Abstract:
BACKGROUND:Golgi phosphoprotein 2 (GOLPH2) has been shown to be involved in chronic inflammatory processes and carcinogenesis. GOLPH2 is prominently overexpressed in hepatocellular carcinoma, melanoma, glioblastoma, prostate, lung, and colorectal cancer. With a low and tightly regulated expression in non-malignant tissues, GOLPH2 has been proposed as an attractive target for cancer therapy. However, GOLPH2 is predominantly located intracellularly and when situated outside of the cell it is proteolytically cleaved and shed from the cell surface. Until now, GOLPH2 has been regarded as an "undruggable" target. OBJECTIVE:We sought to create antibodies that specifically bind to GOLPH2 overexpressing tumor cells. PATIENTS AND METHODS:Antibodies binding to membranous GOLPH2 despite shedding of the protein were generated from a scFV library screening. These antibodies target the part of GOLPH2 that remains at the cell surface after proteolytic cleavage. These antibodies were then tested in vitro and in vivo. RESULTS:Two candidates (G2-1 and G2-2) showed target specific binding in vitro. Utilizing a tumor array (n = 128 tumors) with G2-2 and a reference antibody, a GOLPH2 expression scoring system was established. Rapid internalization of the antibodies was noted so this was exploited to deliver a toxic payload of pyrrolobenzodiazepine (PBD). In two patient-derived xenograft (PDX)-models, colorectal and lung cancer, the G2-2 antibody drug conjugate (ADC) displayed high efficacy with significant tumor responses (P = 0.001; P = 0.013) and improved survival (P = 0.0001; P = 0.0011) compared with controls. CONCLUSIONS:Treatment with GOLPH2-directed antibodies induces durable responses in colorectal and lung cancer models. With a robust companion assay for GOLPH2 positivity at hand our findings prepare for the translation into a clinical trial.
journal_name
Target Oncoljournal_title
Targeted oncologyauthors
Liewen H,Markuly N,Läubli H,Liu Y,Matter MS,Liewen N,Renner C,Zippelius A,Stenner Fdoi
10.1007/s11523-019-00667-zsubject
Has Abstractpub_date
2019-10-01 00:00:00pages
577-590issue
5eissn
1776-2596issn
1776-260Xpii
10.1007/s11523-019-00667-zjournal_volume
14pub_type
杂志文章abstract:BACKGROUND:Sunitinib (S) is a multi-targeted tyrosine kinase inhibitor. It is synergistic with chemotherapy in preclinical models. We hypothesized that sunitinib in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) would be a tolerable and effective regimen in advanced gastric and gastroesophageal jun...
journal_title:Targeted oncology
pub_type: 杂志文章
doi:10.1007/s11523-019-00692-y
更新日期:2020-02-01 00:00:00
abstract::The advent of imatinib mesilate, an oral target therapy, has dramatically changed the natural history of gastrointestinal stromal tumours (GISTs). This rare neoplasm has become the paradigm of targeted therapies in solid tumours, also introducing a home-based cure concept in oncology. However, it should be retained th...
journal_title:Targeted oncology
pub_type: 杂志文章
doi:10.1007/s11523-012-0221-1
更新日期:2012-12-01 00:00:00
abstract::Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) catalyze the first rate-limiting step in the oxidative metabolism of compounds containing indole rings, including the transformation of the essential amino acid L-tryptophan to N-formyl-L-kynurenine. Through direct and indirect means, IDO exerts bo...
journal_title:Targeted oncology
pub_type: 杂志文章,评审
doi:10.1007/s11523-017-0547-9
更新日期:2018-04-01 00:00:00
abstract:BACKGROUND:The prognosis of patients with advanced pancreatic cancer is dismal, and there is a need for novel and effective treatments. OBJECTIVES:Tο determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of a novel gemcitabine (G) and temsirolimus (T) combination (phase I) and estimate the 6-m...
journal_title:Targeted oncology
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1007/s11523-018-0605-y
更新日期:2018-12-01 00:00:00
abstract::The ubiquitin (Ub)+proteasome proteolytic pathway is responsible for the selective degradation of the majority of nuclear and cytosolic proteins. The proteasome is a high molecular weight multicatalytic protease that serves as the catalytic core of the complex Ub-dependent protein degradation pathway and is an excitin...
journal_title:Targeted oncology
pub_type: 杂志文章,评审
doi:10.1007/s11523-010-0165-2
更新日期:2010-12-01 00:00:00
abstract::Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological entity that may occur in patients receiving anti-vascular endothelial growth factor (VEGF) agents such as bevacizumab and tyrosine kinase inhibitors. Little is known about the characteristics of patients at risk for PRES under anti-VEGF agen...
journal_title:Targeted oncology
pub_type: 杂志文章,meta分析,评审
doi:10.1007/s11523-011-0201-x
更新日期:2011-12-01 00:00:00
abstract::Mesothelin is a tumor differentiation antigen, which is highly expressed in several solid neoplasms, including pancreatic cancer. Its selective expression on malignant cells and on only a limited number of healthy tissues has made it an interesting candidate for investigation as a diagnostic and prognostic biomarker a...
journal_title:Targeted oncology
pub_type: 杂志文章,评审
doi:10.1007/s11523-018-0567-0
更新日期:2018-06-01 00:00:00
abstract:BACKGROUND:Immunotherapy based on programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors has revolutionized the treatment of non-small cell lung cancer (NSCLC). Patients with high PD-L1 expression or DNA mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) cancer are re...
journal_title:Targeted oncology
pub_type: 杂志文章
doi:10.1007/s11523-020-00703-3
更新日期:2020-02-01 00:00:00
abstract:BACKGROUND:The WEE1 inhibitor adavosertib (AZD1775) has been investigated in Western patients. OBJECTIVE:This open-label Phase Ib study (NCT02341456) investigated the safety, pharmacokinetics, and clinical activity of adavosertib in combination with carboplatin alone or paclitaxel plus carboplatin in Asian patients wi...
journal_title:Targeted oncology
pub_type: 杂志文章
doi:10.1007/s11523-020-00701-5
更新日期:2020-02-01 00:00:00
abstract:BACKGROUND:In 2017, nivolumab monotherapy was shown to be effective as third- or later-line therapy in patients with advanced gastric or gastroesophageal junction cancer. OBJECTIVE:In this study, we investigated the relationship between the neutrophil-to-lymphocyte ratio (NLR) and the outcomes of nivolumab monotherapy...
journal_title:Targeted oncology
pub_type: 杂志文章
doi:10.1007/s11523-020-00716-y
更新日期:2020-06-01 00:00:00
abstract:BACKGROUND:The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions. OBJECTIVE:We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor ...
journal_title:Targeted oncology
pub_type: 杂志文章
doi:10.1007/s11523-018-0595-9
更新日期:2018-10-01 00:00:00
abstract::Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive malignancy with poor outcome occurring in adolescents and young adults. Therapeutic options for patients with advanced disease are limited. Preclinical studies have shown that VEGFR-2 and VEGFA are overexpressed in DSRCT and that DSRCT xenografts wer...
journal_title:Targeted oncology
pub_type: 杂志文章
doi:10.1007/s11523-012-0251-8
更新日期:2013-09-01 00:00:00
abstract:OBJECTIVE:To determine the efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in molecularly selected patients with advanced non-small cell lung cancer (NSCLC), we performed this pooled analysis. METHOD:Randomized trials of EGFR-TKIs as treatment for advanced NSCLC wer...
journal_title:Targeted oncology
pub_type: 杂志文章,meta分析,收录出版
doi:10.1007/s11523-015-0376-7
更新日期:2016-02-01 00:00:00
abstract::Despite recent advances that have been made in the therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC), effective management of bone metastases remains a key goal not yet reached. The receptor tyrosine kinase MET and the vascular endothelial growth factor receptor (VEGFR) seem to play an i...
journal_title:Targeted oncology
pub_type: 杂志文章,评审
doi:10.1007/s11523-015-0412-7
更新日期:2016-08-01 00:00:00
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journal_title:Targeted oncology
pub_type: 杂志文章
doi:10.1007/s11523-016-0441-x
更新日期:2016-10-01 00:00:00
abstract:BACKGROUND:Serum protein fraction (SPF) is a common parameter reflecting the nutritional and inflammatory status of the human body. However, its role in patients with cancer, particularly those treated with targeted agents, is unknown. OBJECTIVE:We conducted this study to explore the prognostic value of SPF in patient...
journal_title:Targeted oncology
pub_type: 杂志文章
doi:10.1007/s11523-019-00625-9
更新日期:2019-04-01 00:00:00
abstract::The First-Line Erbitux in Lung Cancer (FLEX) trial showed that the addition of cetuximab to chemotherapy followed by weekly cetuximab maintenance significantly improved survival in the first-line treatment of advanced non-small cell lung cancer (NSCLC). The phase IIIb NSCLC Erbitux Trial (NEXT) trial (NCT00820755) inv...
journal_title:Targeted oncology
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1007/s11523-014-0336-7
更新日期:2015-06-01 00:00:00
abstract::The discovery of chemoresistant cancer stem cells (CSCs) in carcinomas has created the need for therapies that specifically target these subpopulations of cells. Here, we characterized a bispecific targeted toxin that is composed of two antibody fragments and a catalytic protein toxin allowing it to bind two CSC marke...
journal_title:Targeted oncology
pub_type: 杂志文章
doi:10.1007/s11523-013-0290-9
更新日期:2014-09-01 00:00:00
abstract::Basal transcription regulation of the epidermal growth factor receptor is dependent upon a CA simple sequence repeat polymorphism in the intron-1 (CA-SSR-1). Here, we evaluate the role of CA-SSR-1 in complete resected esophageal cancer (EC) patients without neoadjuvant or adjuvant treatment. Genomic DNA was extracted ...
journal_title:Targeted oncology
pub_type: 杂志文章
doi:10.1007/s11523-013-0260-2
更新日期:2014-03-01 00:00:00
abstract::In anticancer drug development, there has been increasing consideration for the potential of a compound to cause adverse electrocardiographic changes, especially QT interval prolongation, which can be associated with risk of torsades de pointes and sudden death. Irrespective of overt clinical toxicities, QTc assessmen...
journal_title:Targeted oncology
pub_type: 杂志文章,评审
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更新日期:2015-03-01 00:00:00
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journal_title:Targeted oncology
pub_type: 杂志文章,多中心研究
doi:10.1007/s11523-019-00630-y
更新日期:2019-04-01 00:00:00
abstract::With the incorporation of targeted therapies in routine cancer therapy, it is imperative that the array of toxicities associated with these agents be well-recognized and managed, especially since these toxicities are distinct from those seen with conventional cytotoxic agents. This review will focus on these renal tox...
journal_title:Targeted oncology
pub_type: 杂志文章,评审
doi:10.1007/s11523-015-0368-7
更新日期:2015-12-01 00:00:00
abstract::Several angiogenesis inhibitors have been approved for commercial use and many additional agents are under development for the treatment of various malignancies. Cardiovascular toxicities have been increasingly recognized as effects of this entire class of new anticancer therapeutics. There is a limited but growing un...
journal_title:Targeted oncology
pub_type: 杂志文章,评审
doi:10.1007/s11523-009-0106-0
更新日期:2009-04-01 00:00:00
abstract::Dynamic contrast-enhanced ultrasonography (DCE-US) is a new functional technique enabling a quantitative assessment of solid tumor perfusion using raw linear data. DCE-US allows the calculation of parameters as slope of wash-in or area under the curve (AUC) representing, respectively, blood flow or blood volume. Reduc...
journal_title:Targeted oncology
pub_type: 杂志文章,评审
doi:10.1007/s11523-010-0136-7
更新日期:2010-03-01 00:00:00
abstract::Data regarding the expression of epidermal growth factor receptor (EGFR) in melanoma and its role in the tumor biology are conflicting. In BRAF V600-mutant melanomas, the expression of EGFR has been associated with acquired resistance to BRAF inhibitors. In this study, we assessed EGFR expression and downstream signal...
journal_title:Targeted oncology
pub_type: 杂志文章
doi:10.1007/s11523-014-0318-9
更新日期:2015-03-01 00:00:00
abstract:BACKGROUND:Tyrosine-kinase inhibitors (TKIs) markedly improve progression-free survival (PFS) of patients with advanced non-small-cell lung cancer (NSCLC) mutated for epidermal growth factor receptor (EGFR). Results on overall survival (OS) are less clear-cut. We performed a publication-based meta-analysis to address f...
journal_title:Targeted oncology
pub_type: 杂志文章,meta分析
doi:10.1007/s11523-015-0373-x
更新日期:2016-02-01 00:00:00
abstract::Elderly and poor performance status advanced non-small cell lung cancer (NSCLC) patients often tolerate chemotherapy poorly. Special approaches are needed for these patient populations. Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), erlotinib and gefitinib, are active agents in the t...
journal_title:Targeted oncology
pub_type: 杂志文章,评审
doi:10.1007/s11523-009-0104-2
更新日期:2009-01-01 00:00:00
abstract::Among neuroendocrine carcinomas of the gut, well-differentiated tumors are highly vascularized, featuring specific characteristics on contrast-enhanced imaging. Well-differentiated neuroendocrine tumors spontaneously harbor hypervascular enhancement, coexisting with areas of necrosis mainly located at the center of tu...
journal_title:Targeted oncology
pub_type: 杂志文章
doi:10.1007/s11523-012-0216-y
更新日期:2012-06-01 00:00:00
abstract::Hypoxia is a critical hallmark of solid tumors and involves enhanced cell survival, angiogenesis, glycolytic metabolism, and metastasis. Hyperbaric oxygen (HBO) treatment has for centuries been used to improve or cure disorders involving hypoxia and ischemia, by enhancing the amount of dissolved oxygen in the plasma a...
journal_title:Targeted oncology
pub_type: 杂志文章,评审
doi:10.1007/s11523-012-0233-x
更新日期:2012-12-01 00:00:00
abstract::Hepatocellular carcinoma (HCC) is one of the most common forms of liver cancer diagnosed worldwide. HCC occurs due to chronic liver disease and is often diagnosed at advanced stages. Chemotherapeutic agents such as doxorubicin are currently used as first-line agents for HCC therapy, but these are non-selective cytotox...
journal_title:Targeted oncology
pub_type: 杂志文章,评审
doi:10.1007/s11523-016-0452-7
更新日期:2017-02-01 00:00:00