Metabolic Targeted Therapy for Aggressive B-Cell Lymphomas: Evaluating Glucose Metabolism and the Potential of ¹⁸⁷rhenium- Ethylenedicysteine –N-AcetylGlucosamine (¹⁸⁷Re-ECG) for Therapy

Abstract 117

Aggressive non-Hodgkin lymphomas (NHL), such as diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), are very common in the US with increasing incidences. Although these lymphomas are now potentially curable, almost half the treated patients still develop relapsed/refractory (r/r) disease with poor survival outcomes, indicating an urgent need for better therapeutic approaches with improved efficacy, particularly in r/r lymphomas. The emerging area in lymphoma biology involving energy metabolism, has begun to identify likely potential molecular targets for novel therapeutics that can fundamentally change the conventional treatment of cancer. Glucose metabolism, besides its basic metabolic functions in cell physiology, has been shown to provide the major energy source fueling tumor cell growth and survival. We show here that aggressive B-cell lymphomas highly expressed glucose transporters types 1(Glut1) and 3 (Glut3) and hexokinase II (HKII) in both cell lines and primary cases. Since glucose metabolism is highly active and utilized in aggressive B-cell lymphomas, we explored exploiting this bi-functional pathway(s) as a targeted therapy. Previous studies have shown that ^99mTc-ethylenedicysteine-N-Acetylglucosamine (ECG), a synthetic glucose analogue, accumulates in cancer cell nuclei and various tumors in animal models. Its' also been shown to differentiate tumor vs inflammation in animal models. Rhenium (Re-therapeutic metal) metal displays similar chemical properties to ^99mTc (diagnostic metal), allowing the use of the same backbone (synthetic glucose analogue) for diagnostic and potential therapy. This analogue provides the capability to simultaneously monitor therapeutic activity during induction of tumor treatment therapy while assessing its efficacy. Re-ECG was synthesized by reacting Re-EC with glucosamine tetraacetate. After deprotection of tetraacetate, Re-ECG was produced. Thymidine incorporation assays indicated that Re-ECG inhibits cell proliferation of aggressive dividing lymphoma cells, but was less effective in slow growing lymphoma cells. Further analysis showed that Re-ECG uptake is also more prominent in highly proliferative lymphoma cells, where Re-ECG enters the nucleus and causes DNA damage that leads to lymphoma cell apoptosis. We also evaluated the biodistribution pattern of Re-ECG in a lymphoma SCID mouse model through imaging by single-photon emission computed tomography (SPECT), accelerator mass spectrometry (AMS) and liquid scintillation counting (LSC). The bio-distribution data revealed that radioactivity (¹⁴C-¹⁸⁷Re-ECG) was retained well in tumor tissue 2 hours post-injection with little to no uptake in the plasma when compared to tumor. The compound was excreted over longer incubation time. Over all, we observed that the lymphoma tumor has an extended drug retention time when compared to other tissues. These results suggest that the metallic pharmaceutical agent ¹⁸⁷Re-ECG is an excellent potential candidate for targeted therapy in aggressive r/r lymphomas. This application further defines the term theranostic for personalized medicine approaches utilizing bifunctional imaging/therapeutic agents.