Imaging the DNA damage response with PET and SPECT

Abstract

DNA integrity is constantly challenged by endogenous and exogenous factors that can alter the DNA sequence, leading to mutagenesis, aberrant transcriptional activity, and cytotoxicity. Left unrepaired, damaged DNA can ultimately lead to the development of cancer. To overcome this threat, a series of complex mechanisms collectively known as the DNA damage response (DDR) are able to detect the various types of DNA damage that can occur and stimulate the appropriate repair process. Each DNA damage repair pathway leads to the recruitment, upregulation, or activation of specific proteins within the nucleus, which, in some cases, can represent attractive targets for molecular imaging. Given the well-established involvement of DDR during tumorigenesis and cancer therapy, the ability to monitor these repair processes non-invasively using nuclear imaging techniques may facilitate the earlier detection of cancer and may also assist in monitoring response to DNA damaging treatment. This review article aims to provide an overview of recent efforts to develop PET and SPECT radiotracers for imaging of DNA damage repair proteins.

Keywords: DNA damage; Molecular Imaging; PARP; PET; SPECT; γH2AX.

Fig. 1

A simplified overview of the DNA damage response and the main targets involved. BER, Base Excision Repair; HR, Homologous Recombination; NHEJ, Non-Homologous End Joining; LIG3, DNA Ligase 3; XRCC1, X-ray repair cross-complementing protein 1; PARP-1, poly (ADP-ribose) polymerase 1; BRCA1/2, Breast Cancer 1/2; ATM, Ataxia Telangiectasia Mutated; DNA-PK, DNA-dependent protein kinase catalytic subunit

Fig. 2

A simplified diagram showing the major steps in short-patch base excision repair pathway. In the presence of DNA damage, PARP-1 is activated upon binding to SSBs, leading to recruitment of BER proteins. These proteins will then identify and repair the damage

Fig. 3

A simplified diagram of the principal steps in the repair of double strand breaks by homologous recombination (HR) and non-homologous end joining (NHEJ)

Fig. 4

Immunostaining of fine-needle aspiration tumour specimens from a patient with non-Hodgkin’s lymphoma deposits reveals the appearance of γH2AX (green) and 53BP1 foci within the nucleus (DAPI, blue) 20 min following irradiation. Reproduced with permission from [54]

Fig. 5

A selection of ¹⁸F-radiolabelled PARP-1 inhibitors derived from Olaparib

Fig. 6

Reiner et al. demonstrated that measuring response to Olaparib treatment is possible using [¹⁸F]-BO [83]. Left: In mice bearing A2780 tumour xenografts, tumour-to-muscle contrast ratios markedly reduce following administration of Olaparib. Right: Representative PET/CT images pre- and post-Olaparib administration. Reproduced with permission from [83]

Fig. 7

Top: In orthotopic glioblastoma-bearing mice, PET/MRI images showed pronounced uptake of [¹⁸F]PARPi at 2 h post-injection. Bottom: Pre-injection with a 500-fold excess of Olaparib effectively reduced tumour uptake of [¹⁸F]PARPi, providing evidence of specificity of the imaging agent for PARP-1. Reproduced with permission from [78]

Fig. 8

A selection of radiolabelled PARP-1 inhibitors based on benzimidazole derivatives

Fig. 9

Cornelissen et al. showed that uptake of ¹¹¹In-anti-γH2AX-TAT in MDA-MB-468 breast cancer tumours increased following irradiation in a dose-dependent manner. Reproduced with permission from [110]

Fig. 10

A Kaplan-Meier plot revealing that precancerous lesions and tumours in BALB-neuT mice could be positively identified by ¹¹¹In-anti-γH2AX-TAT SPECT imaging at a younger age compared with palpation or DCE MR imaging