Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model

MacDiarmid, J. A., Langova, V., Bailey, D., Pattison, S. T., Pattison, S. L., Christensen, N., Armstrong, L. R., Brahmbhatt, V. N., Smolarczyk, K., Harrison, M. T., Costa, M., Mugridge, N. B., Sedliarou, I., Grimes, N. A., Kiss, D. L., Stillman, B., Hann, C. L., Gallia, G. L., Graham, R. M., Brahmbhatt, H. (2016) Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model. PLoS One, 11 (4). e0151832. ISSN 1932-6203 (Electronic)1932-6203 (Linking)

[img]
Preview
PDF (Paper)
Stillman PLoS One 2016.PDF - Published Version

Download (5Mb) | Preview
URL: http://www.ncbi.nlm.nih.gov/pubmed/27050167
DOI: 10.1371/journal.pone.0151832

Abstract

BACKGROUND: Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. METHODOLOGY/PRINCIPLE FINDINGS: EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). CONCLUSIONS/SIGNIFICANCE: Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On this basis, we have designed a Phase 1 clinical study of EGFR-targeted, doxorubicin-loaded minicells for effective treatment of human patients with recurrent glioblastoma.

Item Type: Paper
Subjects: diseases & disorders > cancer
organs, tissues, organelles, cell types and functions > organs types and functions > brain
diseases & disorders > cancer > drugs and therapies > chemotherapy
diseases & disorders > cancer > drugs and therapies
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > epidermal growth factor
diseases & disorders > cancer > cancer types > glioblastoma
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein receptor
CSHL Authors:
Communities: CSHL labs > Stillman lab
Highlight: Stillman, Bruce W.
Depositing User: Matt Covey
Date Deposited: 26 Apr 2016 15:44
Last Modified: 20 Jun 2017 15:53
PMCID: PMC4822833
Related URLs:
URI: http://repository.cshl.edu/id/eprint/32619

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving