Abstract
Purpose: Hsp90, a chaperone to numerous molecular pathways in malignant cells, is elevated in aggressive breast cancers. We hypothesized that identifying breast cells with elevated Hsp90 activity in situ could result in early detection of aggressive breast cancers.Experimental Design: We exploited the uptake of an Hsp90 inhibitor by malignant cells to create an imaging probe (HS131) of Hsp90 activity by linking it to a near-infrared (nIR) dye. HS131 uptake into cells correlated with cell membrane expression of Hsp90 and was used to image molecular subtypes of murine and human breast cancers in vitro and in murine models.Results: HS131 imaging was both sensitive and specific in detecting the murine 4T1 breast cancer cell line, as well as subclones with differing metastatic potential. Highly metastatic subclones (4T07) had high HS131 uptake, but subclones with lower metastatic potential (67NR, 168FARN) had low HS131 uptake. We generated isogenic cell lines to demonstrate that overexpression of a variety of specific oncogenes resulted in high HS131 uptake and retention. Finally, we demonstrated that HS131 could be used to detect spontaneous tumors in MMTV-neu mice, as well as primary and metastatic human breast cancer xenografts. HS131 could image invasive lobular breast cancer, a histologic subtype of breast cancer which is often undetectable by mammography.Conclusions: An HSP90-targeting nIR probe is sensitive and specific in imaging all molecular subtypes of murine and human breast cancer, with higher uptake in aggressive and highly metastatic clones. Clinical studies with Hsp90-targeting nIR probes will be initiated shortly. Clin Cancer Res; 23(24); 7531-42. ©2017 AACR.
Highlights
Screening mammographic techniques have undergone refinement and improvement, the conceptual framework for screening relies on detecting anatomic changes and/or tissue microcalcifications in regions of the breast
We demonstrate that a novel near-infrared dye tethered Hsp90 inhibitor (HS131) is able to detect oncogene-driven breast cancers, including multiple different molecular subtypes of human breast cancers
We generated HS152, which consists of the same nIR dye and a linker but no Hsp90 inhibitor
Summary
We constructed a novel nIR-tethered Hsp inhibitor (subsequently referred to as HS131; Fig. 1A). To confirm the binding of HS131 to tumors, second right and left mammary glands as well as tumor cell aggregates at the injected sites of the flank were collected after mice were euthanized, and nIR signals were analyzed ex vivo (Supplementary Fig. S3B and S3D). Mammary glands that received intraductal implantation of 4T1 cells showed stronger nIR signals compared with control mammary glands, confirming the binding of HS131 to tumor cells This finding suggests the potential of HS131 to label early breast cancers even without apparent neovascularization. All breast cancer xenografts with different molecular subtypes showed stronger nIR signals in tumor by intravenous administration of HS131 compared with HS152, and the retention of the nIR signals was detectable even at the 24-hour time point in HS131-injected mice. We confirmed the efficient in vivo labeling of human breast cancer cells by HS131
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