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https://www.readbyqxmd.com/read/28087106/charge-variant-analysis-of-proposed-biosimilar-to-trastuzumab
#1
Pravinkumar Dakshinamurthy, Pavithra Mukunda, Bhargav Prasad Kodaganti, Bharath Ravindra Shenoy, Bairavabalakumar Natarajan, Amol Maliwalave, Vivek Halan, Sathyabalan Murugesan, Sunit Maity
Trastuzumab is a humanized monoclonal antibody (mAb) employed for the treatment of HER2 Positive Breast Cancer. A HER2 overexpressing tumor cell binds to Trastuzumab and attracts immune cells which lead to induction of Antibody Dependent Cellular Cytotoxicity (ADCC) by binding to Fc receptors (CD16a or FcγRIIIa) on an effector cell, such as natural killer (NK) cells. The most commonly expressed receptor on NK cell is CD16a which binds to the Fc portion of Trastuzumab. The ligand-independent HER2-HER3 dimerization is the most potent stimulator of downstream pathways for regulation of cell growth and survival...
January 10, 2017: Biologicals: Journal of the International Association of Biological Standardization
https://www.readbyqxmd.com/read/28078108/egfr-family-and-cmet-expression-profiles-and-prognostic-significance-in-esophagogastric-adenocarcinoma
#2
Ellie Chan, Ahmad Alkhasawneh, Lizette Vila Duckworth, Tabish Aijaz, Tania Zuluaga Toro, Xiaomin Lu, Steven J Hughes, Amy Collinsworth, Thomas J George
BACKGROUND: Targeted therapy with anti-human epidermal growth factor receptor-2 (HER2) monoclonal antibody in patients with HER2 overexpressed esophagogastric adenocarcinoma (EGA) improves survival; however, the effect is transient due to the development of resistance. Some studies suggest that cMet overexpression provides cross talk for epidermal growth factor receptor (EGFR) and HER2 inhibition. We sought to characterize the expression profile of the EGFR family and cMet receptors in untreated, resected EGA...
December 2016: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/28057664/incidence-and-management-of-diarrhea-in-patients-with-her2-positive-breast-cancer-treated-with-pertuzumab
#3
S M Swain, A Schneeweiss, L Gianni, J J Gao, A Stein, M Waldron-Lynch, S Heeson, M S Beattie, B Yoo, J Cortes, J Baselga
BACKGROUND: Pertuzumab disrupts heterodimerization between human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), HER3, and HER4. Thus, pertuzumab could result in adverse events similar to those observed with EGFR antagonists, such as diarrhea. We report the incidence and severity of diarrhea observed with pertuzumab in the CLEOPATRA, NeoSphere, and TRYPHAENA studies. PATIENTS AND METHODS: Patients (n=1443) had metastatic (CLEOPATRA [n=804]) or early-stage breast cancer (NeoSphere [n=416] and TRYPHAENA [n=223])...
January 5, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28049763/the-receptor-tyrosine-kinase-axl-mediates-nuclear-translocation-of-the-epidermal-growth-factor-receptor
#4
Toni M Brand, Mari Iida, Kelsey L Corrigan, Cara M Braverman, John P Coan, Bailey G Flanigan, Andrew P Stein, Ravi Salgia, Jana Rolff, Randall J Kimple, Deric L Wheeler
The epidermal growth factor receptor (EGFR) is a therapeutic target in patients with various cancers. Unfortunately, resistance to EGFR-targeted therapeutics is common. Previous studies identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab, and the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. Thus, we hypothesized that AXL mediated the nuclear translocation of EGFR in the setting of cetuximab resistance...
January 3, 2017: Science Signaling
https://www.readbyqxmd.com/read/28036286/her3-and-linc00052-interplay-promotes-tumor-growth-in-breast-cancer
#5
Ahmad Salameh, Xuejun Fan, Byung-Kwon Choi, Shu Zhang, Ningyan Zhang, Zhiqiang An
Here we report that the lncRNA LINC00052 expression correlates positively with HER3/ErbB3 levels in breast cancer cells. Gene silencing of LINC00052 diminished both LINC00052 and HER3 expression and reduced cancer cell growth in vitro and in vivo. LINC00052 overexpression promoted cancer cell growth in vitro and in vivo and increased HER3-mediated downstream signaling. Importantly, neutralization of HER3 signaling with HER3 targeting monoclonal antibodies blocked LINC00052 mediated cancer cell proliferation in vitro and tumor growth in vivo, suggesting LINC00052 promoting cancer growth through HER3 signaling...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/28032592/feedback-activation-of-her3-attenuates-response-to-egfr-inhibitors-in-colon-cancer-cells
#6
Albert Bosch-Vilaró, Bart Jacobs, Valentina Pomella, Layka Abbasi Asbagh, Richard Kirkland, Joe Michel, Sharat Singh, Xinjun Liu, Phillip Kim, Gregory Weitsman, Paul R Barber, Borivoj Vojnovic, Tony Ng, Sabine Tejpar
The EGFR inhibitor cetuximab is approved for the treatment of colorectal cancer. However, both innate and acquired resistance mechanisms, including compensatory feedback loops, limit its efficacy. Nevertheless, the emergence of these feedback loops has remained largely unexplored to date. Here, we showed feedback upregulation of HER3 and induction of HER3 phosphorylation after cetuximab treatment in colon cancer cells. We also showed that this upregulation occurs, at least partly, through AKT inhibition. Together with this, we observed increased HER2:HER3 dimerization upon cetuximab treatment...
December 9, 2016: Oncotarget
https://www.readbyqxmd.com/read/28031425/phase-ib-study-of-safety-and-pharmacokinetics-of-the-pi3k-inhibitor-sar245408-with-the-her3-neutralizing-human-antibody-sar256212-in-patients-with-solid-tumors
#7
Vandana G Abramson, Jeffrey G Supko, Tarah Ballinger, James M Cleary, John F Hilton, Sara Tolaney, Nicole G Chau, Daniel C Cho, Joanne J Lager, Joseph Pearlberg, Geoffrey I Shapiro, Carlos L Arteaga
PURPOSE: This phase Ib study was designed to determine the maximum tolerated dose, safety, preliminary efficacy, and pharmacokinetics of the HER3 (ErbB3) monoclonal antibody SAR256212 in combination with the oral phosphoinositide 3-kinase (PI3K) inhibitor SAR245408 for patients with metastatic or locally advanced solid tumors. EXPERIMENTAL DESIGN: Patients received the combination of intravenous SAR256212 and oral SAR245408 in a 3+3 dose escalation design until occurrence of disease progression or dose-limiting toxicity...
December 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28000159/her3-as-a-therapeutic-target-in-cancer
#8
REVIEW
Niki Karachaliou, Chiara Lazzari, Alberto Verlicchi, Aaron E Sosa, Rafael Rosell
Targeting members of the human epidermal growth factor receptor family, especially EGFR and HER2, has been an established strategy for the treatment of tumors with abnormally activated receptors due to overexpression, mutation, ligand-dependent receptor dimerization and ligand-independent activation. Less attention has been paid to the oncogenic activity of HER3, although there is growing evidence that it mediates resistance to EGFR and HER2 pathway directed therapies. The main caveat for the development of effective HER3 targeted therapies is the absence of a strong enzymatic activity to target, as well as the limited potential for single-agent activity...
December 20, 2016: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://www.readbyqxmd.com/read/27986750/human-papillomavirus-regulates-her3-expression-in-head-and-neck-cancer-implications-for-targeted-her3-therapy-in-hpv-patients
#9
Toni M Brand, Stefan Hartmann, Neil E Bhola, Noah D Peyser, Hua Li, Yan Zeng, Erin Isaacson Wechsler, Max V Ranall, Sourav Bandyopadhyay, Umamaheswar Duvvuri, Theresa M LaVallee, Richard C K Jordan, Daniel E Johnson, Jennifer R Grandis
PURPOSE: Human papillomavirus (HPV) 16 plays an etiologic role in a growing subset of HNSCCs, where viral expression of the E6 and E7 oncoproteins are necessary for tumor growth and maintenance. Although patients with HPV(+) tumors have a more favorable prognosis, there are currently no HPV-selective therapies. Recent studies identified differential receptor tyrosine kinase (RTK) profiles in HPV(+) vs. HPV(-) tumors. One such RTK, HER3, is overexpressed and interacts with phosphoinositide 3-kinase (PI3K) in HPV(+) tumors...
December 16, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27981460/her2-her3-pathway-in-biliary-tract-malignancies-systematic-review-and-meta-analysis-a-potential-therapeutic-target
#10
Salvatore Galdy, Angela Lamarca, Mairéad G McNamara, Richard A Hubner, Chiara A Cella, Nicola Fazio, Juan W Valle
Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs). An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs...
December 15, 2016: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/27942917/ljm716-in-japanese-patients-with-head-and-neck-squamous-cell-carcinoma-or-her2-overexpressing-breast-or-gastric-cancer
#11
Shunji Takahashi, Takayuki Kobayashi, Junichi Tomomatsu, Yoshinori Ito, Hisanobu Oda, Tatsuhiro Kajitani, Tomoyuki Kakizume, Takeshi Tajima, Hiromi Takeuchi, Heiko Maacke, Taito Esaki
PURPOSE: Human epidermal growth factor receptor 3 (HER3) has been identified as an important component of many receptor tyrosine kinase-driven cancers. LJM716 is a human IgG monoclonal antibody that binds HER3, trapping it in an inactive conformation. In this study, a phase I dose escalation was performed with a primary objective to establish the maximum tolerated dose and/or the recommended dose of LJM716 in Japanese patients with selected advanced solid tumors. Secondary objectives included the evaluation of the safety and tolerability, preliminary antitumor activity, and pharmacokinetics of LJM716 in Japanese patients...
December 9, 2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27941874/hrg-her2-her3-signaling-promotes-ahr-mediated-memo-1-expression-and-migration-in-colorectal-cancer
#12
V Bogoevska, G Wolters-Eisfeld, B T Hofmann, A T El Gammal, B Mercanoglu, F Gebauer, Y K Vashist, D Bogoevski, D Perez, N Gagliani, J R Izbicki, M Bockhorn, C Güngör
Colorectal cancer (CRC) is a complex disease with still unsatisfactory prognosis even in western societies, although substantial progress has been made in pre-screening programs, surgical techniques and targeted therapy options. Mediator of motility-1 (Memo-1) was previously recognized as an important effector of cell migration downstream of receptor tyrosine kinase signaling in breast cancer. This study identified Memo-1 as frequently overexpressed in CRC and established a close link between extracellular HER2 activation, AhR/ARNT transcriptional activity and Memo-1 expression...
December 12, 2016: Oncogene
https://www.readbyqxmd.com/read/27930489/screening-and-preliminary-verification-of-a-phage-display-single-chain-antibody-library-against-coal-workers-pneumoconiosis
#13
Guang-Hui Zhang, Li Li, Changfu Hao, Jing-Chao Ren, Hongyi Zhang, Jie Jiao, Liyun Gao, Shibin Ding, Sanqiao Yao, Wu Yao, Weidong Wu
OBJECTIVES: To construct a phage display human antibody library (PDHAL) against pneumoconiosis for the diagnosis and treatment of coal worker pneumoconiosis (CWP). METHODS: The PDHAL was established via CWP blood and six positive antibodies were discovered. 867 coal workers (558 CWP and 309 without CWP) and 393 controls were recruited to validate the results. RESULTS: A PDHAL against CWP was established, from which six strong positive clones were selected, sequenced and identified as VEGF, interleukin-18, HSP70, HER3, Gz-B and RF...
December 2016: Journal of Occupational and Environmental Medicine
https://www.readbyqxmd.com/read/27913862/prognostic-impact-of-her3-based-on-protein-and-mrna-expression-in-high-grade-serous-ovarian-carcinoma
#14
Ulrike Unger, Carsten Denkert, Ioana Braicu, Jalid Sehouli, Manfred Dietel, Sibylle Loibl, Silvia Darb-Esfahani
HER3 is a member of the epidermal growth factor family and was predominantly described as a negative prognostic factor in various solid tumors as well as in ovarian cancer. In this study, we investigated HER3 on protein and mRNA expression in histologically defined subtypes of ovarian cancer looking for an influence on patient's survival. Altogether, we examined HER3 in ovarian high-grade serous (HGSC, n = 320), low-grade serous (LGSC, n = 55), endometrioid (EC, n = 33), and clear cell (CCC, n = 48) carcinomas using immunohistochemistry (IHC) and quantitative real-time reverse transcription PCR (qRT-PCR)...
December 2, 2016: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/27903463/her2-transmembrane-domain-tmd-mutations-v659-g660-that-stabilize-homo-and-heterodimerization-are-rare-oncogenic-drivers-in-lung-adenocarcinoma-that-respond-to-afatinib
#15
Sai-Hong Ignatius Ou, Alexa B Schrock, Eduard V Bocharov, Samuel J Klempner, Carolina Kawamura Haddad, Gary Steinecker, Melissa Johnson, Barbara J Gitlitz, Jon Chung, Paulo V Campregher, Jeffrey S Ross, Philip J Stephens, Vincent A Miller, James H Suh, Siraj M Ali, Vamsidhar Velcheti
INTRODUCTION: Erb-b2 receptor tyrosine kinase (HER2) transmembrane domain (TMD) mutations (HER2(V659E), HER2(G660D)) have previously been identified in lung adenocarcinomas, but their frequency and clinical significance is unknown. METHODS: We prospectively analyzed 8551 consecutive lung adenocarcinomas using hybrid capture-based comprehensive genomic profiling (CGP) at the request of the individual treating physicians for the purpose of making therapy decisions...
November 27, 2016: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/27893711/the-induction-of-mig6-under-hypoxic-conditions-is-critical-for-dormancy-in-primary-cultured-lung-cancer-cells-with-activating-egfr-mutations
#16
H Endo, J Okami, H Okuyama, Y Nishizawa, F Imamura, M Inoue
The biologic activity of individual cancer cells is highly heterogeneous. Hypoxia, one of the prominent features of a tumor microenvironment, is thought to be causal in generating this cellular heterogeneity. In this study, we revealed that primary lung cancer cells harboring activating epidermal growth factor receptor (EGFR) mutations generally entered a dormant state when hypoxic. We found that heterodimer formation of the ERBB family receptor tyrosine kinases (RTKs), and their subsequent downstream signaling, was diminished under hypoxic conditions, although phosphorylation of the EGFR was retained...
November 28, 2016: Oncogene
https://www.readbyqxmd.com/read/27887869/a-highly-diverse-and-functional-na%C3%A3-ve-ubiquitin-variant-library-for-generation-of-intracellular-affinity-reagents
#17
Isabel Leung, Nick Jarvik, Sachdev S Sidhu
We report the design, construction, and validation of a highly diverse phage-displayed naïve ubiquitin variant (Ubv) library. We first conducted a mutation tolerance scan of 27 residues and confirmed that 24 of these could be substituted by chemically diverse amino acids without compromising the display of Ubvs on phage. Subsequently, we constructed a library containing 6.8×10(10) unique members, in which these 24 positions were diversified with a degenerate codon that encodes for 6 aa that are prevalent in protein interaction sites...
January 6, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27872189/biophysical-evidence-for-intrinsic-disorder-in-the-c-terminal-tails-of-the-epidermal-growth-factor-receptor-egfr-and-her3-receptor-tyrosine-kinases
#18
Theodore R Keppel, Kwabena Sarpong, Elisa M Murray, John Monsey, Jian Zhu, Ron Bose
The epidermal growth factor receptor (EGFR)/ErbB family of receptor tyrosine kinases includes oncogenes important in the progression of breast and other cancers, and they are targets for many drug development strategies. Each member of the ErbB family possesses a unique, structurally uncharacterized C-terminal tail that plays an important role in autophosphorylation and signal propagation. To determine whether these C-terminal tails are intrinsically disordered regions, we conducted a battery of biophysical experiments on the EGFR and HER3 tails...
January 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27871278/the-prognostic-significance-of-human-epidermal-growth-factor-receptor-family-protein-expression-in-operable-pancreatic-cancer-her1-4-protein-expression-and-prognosis-in-pancreatic-cancer
#19
Qin Li, Lei Zhang, XiuHong Li, Han Yan, Liuting Yang, Yingying Li, Teng Li, Jing Wang, Bangwei Cao
BACKGROUND: Prognostic factors aid in the stratification and treatment of cancer. This study evaluated the prognostic significance of human epidermal growth factor receptor (HER) family members (HER1-4) expression in patients with operable pancreatic cancer. METHODS: The expression of individual HER proteins in patient tissue specimens was detected by immunohistochemistry staining. Patient follow-up time was between 1.0 and 78.1 months. RESULTS: Positive expression of HER1, HER2, HER3 and HER4 was detected in 41...
November 21, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27853996/a-phase-1-study-combining-the-her3-antibody-seribantumab-mm-121-and-cetuximab-with-and-without-irinotecan
#20
James M Cleary, Autumn J McRee, Geoffrey I Shapiro, Sara M Tolaney, Bert H O'Neil, Jeffrey D Kearns, Sara Mathews, Rachel Nering, Gavin MacBeath, Akos Czibere, Sunil Sharma, W Michael Korn
Background HER3/EGFR heterodimers have been implicated as a mode of resistance to EGFR-directed therapies. Methods This Phase 1 trial assessed the tolerability, maximum tolerated dose (MTD) and pharmacokinetic (PK) properties of the HER-3 antibody seribantumab in combination with cetuximab (Part I) or cetuximab and irinotecan (Part II) in patients with EGFR-dependent cancers. In Part I, escalating doses of seribantumab and cetuximab were administered. In Part II of the trial, escalating doses of seribantumab/cetuximab were combined with irinotecan 180 mg/m2 administered every two weeks...
November 16, 2016: Investigational New Drugs
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