Advancements in PARP1 Targeted Nuclear Imaging and Theranostic Probes

Abstract

The central paradigm of novel therapeutic approaches in cancer therapy is identifying and targeting molecular biomarkers. One such target is the nuclear DNA repair enzyme Poly-(ADP ribose) polymerase 1 (PARP1). Sensitivity to PARP inhibition in certain cancers such as gBRCA^mut breast and ovarian cancers has led to its exploitation as a target. The overexpression of PARP1 in several types of cancer further evoked interest in its use as an imaging target. While PARP1-targeted inhibitors have fast developed and approved in this past decade, determination of PARP1 expression might help to predict the response to PARP inhibitor treatment. This has the potential of improving prognosis and moving towards tailored therapy options and/or dosages. This review summarizes the recent pre-clinical advancements in imaging and theranostic PARP1 targeted tracers. To assess PARP1 levels, several imaging probes with fluorescent or beta/gamma emitting radionuclides have been proposed and three have advanced to ongoing clinical evaluation. Apart from its diagnostic value in detection of primary tumors as well as metastases, this shall also help in delivering therapeutic radionuclides to PARP1 overexpressing tumors. Henceforth nuclear medicine has now advanced towards conjugating theranostic radionuclides to PARP1 inhibitors. This paves the way for a future of PARP1-targeted theranostics and personalized therapy.

Keywords: Auger and Alpha emitters; PARP inhibition; PARP1 theranostic probes; PARP1 tracers; PET/SPECT imaging.

Figure 1

Schematic representation of PARP1-targeted therapy and imaging approaches. (A) Upon no treatment, PARP1-mediated repair enables cancer cell proliferation and tumour growth. (B) PET/SPECT radionuclide-conjugated PARP inhibitors enable imaging of the tumour tissues and PARP1-expression levels. (C) PARP inhibitor-based targeted therapy causes "Synthetic lethality", thereby inhibiting DNA repair mechanisms. (D) Auger electron (displayed in picture), Beta or Alpha particle-emitting radionuclides are able to cause DNA damage apart from synthetic lethality, and functions as a "two-hit" strategy and enhances apoptosis of cancer cells. For optimal synthetic lethality, supplementation with PARP inhibitors would be required.

Figure 2

PET/CT images of ¹⁸F-FTT uptake in ovarian cancer patients. PET/CT images from a clinical trial (NCT02637934) in three ovarian cancer patients show a wide range of ¹⁸F-FTT uptake in tumor lesions. Standard uptake value (SUV) ranges from 2 (top-left) to 12 (top-right). Yellow arrows indicate sites of tumor. Reproduced with permission from Makvandi et al., titled “A PET imaging agent to evaluate PARP expression in ovarian cancer”, published by The Journal of Clinical Investigation, 2018 [46].