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Chao Xu, Patanjali Ravva, Jun Steve Dang, Johann Laurent, Céline Adessi, Christine McIntyre, Georgina Meneses-Lorente, François Mercier
PURPOSE: To inform lumretuzumab and pertuzumab dose modifications in order to decrease the incidence, severity, and duration of the diarrhea events in metastatic breast cancer patients treated with a combination therapy of lumretuzumab (anti-HER3) in combination with pertuzumab (anti-HER2) and paclitaxel using quantitative clinical pharmacology modeling approaches. METHODS: The safety and pharmacokinetic (PK) data from three clinical trials (lumretuzumab monotherapy n = 47, pertuzumab monotherapy n = 78, and the combination therapy of lumretuzumab, pertuzumab and paclitaxel n = 35) were pooled together to develop a continuous-time discrete states Markov model describing the dynamics of the diarrhea events...
June 18, 2018: Cancer Chemotherapy and Pharmacology
Brooke N McKnight, Akhila N W Kuda-Wedagedara, Kuntal K Sevak, Dalya Abdel-Atti, Wendy N Wiesend, Anson Ku, Dakshnamurthy Selvakumar, Sean D Carlin, Jason S Lewis, Nerissa T Viola-Villegas
Tumor resistance to treatment paved the way toward the development of single agent drugs that target multiple molecular signatures amplified within the malignancy. The discovered crosstalk between EGFR and HER3 as well as the role of HER3 in mediating EGFR resistance made these two receptor tyrosine kinases attractive targets. MEHD7945A or duligotuzumab is a single immunotherapy agent that dually targets both molecular signatures. In this study, a positron emission tomography (PET) companion diagnostic to MEHD7945A is reported and evaluated in pancreatic cancer...
June 13, 2018: Scientific Reports
Genevieve C Kendall, Sarah Watson, Lin Xu, Collette A LaVigne, Whitney Murchison, Dinesh Rakheja, Stephen X Skapek, Franck Tirode, Olivier Delattre, James F Amatruda
Alveolar rhabdomyosarcoma is a pediatric soft-tissue sarcoma caused by PAX3/7-FOXO1 fusion oncogenes and is characterized by impaired skeletal muscle development. We developed human PAX3-FOXO1 -driven zebrafish models of tumorigenesis and found that PAX3-FOXO1 exhibits discrete cell lineage susceptibility and transformation. Tumors developed by 1.6-19 months and were primitive neuroectodermal tumors or rhabdomyosarcoma. We applied this PAX3-FOXO1 transgenic zebrafish model to study how PAX3-FOXO1 leverages early developmental pathways for oncogenesis and found that her3 is a unique target...
June 5, 2018: ELife
Ewa Izycka-Swieszewska, Ewa Bien, Joanna Stefanowicz, Edyta Szurowska, Ewa Szutowicz-Zielinska, Magdalena Koczkowska, Dawid Sigorski, Wojciech Kloc, Wojciech Rogowski, Elzbieta Adamkiewicz-Drozynska
This study presents a unique series of malignant supratentorial gliomas in children previously cured from non-CNS primary cancer. On neuroimaging these tumors were not specific, so the patients were suspected of cerebral recurrence of their primary neoplasm: leukemia in four children and sarcoma in one child. Histologically, the group contained four glioblastomas and one anaplastic astrocytoma. Three patients underwent neurosurgical resection, while the other two underwent stereotactic diagnostic biopsy only...
2018: BioMed Research International
Yunpeng Cai, Anna-Marie Makarova, Jesper Wengel, Kenneth A Howard
BACKGROUND: Antisense gapmer oligonucleotide drugs require delivery and biodistribution enabling technologies to increase the in vivo efficacy. An attractive approach is binding and consequent transport by the endogenous human serum albumin pool mediated by fatty acid incorporation into the gapmer design. METHODS: This work investigates the effect of palmitoyl modification and position on albumin-binding, cellular uptake and in vitro gene silencing of gapmers with either a phosphorothioate (PS) or phosphodiester (PO) backbone...
May 25, 2018: Journal of Gene Medicine
Brandon Leonard, Toni M Brand, Rachel A O'Keefe, Eliot Lee, Yan Zang, Jacquelyn D Kemmer, Hua Li, Jennifer R Grandis, Neil E Bhola
Cetuximab, the FDA-approved anti-EGFR antibody for head and neck squamous cell carcinoma (HNSCC), has displayed limited efficacy due to the emergence of intrinsic and acquired resistance. We and others have demonstrated that cetuximab resistance in HNSCC is driven by alternative receptor tyrosine kinases (RTK) including HER3, MET, and AXL. In an effort to overcome cetuximab resistance and circumvent toxicities associated with the administration of multiple RTK inhibitors, we sought to identify a common molecular target that regulates expression of multiple RTK...
May 23, 2018: Cancer Research
Mariana Brandão, Noam F Pondé, Francesca Poggio, Nuria Kotecki, Mauren Salis, Matteo Lambertini, Evandro de Azambuja
HER2-positive disease is an aggressive subtype of breast cancer that has been revolutionized by anti-HER2 directed therapies. Multiple drugs have been developed and are currently in clinical use, including trastuzumab, lapatinib, pertuzumab, T-DM1 and neratinib, alone or combined in "dual HER2-blockade" regimens. Areas covered: A comprehensive literature review was performed regarding the current state and the future of combination regimens containing anti-HER2 agents, focusing on their efficacy, toxicity and cost-effectiveness...
May 21, 2018: Expert Review of Anticancer Therapy
(no author information available yet)
Unbiased phenotypic combinatorial screening uncovers a bispecific antibody (bAb) targeting HER2 and HER3.
May 18, 2018: Cancer Discovery
Cecile A W Geuijen, Camilla De Nardis, David Maussang, Eric Rovers, Tristan Gallenne, Linda J A Hendriks, Therese Visser, Roy Nijhuis, Ton Logtenberg, John de Kruif, Piet Gros, Mark Throsby
HER2-driven cancers require phosphatidylinositide-3 kinase (PI3K)/Akt signaling through HER3 to promote tumor growth and survival. The therapeutic benefit of HER2-targeting agents, which depend on PI3K/Akt inhibition, can be overcome by hyperactivation of the heregulin (HRG)/HER3 pathway. Here we describe an unbiased phenotypic combinatorial screening approach to identify a bispecific immunoglobulin G1 (IgG1) antibody against HER2 and HER3. In tumor models resistant to HER2-targeting agents, the bispecific IgG1 potently inhibits the HRG/HER3 pathway and downstream PI3K/Akt signaling via a "dock & block" mechanism...
May 14, 2018: Cancer Cell
Ana Ruiz-Saenz, Courtney Dreyer, Marcia R Campbell, Veronica Steri, Nathaniel P Gulizia, Mark M Moasser
Current evidence suggests that HER2-driven tumorigenesis requires HER3. This is likely due to the unique ability of HER3 to activate PI3K/Akt pathway signaling, which is not directly accessible to HER2. By genetic elimination of HER3 or shRNA knockdown of HER3 in HER2-amplified cancer cells, we find residual HER2-driven activation of PI3K/Akt pathway signaling that is driven by HER2 through direct and indirect mechanisms. Indirect mechanisms involved second messenger pathways including Ras or Grb2. Direct binding of HER2 to PI3K occurred through p-Tyr1139, which has a weak affinity for PI3K but becomes significant at very high expression and phosphorylation...
May 14, 2018: Cancer Research
Aurelia H M de Vries Schultink, Robert P Doornbos, Alexander B H Bakker, Kees Bol, Mark Throsby, Cecile Geuijen, David Maussang, Jan H M Schellens, Jos H Beijnen, Alwin D R Huitema
Introduction MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors. Pharmacokinetics (PK) and pharmacodynamics (PD) of MCLA-128 have been evaluated in preclinical studies in cynomolgus monkeys and mice. The aim of this study was to characterize the PK and PD of MCLA-128 and to predict a safe starting dose and efficacious clinical dose for the First-In-Human study. Methods A PK-PD model was developed based on PK data from cynomolgus monkeys and tumor growth data from a mouse JIMT-1 xenograft model...
May 5, 2018: Investigational New Drugs
Jeroen Claus, Gargi Patel, Flavia Autore, Audrey Colomba, Gregory Weitsman, Tanya N Soliman, Selene Roberts, Laura C Zanetti-Domingues, Michael Hirsch, Francesca Collu, Roger George, Elena Ortiz-Zapater, Paul R Barber, Boris Vojnovic, Yosef Yarden, Marisa L Martin-Fernandez, Angus Cameron, Franca Fraternali, Tony Ng, Peter J Parker
While targeted therapy against HER2 is an effective first-line treatment in HER2+ breast cancer, acquired resistance remains a clinical challenge. The pseudokinase HER3, heterodimerisation partner of HER2, is widely implicated in the resistance to HER2-mediated therapy. Here, we show that lapatinib, an ATP-competitive inhibitor of HER2, is able to induce proliferation cooperatively with the HER3 ligand neuregulin. This counterintuitive synergy between inhibitor and growth factor depends on their ability to promote atypical HER2-HER3 heterodimerisation...
May 1, 2018: ELife
Shailima Rampogu, Minky Son, Ayoung Baek, Chanin Park, Rabia Mukthar Rana, Amir Zeb, Saravanan Parameswaran, Keun Woo Lee
Human epidermal growth factor receptors are implicated in several types of cancers characterized by aberrant signal transduction. This family comprises of EGFR (ErbB1), HER2 (ErbB2, HER2/neu), HER3 (ErbB3), and HER4 (ErbB4). Amongst them, HER2 is associated with breast cancer and is one of the most valuable targets in addressing the breast cancer incidences. For the current investigation, we have performed 3D-QSAR based pharmacophore search for the identification of potential inhibitors against the kinase domain of HER2 protein...
June 2018: Computational Biology and Chemistry
Ariana Centa, Ruth Rodríguez-Barrueco, Juan Carlos Montero, Atanasio Pandiella
The neuregulins (NRGs) represent a large family of membrane-anchored growth factors, whose deregulation may contribute to the pathogenesis of several tumors. In fact, targeting of NRG-activated pathways has demonstrated clinical benefit. To improve the efficacy of anti-NRG therapies, it is essential to gain insights into the regions of NRGs that favor their pro-oncogenic properties. Here, we have addressed the protumorigenic impact of different NRG domains. To do this, deletion mutants affecting different NRG domains were expressed in 293 and MCF7 cells...
April 23, 2018: Molecular Oncology
Jose M Piulats, Jumpei Kondo, Hiroko Endo, Hiromasa Ono, Takeshi Hagihara, Hiroaki Okuyama, Yasuko Nishizawa, Yasuhiko Tomita, Masayuki Ohue, Kouki Okita, Hidejiro Oyama, Hidemasa Bono, Takashi Masuko, Masahiro Inoue
Individual and small clusters of cancer cells may detach from the edges of a main tumor and invade vessels, which can act as the origin of metastasis; however, the mechanism for this phenomenon is not well understood. Using cancer tissue-originated spheroids, we studied whether disturbing the 3D architecture of cancer spheroids can provoke the reformation process and progression of malignancy. We developed a mechanical disruption method to achieve homogenous disruption of the spheroids while maintaining cell-cell contact...
March 23, 2018: Oncotarget
Yan Shan Ang, Jia'En Jasmine Li, Pei-Jou Chua, Cheng-Teng Ng, Boon-Huat Bay, Lin-Yue Lanry Yung
Cell surface receptors play an important role in mediating cell communication and are used as disease biomarkers and therapeutic targets. We present a one-pot molecular toolbox, which we term the split proximity circuit (SPC), for the autonomous detection and visualization of cell surface receptor clusters. Detection was powered by antibody recognition and a series of autonomous DNA hybridization to achieve localized, enzyme-free signal amplification. The system under study was the human epidermal growth factor receptor (HER) family, that is, HER2:HER2 homodimer and HER2:HER3 heterodimer, both in cell lysate and in situ on fixed whole cells...
May 15, 2018: Analytical Chemistry
Ines De Pauw, Filip Lardon, Jolien Van den Bossche, Hasan Baysal, Erik Fransen, Vanessa Deschoolmeester, Patrick Pauwels, Marc Peeters, Jan Baptist Vermorken, An Wouters
The epidermal growth factor receptor (EGFR, HER1) is a therapeutic target in head and neck squamous cell carcinoma (HNSCC). After initial promising results with EGFR-targeted therapies such as cetuximab, therapeutic resistance has become a major clinical problem, and new treatment options are therefore necessary. Moreover, the relationship between HER receptors, anti-EGFR therapies, and the human papillomavirus (HPV) status in HNSCC is not fully understood. In contrast to first-generation EGFR inhibitors, afatinib irreversibly inhibits multiple HER receptors simultaneously...
June 2018: Molecular Oncology
Koji Takada, Shinichiro Kashiwagi, Wataru Goto, Yuka Asano, Tamami Morisaki, Hisakazu Fujita, Tsutomu Takashima, Masahiko Ohsawa, Kosei Hirakawa, Masaichi Ohira
BACKGROUND: Chemotherapy with trastuzumab, pertuzumab and docetaxel (TPD regimen) is now strongly recommended as a treatment option for first-line therapy for advanced human epidermal growth factor receptor (HER)2-positive breast cancer. In this study, we analyzed the expression of HER 1-4 proteins, and investigated whether or not their expression was predictive of the response of advanced HER2-positive breast cancer to chemotherapy with the TPD regimen. PATIENTS AND METHODS: The study consisted of 29 cases in which TPD regimen chemotherapy was carried out from September 2013 to November 2015...
April 2018: Anticancer Research
Spencer S Watson, Mark Dane, Koei Chin, Zuzana Tatarova, Moqing Liu, Tiera Liby, Wallace Thompson, Rebecca Smith, Michel Nederlof, Elmar Bucher, David Kilburn, Matthew Whitman, Damir Sudar, Gordon B Mills, Laura M Heiser, Oliver Jonas, Joe W Gray, James E Korkola
Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested ∼2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib...
March 28, 2018: Cell Systems
Hidejiro Torigoe, Hiromasa Yamamoto, Masakiyo Sakaguchi, Chen Youyi, Kei Namba, Hiroki Sato, Kazuhiko Shien, Junichi Soh, Ken Suzawa, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka
Epidermal growth factor receptor (EGFR) is a member of the ErbB (HER) family that is known to play important roles in the pathogenesis of various human cancers. Mutations of the EGFR gene are commonly found as oncogenic driver mutations and have been targeted for treatment of non-small cell lung cancer (NSCLC). Leucine-rich repeat and immunoglobulin-like domain protein-1 (LRIG1) is a cell-surface protein that is known as a negative regulator of the ErbB (HER) family. In this study, we first confirmed that the expression levels of LRIG1 were much lower in NSCLC than in non-malignant cells or tissues...
May 3, 2018: Carcinogenesis
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