Project title: Treatment with fluorescently-tethered Hsp90 inhibitors provides therapeutic effect and diagnostic information for breast cancer in pre-clinical models
Project Description: Heat-shock protein 90 (Hsp90) is a signaling node that can be exploited to distinguish malignant from normal tissues. Our group has leveraged differences in expression of Hsp90 by breast tumor cells to create a targeted fluorophore for highly specific labeling of malignant tissue. The exquisite specificity of this molecular contrast agent to breast cancer paired with the potential to inhibit Hsp90 makes fluorescently-tethered Hsp90 inhibitors ideal candidates for breast cancer surveillance and treatment. High Hsp90 expression in breast cancer patients has been previously associated with poor prognosis and decreased survival. Other studies have shown that Hsp90 may play a role in acquired resistance to neo-adjuvant chemotherapy, hormone therapy, and other targeted therapies. These studies suggest that targeting Hsp90 may uncover unique therapeutic and diagnostic opportunities. While previous chemotherapeutic agents have been either generally cytotoxic or have targeted a single protein (such as Her2), inhibiting Hsp90 results in the misfolding and loss of function of multiple oncoproteins, such as Her2, Akt, and Raf1. While previous fluorescent probes have relied either on the enhanced permeability and retention effect or on complex pharmacokinetics with receptors to provide diagnostic contrast between normal and cancerous cells, fluorescently-tethered Hsp90 inhibitors highlight breast cancer cells through simple and selective uptake. Hs-27 is taken up by all receptor subtypes of breast cancer, however, uptake is greatest in Her2 over-expression cells. Hs-27 fluorescence is greater in MDA-MB-231 mice than in non-tumor mice, with maximal difference occurring around 40-minutes post injection. Applications of this technology include: enhancing margin assessment efforts by providing exogenous contrast between tumor and non-tumor tissue; image-guided-surgery; theranostic capabilities where the same compound can be used to both ‘see-and-treat’ cancer; metastatic lymph node detection to intra-operatively inform surgical decisions when excising lymph nodes.
Confocal imaging and hyperspectral imaging of Hs-27 uptake in vitro and in vivo. (A) Hs-27 is taken up by all receptor subtypes of breast cancer, with uptake being the greatest in Her2-overexpressing BT-474 cells. (B) In vivo, mice had a dorsal skinfold window chamber implanted either with or without MDA-MB-231 cells. Hs-27 fluorescence was greater in MDA-MB-231 mice than in non-tumor mice, with maximal difference occurring around 40-minutes post injection.