Advancements in PARP1 Targeted Nuclear Imaging and Theranostic Probes

Abstract

<jats:p>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 gBRCAmut 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.</jats:p>

H2O2‐Driven Anticancer Activity of Mn Porphyrins and the Underlying Molecular Pathways

“…It was also found that MnP inhibits the antiapoptotic proteins, bcl-2 and mcl-1, which are overexpressed in high-grade serous cancer cells [129], thus promoting apoptotic pathways (see Figure 2). PARP is also overexpressed in several types of ovarian cancer cells, and MnP was found to suppress its activity via increasing levels of inactive cleaved PARP ( Figure 2) [137]. MnP was also found to increase the levels of activated, cleaved caspase 3 [137].…”

“…PARP is also overexpressed in several types of ovarian cancer cells, and MnP was found to suppress its activity via increasing levels of inactive cleaved PARP ( Figure 2) [137]. MnP was also found to increase the levels of activated, cleaved caspase 3 [137]. TP53 and MAPK/ERK are mutated in low-grade serous cancer [127] allowing for the therapeutic interventions with their inhibitors, MnPs prospectively being one of those.…”

Molecular Imaging: PARP-1 and Beyond

“…In disease settings, extensive DNA damage can trigger PARP-1 hyperactivation, leading to redox imbalances and excess accumulation of the highly branched anionic poly(adenosine diphosphate-ribose) polymer, all of which promote the dysregulation of critical cell processes (4). Although moderate genotoxic stimuli facilitate PARP-1 activation and DNA repair, increased PARP-1 activity and expression have been linked to several pathologic states, with the most prominent being the overexpression of PARP-1 across a diverse set of carcinomas ( 5)-an observation that has led to recognition of PARP-1 as an attractive imaging target in human malignancies (5). PARP-1 is also involved in modulating cancer cell immunogenicity and has been implicated in the regulation of inflammatory response mechanisms, including the modulation of disease-associated genes such as chemokines, proinflammatory mediators, and metabolic factors (6).…”

Prognostic and Theranostic Applications of Positron Emission Tomography for a Personalized Approach to Metastatic Castration-Resistant Prostate Cancer

“…While PARP-1 targeted inhibitors have been relatively fast developed and approved, the determination of PARP-1 expression might help to predict the response to PARP inhibitor treatment. Sankaranarayanan et al summarize the recent preclinical advancements in imaging and theranostic PARP-1 targeted tracers [ 92 ]. To estimate PARP1 levels, several imaging probes with fluorescent or gamma/beta-emitting radionuclides have been proposed.…”