Introducing HDAC-Targeting Radiopharmaceuticals for Glioblastoma Imaging and Therapy

Abstract

Despite recent advances in multimodality therapy for glioblastoma (GB) incorporating surgery, radiotherapy, chemotherapy and targeted therapy, the overall prognosis remains poor. One of the interesting targets for GB therapy is the histone deacetylase family (HDAC). Due to their pleiotropic effects on, e.g., DNA repair, cell proliferation, differentiation, apoptosis and cell cycle, HDAC inhibitors have gained a lot of attention in the last decade as anti-cancer agents. Despite their known underlying mechanism, their therapeutic activity is not well-defined. In this review, an extensive overview is given of the current status of HDAC inhibitors for GB therapy, followed by an overview of current HDAC-targeting radiopharmaceuticals. Imaging HDAC expression or activity could provide key insights regarding the role of HDAC enzymes in gliomagenesis, thus identifying patients likely to benefit from HDACi-targeted therapy.

Keywords: glioblastoma; histone deacetylases inhibitors; radiopharmaceuticals; theranostics.

Figure 1

Overview of the broad effects of HDAC inhibitors.

Figure 2

Overview of current radiopharmaceuticals targeting HDAC. The HDAC class targeted is shown. If only one HDAC enzyme is targeted, this was highlighted in color (orange, purple and green).

Figure 3

The chemical structure of [¹⁸F]F-SAHA (A), [¹⁸F]FET-SAHA (B), [¹⁸F]F-panobinostat (C) and [⁶⁴Cu]Cu-CUDC-101 (E). [¹⁸F]F-panobinostat PET imaging when delivered via convection-enhanced delivery (CED) or intraperitoneal (IP) (D). In vivo PET imaging of [⁶⁴Cu]Cu-CUDC-101 in MDA-MB-231-bearing tumor mice, with or without co-injection of cold CUDC-101 (F,G). Images reproduced with permission from [180,184]. Copyright 2013 and 2018 American Chemical Society.