1 March 2018 Optimizing fluorescently tethered Hsp90 inhibitor dose for maximal specific uptake by breast tumors
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Abstract
Despite improvements in surgical resection, 20-40% of patients undergoing breast conserving surgery require at least one additional re-excision. Leveraging the unique surface expression of heat shock protein 90 (Hsp90), a chaperone protein involved in several key hallmarks of cancer, in breast cancer provides an exciting opportunity to identify residual disease during surgery. We developed a completely non-destructive strategy using HS-27, a fluorescently-tethered Hsp90 inhibitor, to assay surface Hsp90 expression on intact tissue specimens using a fluorescence microendoscope with a field of view of 750 μm and subcellular resolution of 4 μm. HS-27 consists of an FDA approved Hsp90 inhibitor tethered to fluorescein isothiocyanate (EX 488nm, EM 525nm). Here, we optimized ex vivo HS-27 administration in pre-clinical breast cancer models and validated our approach on 21 patients undergoing standard of care ultrasound guided core needle biopsy. HS-27 administration time was fixed at 1- minute to minimize imaging impact on clinical workflow. HS-27 and HS-217 (non-specific control) doses were modulated from 1 μM up to 100 μM to identify the dose maximizing the ratio of specific uptake (HS-27 fluorescence) to non-specific uptake (HS-217 fluorescence). The specificity ratio was maximized at 100 μM and was significantly greater than all other doses (p<0.05). We applied our optimized imaging protocol to clinical samples and demonstrated significantly greater uptake of HS-27 by tumor than non-tumor tissue (p<0.05). The ubiquitous nature of HS-27 binding to all subtypes of breast cancer makes this technology attractive for assessing tumor margins, as one agent can be used for all subtypes.
Conference Presentation
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Brian T. Crouch, Joy Duer, Roujia Wang, Jennifer Gallagher, Allison Hall, Mary Scott Soo, Philip Hughes, Timothy A. J. Haystead, Nirmala Ramanujam, "Optimizing fluorescently tethered Hsp90 inhibitor dose for maximal specific uptake by breast tumors", Proc. SPIE 10478, Molecular-Guided Surgery: Molecules, Devices, and Applications IV, 1047804 (1 March 2018); doi: 10.1117/12.2285210; https://doi.org/10.1117/12.2285210
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