Bone-induced expression of integrin b3 enables targeted nanotherapy of breast cancer metastases

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. LanzaKatherine N. Weilbaecher

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 b3 (b3), which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, b3 was strongly expressed on bone metastatic cancer cells, but not primary mammary tumors or visceral metastases. In tumor tissue from breast cancer patients, b3 was significantly elevated on bone metastases relative to primary tumors from the same patient (n ¼ 42). Mechanistic investigations revealed that TGFb signaling through SMAD2/ SMAD3 was necessary for breast cancer induction of b3 within the bone. Using a micelle-based nanoparticle therapy that recognizes integrin avb3 (avb3-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 avb3-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 chemother-apeutics to breast cancer cells within the bone by exploiting their selective expression of integrin avb3 at that metastatic site.

Original languageEnglish (US)
Pages (from-to)6299-6312
Number of pages14
JournalCancer Research
Volume77
Issue number22
DOIs
StatePublished - Nov 15 2017

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docetaxel
Integrins
Breast Neoplasms
Neoplasm Metastasis
Bone and Bones
Bone Neoplasms
Neoplasms
Micelles
Tumor Burden
Palliative Care
Nanoparticles
Therapeutics
Cell Proliferation
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Ross, M. H., Esser, A. K., Fox, G. C., Schmieder, A. H., Yang, X., Hu, G., ... Weilbaecher, K. N. (2017). Bone-induced expression of integrin b3 enables targeted nanotherapy of breast cancer metastases. Cancer Research, 77(22), 6299-6312. https://doi.org/10.1158/0008-5472.CAN-17-1225
Ross, Michael H. ; Esser, Alison K. ; Fox, Gregory C. ; Schmieder, Anne H. ; Yang, Xiaoxia ; Hu, Grace ; Pan, Dipanjan ; Su, Xinming ; Xu, Yalin ; Novack, Deborah V. ; Walsh, Thomas ; Colditz, Graham A. ; Lukaszewicz, Gabriel H. ; Cordell, Elizabeth ; Novack, Joshua ; Fitzpatrick, James A.J. ; Waning, David L. ; Mohammad, Khalid S. ; Guise, Theresa A. ; Lanza, Gregory M. ; Weilbaecher, Katherine N. / Bone-induced expression of integrin b3 enables targeted nanotherapy of breast cancer metastases. In: Cancer Research. 2017 ; Vol. 77, No. 22. pp. 6299-6312.
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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 b3 (b3), which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, b3 was strongly expressed on bone metastatic cancer cells, but not primary mammary tumors or visceral metastases. In tumor tissue from breast cancer patients, b3 was significantly elevated on bone metastases relative to primary tumors from the same patient (n ¼ 42). Mechanistic investigations revealed that TGFb signaling through SMAD2/ SMAD3 was necessary for breast cancer induction of b3 within the bone. Using a micelle-based nanoparticle therapy that recognizes integrin avb3 (avb3-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 avb3-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 chemother-apeutics to breast cancer cells within the bone by exploiting their selective expression of integrin avb3 at that metastatic site.",
author = "Ross, {Michael H.} and Esser, {Alison K.} and Fox, {Gregory C.} and Schmieder, {Anne H.} and Xiaoxia Yang and Grace Hu and Dipanjan Pan and Xinming Su and Yalin Xu and Novack, {Deborah V.} and Thomas Walsh and Colditz, {Graham A.} and Lukaszewicz, {Gabriel H.} and Elizabeth Cordell and Joshua Novack and Fitzpatrick, {James A.J.} and Waning, {David L.} and Mohammad, {Khalid S.} and Guise, {Theresa A.} and Lanza, {Gregory M.} and Weilbaecher, {Katherine N.}",
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Ross, MH, Esser, AK, Fox, GC, Schmieder, AH, Yang, X, Hu, G, Pan, D, Su, X, Xu, Y, Novack, DV, Walsh, T, Colditz, GA, Lukaszewicz, GH, Cordell, E, Novack, J, Fitzpatrick, JAJ, Waning, DL, Mohammad, KS, Guise, TA, Lanza, GM & Weilbaecher, KN 2017, 'Bone-induced expression of integrin b3 enables targeted nanotherapy of breast cancer metastases', Cancer Research, vol. 77, no. 22, pp. 6299-6312. https://doi.org/10.1158/0008-5472.CAN-17-1225

Bone-induced expression of integrin b3 enables targeted nanotherapy of breast cancer metastases. / Ross, Michael H.; Esser, Alison K.; Fox, Gregory C.; Schmieder, Anne H.; Yang, Xiaoxia; Hu, Grace; Pan, Dipanjan; Su, Xinming; Xu, Yalin; Novack, Deborah V.; Walsh, Thomas; Colditz, Graham A.; Lukaszewicz, Gabriel H.; Cordell, Elizabeth; Novack, Joshua; Fitzpatrick, James A.J.; Waning, David L.; Mohammad, Khalid S.; Guise, Theresa A.; Lanza, Gregory M.; Weilbaecher, Katherine N.

In: Cancer Research, Vol. 77, No. 22, 15.11.2017, p. 6299-6312.

Research output: Contribution to journalArticle

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T1 - Bone-induced expression of integrin b3 enables targeted nanotherapy of breast cancer metastases

AU - Ross, Michael H.

AU - Esser, Alison K.

AU - Fox, Gregory C.

AU - Schmieder, Anne H.

AU - Yang, Xiaoxia

AU - Hu, Grace

AU - Pan, Dipanjan

AU - Su, Xinming

AU - Xu, Yalin

AU - Novack, Deborah V.

AU - Walsh, Thomas

AU - Colditz, Graham A.

AU - Lukaszewicz, Gabriel H.

AU - Cordell, Elizabeth

AU - Novack, Joshua

AU - Fitzpatrick, James A.J.

AU - Waning, David L.

AU - Mohammad, Khalid S.

AU - Guise, Theresa A.

AU - Lanza, Gregory M.

AU - Weilbaecher, Katherine N.

PY - 2017/11/15

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N2 - 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 b3 (b3), which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, b3 was strongly expressed on bone metastatic cancer cells, but not primary mammary tumors or visceral metastases. In tumor tissue from breast cancer patients, b3 was significantly elevated on bone metastases relative to primary tumors from the same patient (n ¼ 42). Mechanistic investigations revealed that TGFb signaling through SMAD2/ SMAD3 was necessary for breast cancer induction of b3 within the bone. Using a micelle-based nanoparticle therapy that recognizes integrin avb3 (avb3-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 avb3-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 chemother-apeutics to breast cancer cells within the bone by exploiting their selective expression of integrin avb3 at that metastatic site.

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