Abstract
The sigma-2 receptor is expressed in higher density in proliferating (P) tumor cells versus quiescent (Q) tumor cells, thus providing an attractive target for imaging the proliferative status (i.e., P:Q ratio) of solid tumors. Here we evaluate the utility of the sigma-2 receptor ligand 2-(2-[18F]fluoroethoxy)-N-(4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl)-5-methyl-benzamide, [18F]ISO-1, in two different rodent models of breast cancer. In the first study, small animal Positron Emission Tomography (PET) imaging studies were conducted with [18F]ISO-1 and 18FDG in xenografts of mouse mammary tumor 66 and tracer uptake was correlated with the in vivo P:Q ratio determined by flow cytometric measures of BrdU-labeled tumor cells. The second model utilized a chemically-induced (N-methyl-N-nitrosourea [MNU]) model of rat mammary carcinoma to correlate measures of [18F]ISO-1 and FDG uptake with MR-based volumetric measures of tumor growth. In addition, [18F]ISO-1 and FDG were used to assess the response of MNU-induced tumors to bexarotene and Vorozole therapy. In the mouse mammary 66 tumors, a strong linear correlation was observed between the [18F]ISO-1 tumor: background ratio and the proliferative status (P:Q ratio) of the tumor (R = 0.87). Similarly, measures of [18F]ISO-1 uptake in MNU-induced tumors significantly correlated (R = 0.68, P<0.003) with changes in tumor volume between consecutive MR imaging sessions. Our data suggest that PET studies of [18F]ISO-1 provide a measure of both the proliferative status and tumor growth rate, which would be valuable in designing an appropriate treatment strategy.
Highlights
In the clinical management of cancer, major research efforts are devoted to the optimization of chemo- and radio-therapies
The goal of the current study was to assess the capacity of FDG and the sigma-2 receptor ligand, [18F]ISO-1, to measure two different clinically-relevant properties of solid tumors, proliferative status (P:Q ratio) and tumor growth rate
One potential limitation of FDG is in the imaging of cell proliferation; tumor cells have a higher metabolic activity than surrounding normal tissue, the uptake of FDG has shown inconsistent results with respect to the correlation of tracer uptake and in vitro measures of cell proliferation [3]
Summary
In the clinical management of cancer, major research efforts are devoted to the optimization of chemo- and radio-therapies. Subsequent to phosphorylation by the enzyme hexokinase to yield FDG-6phosphate, it is trapped in tumors, providing a non-invasive measure of glucose utilization. Because tumors exhibit asynchronous growth and contain cells in every phase of the cellcycle, G1, S, G2 and M phases, a pulse label measurement of the S-phase fraction of a tumor with [18F]FLT is expected to underestimate the total number of proliferating cells. Since radiotherapy and most chemotherapeutic agents target proliferating tumor cells more effectively than quiescent cells, knowledge of the proliferative status (i.e., P:Q ratio) of a tumor can be used to design appropriate radio- or chemo- therapy treatment strategies [5]. Hyperfractionated radiation therapy or cell-cycle-specific therapeutic agents can be used in tumors with a high proliferative status [6,7]. The proliferative status of a tumor can be used to identify patients who will benefit from therapies targeting proteins expressed in cycling cells but absent in quiescent tumor cells [8,9]
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