NTSR1 glycosylation and MMP dependent cleavage generate three distinct forms of the protein.

NTSR1 abnormal expression by cancer cells makes it a strategic target for antitumoral therapies, such as compounds that use NTSR1 binding probes to deliver cytotoxic agents to tumor cells. Success of these therapies relies on NTSR1 protein availability and accessibility; therefore, understanding the protein's biology is crucial. We studied NTSR1 protein in exogenously and endogenously expressing non-tumoral and tumoral cells.

Pretherapy Ferumoxytol-enhanced MRI to Predict Response to Liposomal Irinotecan in Metastatic Breast Cancer.

Purpose To investigate ferumoxytol (FMX)-enhanced MRI as a pretreatment predictor of response to liposomal irinotecan (nal-IRI) for thoracoabdominal and brain metastases in women with metastatic breast cancer (mBC). Materials and Methods In this phase 1 expansion trial (ClinicalTrials.gov identifier, NCT01770353; 27 participants), 49 thoracoabdominal (19 participants; mean age, 48 years ± 11 [SD]) and 19 brain (seven participants; mean age, 54 years ± 8) metastases were analyzed on MR images acquired before, 1-4 hours after, and 16-24 hours after FMX administration.

Liposomal Irinotecan Shows a Larger Therapeutic Index than Non-liposomal Irinotecan in Patient-Derived Xenograft Models of Pancreatic Cancer.

Introduction: Liposomal irinotecan promotes controlled sustained release of irinotecan (CPT-11), therefore, we hypothesize that the therapeutic index (quantitative measurement of the relative efficacy/safety ratio of a drug) will be higher for liposomal than non-liposomal irinotecan.

Methods: We compared the therapeutic indexes of liposomal and non-liposomal irinotecan in mice bearing subcutaneous patient-derived xenograft (PDX) pancreatic tumors under dosing regimens approximating the clinical setting. Following preliminary drug sensitivity/antitumor activity analyses on three PDX tumor models, one model was selected for analyses of efficacy, biomarker, toxicology, pharmacokinetics in mice receiving liposomal irinotecan (2.

Augmenting Experimental Gastric Cancer Activity of Irinotecan through Liposomal Formulation and Antiangiogenic Combination Therapy.

Gastric adenocarcinoma (GAC) is the third most common cause of cancer-related deaths worldwide. Combination chemotherapy remains the standard treatment for advanced GAC. Liposomal irinotecan (nal-IRI) has improved pharmacokinetics (PK) and drug biodistribution compared with irinotecan (IRI, CPT-11).

Antitumor effects of the multi-target tyrosine kinase inhibitor cabozantinib: a comprehensive review of the preclinical evidence.

Introduction: Altered receptor tyrosine kinase (RTK) signaling contributes to tumorigenesis and suppression of immune-mediated destruction of cancer cells. Cabozantinib is an oral tyrosine kinase inhibitor that inhibits several RTKs involved in tumorigenesis, and is approved for the treatment of patients with progressive metastatic medullary thyroid cancer, advanced renal cell carcinoma, and hepatocellular carcinoma that has been previously treated with sorafenib.

Areas Covered: We present an up-to-date evaluation of preclinical evidence for RTK inhibition with cabozantinib, specifically VEGFR, MET, KIT, RET, AXL, FLT3, and associated antitumor effects.

Longitudinal PET Imaging to Monitor Treatment Efficacy by Liposomal Irinotecan in Orthotopic Patient-Derived Pancreatic Tumor Models of High and Low Hypoxia.

Purpose: Hypoxia is linked to aggressiveness, resistance to therapy, and poor prognosis of pancreatic tumors. Liposomal irinotecan (nal-IRI, ONIVYDE®) has shown potential in reducing hypoxia in the HT29 colorectal cancer model, and here, we investigate its therapeutic activity and ability to modulate hypoxia in patient-derived orthotopic tumor models of pancreatic cancer.

Procedures: Mice were randomized into nal-IRI treated and untreated controls.

Extended topoisomerase 1 inhibition through liposomal irinotecan results in improved efficacy over topotecan and irinotecan in models of small-cell lung cancer.

Liposomal irinotecan (irinotecan liposome injection, nal-IRI), a liposomal formulation of irinotecan, is designed for extended circulation relative to irinotecan and for exploiting discontinuous tumor vasculature for enhanced drug delivery to tumors. Following tumor deposition, nal-IRI is taken up by phagocytic cells followed by irinotecan release and conversion to its active metabolite, SN-38. Sustained inhibition of topoisomerase 1 by extended SN-38 exposure as a result of delivery by nal-IRI is hypothesized to enable superior antitumor activity compared with traditional topoisomerase 1 inhibitors such as conventional irinotecan and topotecan.

Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study.

To determine whether deposition characteristics of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to nanoliposomal irinotecan (nal-IRI). Eligible patients with previously treated solid tumors had FMX-MRI scans before and following (1, 24, and 72 hours) FMX injection. After MRI acquisition, R2* signal was used to calculate FMX levels in plasma, reference tissue, and tumor lesions by comparison with a phantom-based standard curve.

Longitudinal tumor hypoxia imaging with [(18)F]FAZA-PET provides early prediction of nanoliposomal irinotecan (nal-IRI) treatment activity.

Background: Non-invasive measurement of tumor hypoxia has demonstrated potential for the evaluation of disease progression, as well as prediction and assessment of treatment outcome. [(18)F]fluoroazomycin arabinoside (FAZA) positron emission tomography (PET) has been identified as a robust method for quantification of hypoxia both preclinically and clinically. The goal of this investigation was to evaluate the feasibility and value of repeated FAZA-PET imaging to quantify hypoxia in tumors that received multi-dose chemotherapy.

Preclinical activity of nanoliposomal irinotecan is governed by tumor deposition and intratumor prodrug conversion.

A major challenge in the clinical use of cytotoxic chemotherapeutics is maximizing efficacy in tumors while sparing normal tissue. Irinotecan is used for colorectal cancer treatment but the extent of its use is limited by toxic side effects. Liposomal delivery systems offer tools to modify pharmacokinetic and safety profiles of cytotoxic drugs.

Impact of tumor HER2/ERBB2 expression level on HER2-targeted liposomal doxorubicin-mediated drug delivery: multiple low-affinity interactions lead to a threshold effect.

Numerous targeted nanotherapeutics have been described for potential treatment of solid tumors. Although attention has focused on antigen selection and molecular design of these systems, there has been comparatively little study of how cellular heterogeneity influences interaction of targeted nanoparticles with tumor cells. Antigens, such as HER2/ERBB2, are heterogeneously expressed across different indications, across patients, and within individual tumors.

HER2-targeted liposomal doxorubicin displays enhanced anti-tumorigenic effects without associated cardiotoxicity.

Anthracycline-based regimens are a mainstay of early breast cancer therapy, however their use is limited by cardiac toxicity. The potential for cardiotoxicity is a major consideration in the design and development of combinatorial therapies incorporating anthracyclines and agents that target the HER2-mediated signaling pathway, such as trastuzumab. In this regard, HER2-targeted liposomal doxorubicin was developed to provide clinical benefit by both reducing the cardiotoxicity observed with anthracyclines and enhancing the therapeutic potential of HER2-based therapies that are currently available for HER2-overexpressing cancers.

Molecular Association of the Neural Adhesion Molecules L1 and N-CAM in the Surface Membrane of Neuroblastoma Cells is Shown by Chemical Cross-linking.

The two neural cell adhesion molecules L1 and N-CAM could be shown to be associated in the surface membrane of cultured neuroblastoma cells by chemical cross-linking with 3,3'-dithiobis(sulphosuccinimidyl-propionate) and subsequent immunopurification and precipitation using antibodies to L1 and N-CAM. Glycoproteins recognized in neuroblastoma cells by antibodies to mouse liver membranes were not chemically cross-linked to L1 or N-CAM. These observations suggest that a molecular association between the two molecules may be the basis for their functional cooperativity (Kadmon et al.