiple types of tumors including hematological malignancies such as AML, it remains unknown whether this agent would also be able to target cancer stem cells like LSCs...
May 18, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28518123/expression-of-exogenous-cytokine-in-patient-derived-xenografts-via-injection-with-a-cytokine-transduced-stromal-cell-line
#14
Jacqueline S Coats, Ineavely Baez, Cornelia Stoian, Terry-Ann M Milford, Xiaobing Zhang, Olivia L Francis, Ruijun Su, Kimberly J Payne
Patient-derived xenograft (PDX) mice are produced by transplanting human cells into immune deficient mice. These models are an important tool for studying the mechanisms of normal and malignant hematopoiesis and are the gold standard for identifying effective chemotherapies for many malignancies. PDX models are possible because many of the mouse cytokines also act on human cells. However, this is not the case for all cytokines, including many that are critical for studying normal and malignant hematopoiesis in human cells...
May 10, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28515148/nemo-a-transcriptional-target-of-estrogen-and-progesterone-is-linked-to-tumor-suppressor-pml-in-breast-cancer
#15
Kelli E Valdez, Hanan S Elsarraj, Yan Hong, Sandra L Grimm, Lawrence R Ricci, Fang Fan, Ossama Tawfik, Lisa May, Therese Cusick, Marc Inciardi, Mark Redick, Jason Gatewood, Onalisa Winblad, Susan G Hilsenbeck, Dean P Edwards, Christy Hagan, Andrew K Godwin, Carol J Fabian, Fariba Behbod
The beneficial versus detrimental roles of estrogen plus progesterone (E+P) in breast cancer remains controversial. Here we report a beneficial mechanism of E+P treatment in breast cancer cells driven by transcriptional upregulation of the NFκB modulator NEMO, which in turn promotes expression of the tumor suppressor protein PML. E+P treatment of patient-derived epithelial cells derived from ductal carcinoma in situ (DCIS) increased secretion of the pro-inflammatory cytokine IL-6. Mechanistic investigations indicated that IL-6 upregulation occurred as a result of transcriptional upregulation of NEMO, the gene for which harbored estrogen receptor (ER) binding sites within its promoter...
May 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28513420/optimization-of-glioblastoma-mouse-orthotopic-xenograft-models-for-translational-research
#16
Susan M Irtenkauf, Susan Sobiechowski, Laura A Hasselbach, Kevin K Nelson, Andrea D Transou, Enoch T Carlton, Tom Mikkelsen, Ana C deCarvalho
Glioblastoma is an aggressive primary brain tumor predominantly localized to the cerebral cortex. We developed a panelofpatient-derived mouse orthotopic xenografts (PDOX) for preclinical drug studies by implanting cancer stem cells (CSC) cultured from fresh surgical specimens intracranially into 8-wk-old female athymic nude mice. Here we optimize the glioblastoma PDOX model by assessing the effect of implantation location on tumor growth, survival, and histologic characteristics. To trace the distribution of intracranial injections, toluidine blue dye was injected at 4 locations with defined mediolateral, anterioposterior, and dorsoventral coordinates within the cerebral cortex...
May 16, 2017: Comparative Medicine
https://www.readbyqxmd.com/read/28512172/in-vivo-hemin-conditioning-targets-the-vascular-and-immunological-compartments-and-restrains-prostate-tumor-development
#17
Felipe M Jaworski, Lucas Gentilini, Geraldine Gueron, Roberto P Meiss, Emiliano G Ortiz, Paula M Berguer, Asif Ahmed, Nora M Navone, Gabriel A Rabinovich, Daniel Compagno, Diego J Laderach, Elba S Vazquez
Purpose: Conditioning strategies constitute a relatively unexplored and exciting opportunity to shape tumor fate by targeting the tumor microenvironment. In this study we assessed how hemin, a pharmacological inducer of Heme Oxygenase-1 (HO-1), impacts upon prostate cancer (PCa) development in an in vivo conditioning model. <p>Experimental Design: The stroma of C57BL/6 mice was conditioned by subcutaneous administration of hemin prior to TRAMP-C1 tumor challenge. Complementary in vitro and in vivo assays were performed to evaluate hemin effect on both angiogenesis and the immune response...
May 16, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28505327/histone-deacetylase-inhibitor-saha-is-a-novel-promising-treatment-for-cushing-s-disease
#18
Jie Lu, Grégoire P Chatain, Alejandro Bugarini, Xiang Wang, Dragan Maric, Stuart Walbridge, Zhengping Zhuang, Prashant Chittiboina
Context: Remission failure following transsphenoidal surgery in Cushing's disease (CD) from pituitary corticotroph tumors (CtT) remains clinically challenging. Histone deacetylase (HDAC) inhibitors are antitumor drugs approved for oral clinical use, with potential to affect adrenocorticotropin (ACTH) hypersecretion by inhibiting proopiomelanocortin (POMC) transcription. Objective: Testing efficacy of suberolyl hydroxamic acid (SAHA) on human and murine ACTH-secreting tumor cells...
May 12, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28501555/antitumor-effect-of-azd4547-in-a-fibroblast-growth-factor-receptor-2-amplified-gastric-cancer-patient-derived-cell-model
#19
Jiryeon Jang, Hee Kyung Kim, Heejin Bang, Seung Tae Kim, Sun Young Kim, Se Hoon Park, Ho Yeong Lim, Won Ki Kang, Jeeyun Lee, Kyoung-Mee Kim
BACKGROUND: FGFR2 amplification is associated with aggressive gastric cancer (GC), and targeted drugs have been developed for treatment of GC. We evaluated the antitumor activity of an FGFR inhibitor in FGFR2-amplified GC patients with peritoneal carcinomatosis. METHODS: Two GC patients with FGFR2 amplification confirmed by fluorescence in situ hybridization showed peritoneal seeding and malignant ascites. We used the patient-derived xenograft model; patient-derived cells (PDCs) from malignant ascites were used to assess FGFR2 expression and its downstream pathway using immunofluorescence analysis and immunoblot assay in vitro...
May 10, 2017: Translational Oncology
https://www.readbyqxmd.com/read/28499452/current-status-and-perspectives-of-patient-derived-xenograft-models-in-cancer-research
#20
REVIEW
Yunxin Lai, Xinru Wei, Shouheng Lin, Le Qin, Lin Cheng, Peng Li
Cancers remain a major public health problem worldwide, which still require profound research in both the basic and preclinical fields. Patient-derived xenograft (PDX) models are created when cancerous cells or tissues from patients' primary tumors are implanted into immunodeficient mice to simulate human tumor biology in vivo, which have been extensively used in cancer research. The routes of implantation appeared to affect the outcome of PDX research, and there has been increasing applications of patient-derived orthotopic xenograft (PDOX) models...
May 12, 2017: Journal of Hematology & Oncology
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