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Biodistribution Analyses of a Near-Infrared, Fluorescently Labeled, Bispecific Monoclonal Antibody Using Optical Imaging.

In recent years, biodistribution analyses of pharmaceutical compounds in preclinical animal models have become an integral part of drug development. Here we report on the use of optical imaging biodistribution analyses in a mouse xenograft model to identify tissues that nonspecifically retained a bispecific antibody under development. Although our bispecific antibody bound both the epidermal growth factor receptor and insulin growth factor 1 receptor are expressed on H358, nonsmall-cell lung carcinoma cells, the fluorescence from labeled bispecific antibody was less intense than expected in xenografted tumors. Imaging analyses of live mice and major organs revealed that the majority of the Alexa Fluor 750 labeled bispecific antibody was sequestered in the liver within 2 h of injection. However, results varied depending on which near-infrared fluorophore was used, and fluorescence from the livers of mice injected with bispecific antibody labeled with Alexa Fluor 680 was less pronounced than those labeled with Alexa Fluor 750. The tissue distribution of control antibodies remained unaffected by label and suggests that the retention of fluorophores in the liver may differ. Given these precautions, these results support the incorporation of optical imaging biodistribution analyses in biotherapeutic development strategies.

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Pharmacokinetics and safety of intravenous cidofovir for life-threatening viral infections in pediatric hematopoietic stem cell transplant recipients.

Children undergoing hematopoietic stem cell transplantation (HSCT) are at risk for life-threatening viral infections. Cidofovir is often used as a first-line agent for adenovirus infections, despite the absence of randomized controlled trials with HSCT patients, and as a second-line agent for resistant herpesvirus infections. The frequency and severity of adverse effects, particularly nephrotoxicity, in pediatric HSCT recipients are unclear, and pharmacokinetics (PK) of cidofovir in children have not previously been reported. This study was an open-label, nonrandomized, single-dose pilot study to determine the safety and PK of cidofovir in pediatric HSCT recipients with symptomatic adenovirus, nucleoside-resistant cytomegalovirus (CMV) or herpes simplex virus (HSV), and/or human papovavirus infections. Subsequent dosing and frequency were determined by clinical response and side effects, as assessed by the treating physician. Blood and urine samples were obtained from patients for PK studies and assessment of toxicity and virologic response. Twelve patients were enrolled (median age, 9 years; 33.5 days posttransplantation). Four of seven patients with adenovirus infection were successfully treated and eventually cleared their infections. Four of twelve patients died of disseminated viral disease and multiorgan failure. Two of twelve patients had evidence of acute kidney injury after the first dose, and one of these patients developed chronic kidney disease; two other patients developed late nephrotoxicity. The mean drug half-life was 9.5 h. There was no correlation between nephrotoxicity and plasma maximum concentration, clearance, or half-life. PK were similar to those reported for adults, although the drug half-life was significantly longer than that for adults. Cidofovir was well tolerated in the majority of patients. However, effective therapeutic strategies are urgently needed to support patients until immune reconstitution is achieved.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.

mTORC1-Dependent Metabolic Reprogramming Underlies Escape from Glycolysis Addiction in Cancer Cells.

Although glycolysis is substantially elevated in many tumors, therapeutic targeting of glycolysis in cancer patients has not yet been successful, potentially reflecting the metabolic plasticity of tumor cells. In various cancer cells exposed to a continuous glycolytic block, we identified a recurrent reprogramming mechanism involving sustained mTORC1 signaling that underlies escape from glycolytic addiction. Active mTORC1 directs increased glucose flux via the pentose phosphate pathway back into glycolysis, thereby circumventing a glycolysis block and ensuring adequate ATP and biomass production. Combined inhibition of glycolysis and mTORC1 signaling disrupted metabolic reprogramming in tumor cells and inhibited their growth in vitro and in vivo. These findings reveal novel combinatorial therapeutic strategies to realize the potential benefit from targeting the Warburg effect.
Copyright © 2016 Elsevier Inc. All rights reserved.

Trastuzumab emtansine (T-DM1) plus docetaxel with or without pertuzumab in patients with HER2-positive locally advanced or metastatic breast cancer: Results from a phase Ib/IIa study.

Trastuzumab emtansine (T-DM1) exhibited enhanced antitumor activity when combined with docetaxel or pertuzumab in preclinical studies. This phase Ib/IIa study assessed the feasibility of T-DM1+docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and T-DM1+docetaxel±pertuzumab in patients with HER2-positive locally advanced breast cancer (LABC).
Phase Ib (part 1) explored dose escalation, with T-DM1+docetaxel administered for ≥6 cycles in patients with MBC. Phase Ib (part 2) began with the maximum tolerated dose (MTD) identified in part 1. Patients with LABC were administered ≤6 cycles of T-DM1+docetaxel or T-DM1+docetaxel+pertuzumab. Phase IIa explored the MTDs identified in phase Ib.
Administered with T-DM1 (3.6 mg/kg), the docetaxel MTD was 60 mg/m(2) in MBC. In LABC, the MTD was 100 mg/m(2) docetaxel in combination with T-DM1 (3.6 mg/kg), given with granulocyte colony stimulating factor (G-CSF). Administered with T-DM1 (3.6 mg/kg)+pertuzumab (840 mg, cycle 1; 420 mg, subsequent cycles), the docetaxel MTD in LABC was 75 mg/m(2) with G-CSF support. Neutropenia was the most common grade 3-4 adverse event (MBC, 72%; LABC, 29%). In total, 48% (12/25) of MBC patients and 47% (34/73) of LABC patients experienced adverse events requiring dose modification. In MBC (median prior systemic agents=5), the objective response rate was 80.0% (20/25; 95% confidence interval [CI] 59.3-93.2) and median progression-free survival was 13.8 months (range, 1.6-33.5). The pathologic complete response (ypT0/is, ypN0) rate in LABC was 60.3% (44/73; 95% CI 48.1-71.5). Pharmacokinetic analyses indicated a low risk of drug-drug interaction between T-DM1 and docetaxel.
T-DM1 combined with docetaxel±pertuzumab appeared efficacious in MBC or LABC; however, nearly half of patients experienced adverse events requiring dose reductions with these T-DM1-combinations.ClinicalTrials.gov identifier. NCT00934856.
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

Comprehensive Genomic Profiling of Anal Squamous Cell Carcinoma Reveals Distinct Genomically Defined Classes.

Squamous cell cancers of the anal canal (ASCC) are increasing in frequency and lack effective therapies for advanced disease. Although an association with human papillomavirus (HPV) has been established, little is known about the molecular characterization of ASCC. A comprehensive genomic analysis of ASCC was undertaken to identify novel genomic alterations that will inform therapeutic choices for patients with advanced disease.
Hybrid-capture based next generation sequencing of exons from 236 cancer-related genes and intronic regions from 19 genes commonly rearranged in cancer was performed on 70 patients with ASCC. HPV status was assessed by aligning tumor sequencing reads to HPV viral genomes. Genomic alterations were identified using an established algorithm and correlated with HPV status.
Sixty one samples (87%) were HPV-positive. A mean of 3.5 genomic alterations per sample was identified. Recurrent alterations in phosphoinositol-3-kinase pathway (PI3K/AKT/mTOR) genes including amplifications and homozygous deletions were present in 63% of cases. Clinically relevant genomic alterations in genes involved in DNA repair, chromatin remodeling, or receptor tyrosine kinase signaling were observed in 30% of cases. Loss-of-function mutations in TP53 and CDKN2A were significantly enhanced in HPV-negative cases (p&lt;0.0001).
This is the first comprehensive genomic analysis of ASCC, and the results suggest new therapeutic approaches. Differing genomic profiles between HPV-associated and HPV-negative ASCC warrants further investigation and may require novel therapeutic and preventive strategies.
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].