Cysteine Cathepsins in Breast Cancer: Promising Targets for Fluorescence-Guided Surgery

Abstract

The majority of breast cancer patients is treated with breast-conserving surgery (BCS) combined with adjuvant radiation therapy. Up to 40% of patients has a tumor-positive resection margin after BCS, which necessitates re-resection or additional boost radiation. Cathepsin-targeted near-infrared fluorescence imaging during BCS could be used to detect residual cancer in the surgical cavity and guide additional resection, thereby preventing tumor-positive resection margins and associated mutilating treatments. The cysteine cathepsins are a family of proteases that play a major role in normal cellular physiology and neoplastic transformation. In breast cancer, the increased enzymatic activity and aberrant localization of many of the cysteine cathepsins drive tumor progression, proliferation, invasion, and metastasis. The upregulation of cysteine cathepsins in breast cancer cells indicates their potential as a target for intraoperative fluorescence imaging. This review provides a summary of the current knowledge on the role and expression of the most important cysteine cathepsins in breast cancer to better understand their potential as a target for fluorescence-guided surgery (FGS). In addition, it gives an overview of the cathepsin-targeted fluorescent probes that have been investigated preclinically and in breast cancer patients. The current review underscores that cysteine cathepsins are highly suitable molecular targets for FGS because of favorable expression and activity patterns in virtually all breast cancer subtypes. This is confirmed by cathepsin-targeted fluorescent probes that have been shown to facilitate in vivo breast cancer visualization and tumor resection in mouse models and breast cancer patients. These findings indicate that cathepsin-targeted FGS has potential to improve treatment outcomes in breast cancer patients.

Bioinspired color-near infrared endoscopic imaging system for molecular guided cancer surgery

“…Enzyme-or pH-activated probes have the potential to address some of these shortcomings as demonstrated by results from phase 2 and phase 3 clinical trials, though none of these probes are FDA-approved at this time. 46,47 Since there is still no universal molecular probe that works for all types of cancers, the next frontier for FGS will involve a cocktail of carefully selected tracers to highlight all tumors and involved lymph nodes.…”

“…However, about ∼20% of adenocarcinoma patients and the majority of squamous cell and non-small cell lung cancer patients will not benefit from the pafolacianine probe due to a lack of folate alpha receptors in the primary tumors. Enzyme- or pH-activated probes have the potential to address some of these shortcomings as demonstrated by results from phase 2 and phase 3 clinical trials, though none of these probes are FDA-approved at this time 46 , 47 . Since there is still no universal molecular probe that works for all types of cancers, the next frontier for FGS will involve a cocktail of carefully selected tracers to highlight all tumors and involved lymph nodes.…”

Activity-Based Fluorescence Diagnostics for Cancer

“…Cysteine cathepsin activities are attractive targets for cancer imaging because these enzymes are overexpressed in diverse cell types within tumors, including cancer cells and tumor-associated macrophages. − In order to utilize more specific enzymes for fluorescence activation instead of broad proteases found in the lysosome, they also developed cathepsin D, cathepsin B, and cathepsin K sensitive NIR fluorescence probes based on the dye–dye FRET mechanism, respectively. − …”

Tumor-targeted precision surgery

“…AKRO-QC-ICG is a topically applied fluorescent imaging agent that consists of an analogue of indocyaninegreen (ICG) and a quencher conjugated to a core Cbz-Phe-Lys peptide sequence (37). The imaging agent is cleaved and activated by the cysteine cathepsins B, L and S, proteolytic enzymes that are highly upregulated in multiple cancer types, including breast cancer (38,39). It exploits a latent lysosomotropic effect (LLE) that causes accumulation of the fluorescent fragments of the probe in lysosomes, resulting in increased signal strength and duration (37).…”