Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases.

Abstract

Bone metastases occur in approximately 70% of metastatic breast cancer patients, often leading to skeletal injuries. Current treatments are mainly palliative and underscore the unmet clinical need for improved therapies. In this study, we provide preclinical evidence for an antimetastatic therapy based on targeting integrin β3 (β3), which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, β3 was strongly expressed on bone metastatic cancer cells, but not primary mammary tumors or visceral metastases. In tumor tissue from breast cancer patients, β3 was significantly elevated on bone metastases relative to primary tumors from the same patient (n = 42). Mechanistic investigations revealed that TGFβ signaling through SMAD2/SMAD3 was necessary for breast cancer induction of β3 within the bone. Using a micelle-based nanoparticle therapy that recognizes integrin αvβ3 (αvβ3-MPs of ∼12.5 nm), we demonstrated specific localization to breast cancer bone metastases in mice. Using this system for targeted delivery of the chemotherapeutic docetaxel, we showed that bone tumor burden could be reduced significantly with less bone destruction and less hepatotoxicity compared with equimolar doses of free docetaxel. Furthermore, mice treated with αvβ3-MP-docetaxel exhibited a significant decrease in bone-residing tumor cell proliferation compared with free docetaxel. Taken together, our results offer preclinical proof of concept for a method to enhance delivery of chemotherapeutics to breast cancer cells within the bone by exploiting their selective expression of integrin αvβ3 at that metastatic site. Cancer Res; 77(22); 6299-312. ©2017 AACR.

• Authors: Michael H Ross, Alison K Esser, Gregory C Fox, Anne H Schmieder, Xiaoxia Yang, Grace Hu, Dipanjan Pan, Xinming Su, Yalin Xu, Deborah V Novack, Thomas Walsh, Graham A Colditz, Gabriel H Lukaszewicz, Elizabeth Cordell, Joshua Novack, James A J Fitzpatrick, David L Waning, Khalid S Mohammad, Theresa A Guise, Gregory M Lanza, Katherine N Weilbaecher
• Journal: Cancer research (Cancer Res) Vol. 77 Issue 22 Pg. 6299-6312 (11 15 2017) ISSN: 1538-7445 [Electronic] United States
• PMID: 28855208 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Integrin alphaVbeta3
• Integrin beta3
• Taxoids
• Transforming Growth Factor beta
• Docetaxel

Topics

• Animals
• Bone Neoplasms (drug therapy, genetics, secondary)
• Breast Neoplasms (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Docetaxel
• Female
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Humans
• Integrin alphaVbeta3 (antagonists & inhibitors, genetics, metabolism)
• Integrin beta3 (genetics, metabolism)
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Nude
• Molecular Targeted Therapy (methods)
• Nanoparticles (administration & dosage, chemistry)
• Signal Transduction (drug effects, genetics)
• Taxoids (administration & dosage, chemistry)
• Transforming Growth Factor beta (genetics, metabolism)
• Xenograft Model Antitumor Assays