Abstract P2-02-17: Metabolism-driven cancer identification with GLUT5-specific molecular probes
Authors: Ghosh A , Kannan S , Begoyan VV , Weselinski LJ , Rao S , Tanasova M 
Published: May 2019

Background: Current cancer imaging agents are limited in their ability to distinguish cancers from normal cells (low cancer-selectivity) and identify cancers at different stages of development (low cancer-specificity). This limitation makes biopsy mandatory for diagnosis and continuous treatment monitoring. Analysis of biopsy samples may also have some ambiguity in clearly identifying malignant and metastatic cells, resulting in cases of mischaracterization and overdiagnosis. Hence, cancer-selective and cancer-specific imaging agents are needed. Distinguishing cancer types and stages can be achieved by addressing differences in their nutrient uptake, manifested as changes in the expression of facilitative sugar transporters (GLUTs). Here, we present a novel approach to target the enhanced metabolism in breast cancers with sugar-like fluorescently labeled probes – ManCous - engineered for specific uptake by fructose transporter GLUT5. The differential accumulation of these probes in cancer cells parallels the differential activity of GLUT5 and results in active fluorescence accumulation within cancers with the highest levels observed in premalignant phenotypes.

Results: Locking fructose conformation in the furanose form was found to provide a sugar-like mimics recognized explicitly by GLUT5. The corresponding coumarin conjugates – ManCous (Figure 1A) - were found to exhibit GLUT5-specific uptake and work as reporters of GLUT5 activity in cells. Differential activity of GLUT5 in cells was found to parallel the differences in the uptake of ManCous. Significant differences in accumulation of ManCou-induced fluorescence were observed between normal and cancer cells and between cancer phenotypes (Figure 1A). Namely, an 8-fold difference in ManCou accumulation was observed between normal and adenocarcinoma MCF7 cells, and 70-fold difference was observed between normal and premalignant MCF10aNeoT cells. The uptaken ManCou were found to be metabolized by hexokinase to form phosphorylated analogs and effectively compete with glucose for hexokinase II (Figure 1B). The probes were found to be non-cytotoxic at concentrations below 100 μM, with higher cytotoxicity towards cancer cells at probe concentrations above 100 μM

Conclusions: The dependence of breast cancer cells on fructose provides a firm basis for developing imaging approaches to discriminate between normal and cancer cells as well as potentially between cancer phenotypes. While current probes are restricted to in-vitro imaging, further probe evolution is expected to lead to new in vivo agents, owing to a proper modification of the scaffold with the relevant radioactive (PET) or other imaging entity and retention of transporter specificity. The development of transporter-specific GLUT5 affinity probes could further contribute to enhancing the impact of fructose uptake inhibition for approaching cancer-specific therapies.

Citation Format: Ghosh A, Kannan S, Begoyan VV, Weselinski LJ, Rao S, Tanasova M. Metabolism-driven cancer identification with GLUT5-specific molecular probes [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-02-17.