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Patient derived xenograft PDX

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https://www.readbyqxmd.com/read/28526733/discovery-and-optimization-of-hkt288-a-cadherin-6-targeting-adc-for-the-treatment-of-ovarian-and-renal-cancer
#1
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/28524233/bortezomib-sensitizes-human-osteosarcoma-cells-to-adriamycin-induced-apoptosis-through-ros-dependent-activation-of-p-eif2%C3%AE-atf4-chop-axis
#2
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
#3
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
#4
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
#5
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
#6
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/28518123/expression-of-exogenous-cytokine-in-patient-derived-xenografts-via-injection-with-a-cytokine-transduced-stromal-cell-line
#7
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/28499452/current-status-and-perspectives-of-patient-derived-xenograft-models-in-cancer-research
#8
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
https://www.readbyqxmd.com/read/28496009/dynamic-changes-in-clonal-cytogenetic-architecture-during-progression-of-chronic-lymphocytic-leukemia-in-patients-and-patient-derived-murine-xenografts
#9
Nicholas J Davies, Marwan Kwok, Clive Gould, Ceri E Oldreive, Jingwen Mao, Helen Parry, Edward Smith, Angelo Agathanggelou, Guy Pratt, Alexander Malcolm R Taylor, Paul Moss, Mike Griffiths, Tatjana Stankovic
Subclonal heterogeneity and clonal selection influences disease progression in chronic lymphocytic leukemia (CLL). It is therefore important that therapeutic decisions are made based on an understanding of the CLL clonal architecture and its dynamics in individual patients. Identification of cytogenetic abnormalities by FISH remains the cornerstone of contemporary clinical practice and provides a simple means for prognostic stratification. Here, we demonstrate that multiplexed-FISH can enhance recognition of CLL subclonal repertoire and its dynamics during disease progression, both in patients and CLL patient-derived xenografts (PDX)...
April 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/28482026/pre-clinical-drug-screen-reveals-topotecan-actinomycin-d-and-volasertib-as-potential-new-therapeutic-candidates-for-etmr-brain-tumor-patients
#10
Christin Schmidt, Nil A Schubert, Sebastian Brabetz, Norman Mack, Benjamin Schwalm, Jennifer A Chan, Florian Selt, Christel Herold-Mende, Olaf Witt, Till Milde, Stefan M Pfister, Andrey Korshunov, Marcel Kool
Background: Embryonal tumor with multilayered rosettes (ETMR) is a rare and aggressive embryonal brain tumor that solely occurs in infants and young children and has only recently been recognized as a separate brain tumor entity in the WHO classification for CNS tumors. Patients have a very dismal prognosis with a median survival of 12 months upon diagnosis despite aggressive treatment. The aim of this study was to develop novel treatment regimens in a pre-clinical drug screen in order to inform potentially more active clinical trial protocols...
May 8, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28473534/elacestrant-rad1901-a-selective-estrogen-receptor-degrader-serd-has-anti-tumor-activity-in-multiple-er-breast-cancer-patient-derived-xenograft-models
#11
Teeru Bihani, Hitisha K Patel, Heike Arlt, Nianjun Tao, Hai Jiang, Jeff Brown, Dinesh M Purandare, Gary Hattersley, Fiona Garner
PURPOSE: Estrogen receptor-positive (ER+) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of anti-estrogen therapy. Selective estrogen receptor degraders (SERDs) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER+ breast cancer...
May 4, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28472820/clinical-value-of-r-spondins-in-triple-negative-and-metaplastic-breast-cancers
#12
F Coussy, F Lallemand, S Vacher, A Schnitzler, W Chemlali, M Caly, A Nicolas, S Richon, D Meseure, R El Botty, L De-Plater, L Fuhrmann, T Dubois, S Roman-Roman, V Dangles-Marie, E Marangoni, I Bièche
BACKGROUND: RSPO ligands, activators of the Wnt/β-catenin pathway, are overexpressed in different cancers. The objective of this study was to investigate the role of RSPOs in breast cancer (BC). METHODS: Expression of RSPO and markers of various cancer pathways were measured in breast tumours and cell lines by qRT-PCR. The effect of RSPO on the Wnt/β-catenin pathway activity was determined by luciferase assay, western blotting, and qRT-PCR. The effect of RSPO2 inhibition on proliferation was determined by using RSPO2 siRNAs...
May 4, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28468778/modeling-of-patient-derived-xenografts-in-colorectal-cancer
#13
Anastasia Katsiampoura, Kanwal Raghav, Zhi-Qin Jiang, David G Menter, Andreas Varkaris, Maria P Morelli, Shanequa Manuel, Ji Wu, Alexey V Sorokin, Bahar Salimian Rizi, Cristopher Bristow, Feng Tian, Susan Airhart, Mingshan Cheng, Bradley M Broom, Jeffrey Morris, Michael J Overman, Garth Powis, Scott Kopetz
Developing realistic preclinical models using clinical samples that mirror complex tumor biology and behavior are vital to advancing cancer research. While cell-line cultures have been helpful in generating preclinical data, the genetic divergence between these and corresponding primary tumors has limited clinical translation. Conversely, patient derived xenografts (PDXs) in colorectal cancer (CRC) are highly representative of the genetic and phenotypic heterogeneity in the original tumor. Coupled with high-throughput analyses and bioinformatics, these PDXs represent robust preclinical tools for biomarkers, therapeutic target and drug discovery...
May 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28465075/carbon-nanotube-capsules-enhance-the-in-vivo-efficacy-of-cisplatin
#14
Adem Guven, Gabriel J Villares, Susan G Hilsenbeck, Alaina Lewis, John D Landua, Lacey E Dobrolecki, Lon J Wilson, Michael T Lewis
Over the past few years, numerous nanotechnology-based drug delivery systems have been developed in an effort to maximize therapeutic effectiveness of conventional drug delivery, while limiting undesirable side effects. Among these, carbon nanotubes (CNTs) are of special interest as potential drug delivery agents due to their numerous unique and advantageous physical and chemical properties. Here, we show in vivo favorable biodistribution and enhanced therapeutic efficacy of cisplatin (CDDP) encapsulated within ultra-short single-walled carbon nanotube capsules (CDDP@US-tubes) using three different human breast cancer xenograft models...
April 29, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28461031/phase-2-trial-of-everolimus-and-letrozole-in-relapsed-estrogen-receptor-positive-high-grade-ovarian-cancers
#15
Gerardo Colon-Otero, S John Weroha, Nathan R Foster, Paul Haluska, Xiaonan Hou, Andrea E Wahner-Hendrickson, Aminah Jatoi, Matthew S Block, Tri A Dinh, Matthew W Robertson, John A Copland
OBJECTIVES: We report the results of a phase 2 clinical trial of the combination of everolimus and letrozole in patients with relapsed estrogen receptor-positive high-grade ovarian cancer. The trial's primary endpoint was the proportion of patients alive and progression-free after 12weeks of therapy with the combination of everolimus and letrozole. A 12-week PFS of 45% or greater was considered a positive result. The feasibility of generating patient-derived xenograft (PDX) models from biopsy specimens was also evaluated...
April 28, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28460430/metabolic-heterogeneity-signature-of-primary-treatment-na%C3%A3-ve-prostate-cancer
#16
Dong Lin, Susan L Ettinger, Sifeng Qu, Hui Xue, Noushin Nabavi, Stephen Yiu Chuen Choi, Robert H Bell, Fan Mo, Anne M Haegert, Peter W Gout, Neil Fleshner, Martin E Gleave, Michael Pollak, Colin C Collins, Yuzhuo Wang
To avoid over- or under-treatment of primary prostate tumours, there is a critical need for molecular signatures to discriminate indolent from aggressive, lethal disease. Reprogrammed energy metabolism is an important hallmark of cancer, and abnormal metabolic characteristics of cancers have been implicated as potential diagnostic/prognostic signatures. While genomic and transcriptomic heterogeneity of prostate cancer is well documented and associated with tumour progression, less is known about metabolic heterogeneity of the disease...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28460066/co-clinical-trials-demonstrate-predictive-biomarkers-for-dovitinib-an-fgfr-inhibitor-in-lung-squamous-cell-carcinoma
#17
H R Kim, H N Kang, H S Shim, E Y Kim, J Kim, D J Kim, J G Lee, C Y Lee, M H Hong, S-M Kim, H Kim, K-H Pyo, M R Yun, H J Park, J Y Han, H A Youn, M-J Ahn, S Paik, T-M Kim, B C Cho
Background: We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC). Methods: : The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling...
April 27, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28458286/development-of-new-adc-technology-with-topoisomerase-i-inhibitor
#18
Toshinori Agatsuma
 Antibody-drug conjugates (ADCs) selectively deliver large amounts of antitumor drugs to tumor tissue and show significant antitumor effects with a wide therapeutic window. We developed a new linker-drug technology platform with an exatecan derivative, which is a highly potent topoisomerase I inhibitor. The major advantages of the technology are: 1) high and homogeneous drug-to-antibody ratio (DAR) availability; 2) potent antitumor activity in conjunction with bystander killing; 3) few safety concerns because of the stable linker limiting release of free drug; and 4) a wide application to therapeutic antibodies...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/28451789/current-update-of-patient-derived-xenograft-model-for-translational-breast-cancer-research
#19
REVIEW
Tsutomu Kawaguchi, Barbara A Foster, Jessica Young, Kazuaki Takabe
Despite recent advances in the treatment of patients with breast cancer (BrCa), BrCa remains the third leading cause of cancer death for women in the US due to intrinsic or acquired resistance to therapy. Continued understanding of gene expression profiling and genomic sequencing has clarified underlying intratumoral molecular heterogeneity. Recently, the patient-derived xenograft (PDX) models have emerged as a novel tool to address the issues of BrCa genomics and tumor heterogeneity, and to critically transform translational BrCa research in the preclinical setting...
April 27, 2017: Journal of Mammary Gland Biology and Neoplasia
https://www.readbyqxmd.com/read/28450563/sstr-mediated-breast-cancer-imaging-is-there-a-role-for-radiolabeled-sstr-antagonists
#20
Simone U Dalm, Joost Haeck, Gabriela N Doeswijk, Erik de Blois, Marion de Jong, Carolien van Deurzen
INTRODUCTION: Recent studies showed enhanced tumor targeting by novel somatostatin receptor (SSTR) antagonists compared to clinically widely used agonists. However, these results have mostly been obtained in neuroendocrine tumors and only limited data is available for cancer types with lower SSTR expression, including breast cancer (BC). To date, only two studies reported higher binding of the antagonist versus the agonist in BC, but in both studies a limited number of cases were evaluated. In this pre-clinical study, we further investigated whether the application of a SSTR antagonist could improve SSTR-mediated BC imaging in a large panel of BC specimens...
April 27, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
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