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Mainz, Germany

Goetz M.,Universtitasmedizin Mainz | Goetz M.,Universitatsklinik Tubingen | Hoetker M.S.,Universtitasmedizin Mainz | Diken M.,Translational Oncology | And 2 more authors.

Background and study aims: Molecular imaging has mainly been studied for detection of lesions using diagnostic probes. The aim of the current trial was to evaluate in vivo confocal laser endomicroscopy (CLE) with cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), for detection and moreover early prediction of response to molecular chemotherapy in models of human colorectal cancer (CRC). Methods: Xenografts with cetuximab-sensitive (HT29) and cetuximab-resistant (SW620) human CRC cell lines were induced in 44 mice. CLE was performed 48 h after injection of a fluorescently labelled cetuximab test dose, and compared with isotype antibody or untreated controls on d0, and d30 (HT29) or d15 (SW620). Initial fluorescence intensity was examined in relation to clinical readouts (tumor growth, thriving, mortality) during cetuximab treatment vs. controls. Results were validated in vivo with wide-field molecular imaging in three HT29 mice and ex vivo using fluorescence-activated cell sorting (FACS) and immunohistochemistry. Results: All HT29 xenografts showed specific fluorescence in vivo after cetuximab injection on d0 and d30. Fluorescence at d0 was significantly stronger in cetuximab-treated HT29 tumors than in HT29 controls (P = 0.0017) or cetuximab-treated SW620 tumors (P = 0.0027), and accorded with significantly slower tumor progression (P = 0.0009), better overall survival (P = 0.02), and better physical condition (P < 0.0001). Cetuximab sensitivity could be predicted from fluorescence intensity at d0 with high positive predictive value. Conclusions: Molecular CLE was for the first time linked to early prediction of response to targeted therapy in models of human CRC. Therapeutic antibodies can be used as molecular beacons in CLE and wide-field techniques. These results may indicate a promising principle for early patient stratification. © Georg Thieme Verlag KG Stuttgart · New York. Source

Peng J.,Translational Oncology | Peterson D.,Translational Oncology | Yue P.,Genentech | Settleman J.,Genentech
Cancer Research

Selective kinase inhibitors have emerged as an important class of cancer therapeutics, and several such drugs are now routinely used to treat advanced-stage disease. However, their clinical benefit is typically short-lived because of the relatively rapid acquisition of drug resistance following treatment response. Accumulating preclinical and clinical data point to a role for a heterogeneous response to treatment within a subpopulation of tumor cells that are intrinsically drug-resistant, such as cancer stem cells. We have previously described an epigenetically determined reversibly drug-tolerant subpopulation of cancer cells that share some properties with cancer stem cells. Here, we define a requirement for the previously established cancer stem cell marker ALDH (aldehyde dehydrogenase) in the maintenance of this drug-tolerant subpopulation. We find that ALDH protects the drug-tolerant subpopulation from the potentially toxic effects of elevated levels of reactive oxygen species (ROS) in these cells, and pharmacologic disruption of ALDH activity leads to accumulation of ROS to toxic levels, consequent DNA damage, and apoptosis specifically within the drug-tolerant subpopulation. Combining ALDH inhibition with other kinase-directed treatments delayed treatment relapse in vitro and in vivo, revealing a novel combination treatment strategy for cancers that might otherwise rapidly relapse following single-agent therapy. Cancer Res; 74(13); 3579-90. © 2014 American Association for Cancer Research. Source

Pathmanathan N.,Westmead Breast Cancer Institute | Pathmanathan N.,Institute of Clinical Pathology and Medical Research | Pathmanathan N.,University of Sydney | Balleine R.L.,University of Sydney | And 15 more authors.
Journal of Clinical Pathology

Aim To evaluate the utility of Ki67 as a prognostic marker in a series of patients with node-negative breast cancer untreated with adjuvant systemic therapy. Methods The cohort consisted of 203 cases treated with breast conserving surgery and radiation only; median follow-up was 183 months (range 156-277 months). An immunohistochemical panel of oestrogen receptor (ER), progesterone receptor (PR), cytokeratin (CK)5/6 and Ki67 and human epidermal growth factor 2 in situ hybridization (HER2-ISH) was performed on the tumour samples. Ki67 scores were evaluable in 193/203 patients (95.1%). The primary outcome was breast cancer specific survival (BCSS). Results Of the cohort, 29 (14.2%) died of breast cancer. A cut off of 10% separated tumours into a 'Ki67-low' (n=70) or 'Ki67-high' group (n=123). The breast cancer specific survival was 97.1% and 77.6% for Ki67-low and Ki67-high groups, respectively. Univariate analysis showed that in this lymph node-negative cohort, the predictors for BCSS were tumour size, Ki67, LVI, age and histological grade 3. Multivariable analysis showed that Ki67 index and lymphovascular space invasion were independent predictors of breast cancer death. To examine the utility of Ki67 in assignment of immunohistochemically molecular subtypes, cases were assigned into Luminal A (ER-positive, HER2-negative, Ki67 ≤14%), Luminal B (ER-positive, HER2-negative, Ki67 <14%) and triple negative (ER/PR-negative and HER2-negative, any Ki67). The 15-year breast cancer specific survival was 91.7%, 79.4% and 75.8%, respectively. Conclusions A statistically significant difference in breast cancer specific survival is seen in groups defined using Ki67 and receptor status, whereas histological grading was not a significant predictor of survival. Ki67 immunostaining provides prognostic information beyond traditionally assessed clinicopathological variables. Source

Mai E.,Genentech | Zheng Z.,Translational Oncology | Chen Y.,Cancer Pathways and Targets | Peng J.,Translational Oncology | And 8 more authors.
Molecular Cancer Therapeutics

Onartuzumab, a humanized, monovalent monoclonal anti-MET antibody, antagonizes MET signaling by inhibiting binding of its ligand, hepatocyte growth factor (HGF).Weinvestigated the effects of onartuzumab on cell-associated and circulating (shed) MET (sMET) and circulating HGF in vitro and nonclinically to determine their utility as pharmacodynamic biomarkers for onartuzumab. Effects of onartuzumab on cell-associatedMET were assessed by flow cytometry and immunofluorescence. sMET and HGF were measured in cell supernatants and in serum or plasma from multiple species (mouse, cynomolgus monkey, and human) using platebased immunoassays. Unlike bivalent anti-MET antibodies, onartuzumab stably associates with MET on the surface of cells without inducing MET internalization or shedding. Onartuzumab delayed the clearance of human xenograft tumor-produced sMET from the circulation of mice, and endogenous sMET in cynomolgus monkeys. In mice harboring MET-expressing xenograft tumors, in the absence of onartuzumab, levels of human sMET correlated with tumor size, and may be predictive of MET-expressing tumor burden. Because binding of sMET to onartuzumab in circulation resulted in increasing sMET serum concentrations due to reduced clearance, this likely renders sMET unsuitable as a pharmacodynamic biomarker for onartuzumab. There was no observed effect of onartuzumab on circulating HGF levels in xenograft tumor-bearing mice or endogenous HGF in cynomolgus monkeys. Although sMET and HGF may serve as predictive biomarkers for MET therapeutics, these data do not support their use as pharmacodynamic biomarkers for onartuzumab. Mol Cancer Ther; 13(2); 540-52. © 2013 American Association for Cancer Research. Source

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