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Therapeutic inhibition of breast cancer bone metastasis progression and lung colonization: breaking the vicious cycle by targeting α5β1 integrin

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Abstract

At diagnosis, 10 % of breast cancer patients already have locally advanced or metastatic disease; moreover, metastasis eventually develops in at least 40 % of early breast cancer patients. Osteolytic bone colonization occurs in 80–85 % of metastatic breast cancer patients and is thought to be an early step in metastatic progression. Thus, breast cancer displays a strong preference for metastasis to bone, and most metastatic breast cancer patients will experience its complications. Our prior research has shown that the α5β1 integrin fibronectin receptor mediates both metastatic and angiogenic invasion. We invented a targeted peptide inhibitor of activated α5β1, Ac-PHSCN-NH2 (PHSCN), as a validated lead compound to impede both metastatic invasion and neovascularization. Systemic PHSCN monotherapy prevented disease progression for up to 14 months in Phase I clinical trial. Here, we report that the next-generation construct, Ac-PhScN-NH2 (PhScN), which contains D-isomers of histidine (h) and cysteine (c), is greater than 100,000-fold more potent than PHSCN at blocking basement membrane invasion. Moreover, PhScN is also up to 10,000-fold more potent than PHSCN at inhibiting lung extravasation and colonization in athymic mice for both MDA-MB-231 metastatic and SUM149PT inflammatory breast cancer cells. Furthermore, we show that systemic treatment with 50 mg/kg PhScN monotherapy reduces established intratibial MDA-MB-231 bone colony progression by 80 %. Thus, PhScN is a highly potent, well-tolerated inhibitor of both lung colonization and bone colony progression.

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Abbreviations

SF:

Serum free

FBS:

Fetal bovine serum

Bio:

Biotin

IC50:

Concentration for 50 % inhibition

pFn:

Plasma fibronectin

DRI:

Dose reduction index

DiI:

1,1′-Dilinoleyl-3,3,3′3′-tetramethylindocarbocyanine perchlorate

MAP:

Multiantigenic peptide

MAb:

Monoclonal antibody

SEM:

Standard error of mean

Me:

Methyl

OAc:

Acetyl

μg:

Microgram

ng:

Nanogram

pg:

Picogram

mw:

Molecular weight

K d :

Dissociation constant

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Acknowledgments

The authors wish to thank Steve Kronenberg in the Department of Radiation Oncology, University of Michigan for drawing the bone metastasis model depicted in Scheme 1. We also wish to thank the University of Michigan Office of Technology Transfer for their work on patent 8,940,701: Compounds for, and methods of treating cancer and inhibiting invasion and metastases. The in vitro studies and lung metastasis research described here were supported by a Department of Defense Idea Expansion Award F028579. The bone metastasis research described here was supported by a grant from the Michigan Economic Development Corporation, through the University of Michigan Medical School’s Strategic Research Initiative, U-M MTRAC for Life Sciences.

Authors’ contributions

Hongren Yao performed all of the tissue preparations and confocal microscopic studies necessary for the analysis of the effects of PhScN on lung extravasation and lung colonization. He also performed all of the intratibial injections and tissue preparations, as well as all of the confocal microscopic analysis of bone marrow progression. Donna Veine performed all of the K d determinations, competition binding assays, in vitro invasion assay preparations, data analysis, figure preparation and assisted in manuscript writing. Donna Livant performed all of the in vitro invasion assay data collections, as well as planning and directing the project, and writing the manuscript.

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Authors and Affiliations

  1. Department of Radiation Oncology and Comprehensive Cancer Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI, 48109-5637, USA

    Hongren Yao, Donna M. Veine & Donna L. Livant

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  1. Hongren Yao
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  2. Donna M. Veine
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Correspondence to Donna L. Livant.

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Conflict of interest

The author, Donna Livant, received salary from the University of Michigan, which owns the patent on her invention, patent 8,940,701: Compounds for, and methods of treating cancer and inhibiting invasion and metastases. The authors, Hongren Yao and Donna Veine declare that they have no competing interests.

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Yao, H., Veine, D.M. & Livant, D.L. Therapeutic inhibition of breast cancer bone metastasis progression and lung colonization: breaking the vicious cycle by targeting α5β1 integrin. Breast Cancer Res Treat 157, 489–501 (2016). https://doi.org/10.1007/s10549-016-3844-6

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