Abstract
Poly(ADP-ribose)polymerase-1 (PARP1) is a DNA repair enzyme highly expressed in the nuclei of mammalian cells, with a structure and function that have attracted interest since its discovery. PARP inhibitors, moreover, can be used to induce synthetic lethality in cells where the homologous recombination (HR) pathway is deficient. Several small molecule PARP inhibitors have been approved by the FDA for multiple cancers bearing this deficiency These PARP inhibitors also act as radiosensitizing agents by delaying single strand break (SSB) repair and causing subsequent double strand break (DSB) generation, a concept that has been leveraged in various preclinical models of combination therapy with PARP inhibitors and ionizing radiation. Researchers have determined the efficacy of various PARP inhibitors at sub-cytotoxic concentrations in radiosensitizing multiple human cancer cell lines to ionizing radiation. Furthermore, several groups have begun evaluating combination therapy strategies in mouse models of cancer, and a fluorescent imaging agent that allows for subcellular imaging in real time has been developed from a PARP inhibitor scaffold. Other PARP inhibitor scaffolds have been radiolabeled to create PET imaging agents, some of which have also entered clinical trials. Most recently, these highly targeted small molecules have been radiolabeled with therapeutic isotopes to create radiotherapeutics and radiotheranostics in cancers whose primary interventions are surgical resection and whole-body radiotherapy. In this review we discuss the utilization of these small molecules in combination therapies and in scaffolds for imaging agents, radiotherapeutics, and radiotheranostics. Development of these radiolabeled PARP inhibitors has presented promising results for new interventions in the fight against some of the most intractable cancers.
Highlights
Poly(ADP-ribose)polymerase-1 (PARP1) is a 116 kDa DNA repair enzyme with nuclear concentrations ranging from 2 × 105 to 1 × 106 enzymes/nucleus in eukaryotic cells (Ludwig et al, 1988; Herceg and Wang, 2001)
Exploiting synthetic lethality—a relationship between two cellular mechanisms wherein the functional loss of one is survivable but the loss of both is lethal—was proposed as a treatment for cancer almost a quarter of a century ago (Hartwell et al, 1997). This strategy was validated during the phase I trial of the PARP1/2 inhibitor olaparib, when the majority of patients with BRCA1/2 mutations saw a benefit from PARPi intervention (Fong et al, 2009)
At the time of writing, four therapeutic PARP inhibitors have been approved by the FDA and four more are in various stages of clinical trials
Summary
Poly(ADP-ribose)polymerase-1 (PARP1) is a 116 kDa DNA repair enzyme with nuclear concentrations ranging from 2 × 105 to 1 × 106 enzymes/nucleus in eukaryotic cells (Ludwig et al, 1988; Herceg and Wang, 2001). Preclinical data has demonstrated that PARP inhibition can increase radiosensitivity in cancer cells (Wang et al, 2019). The efficacy of combination therapies employing PARP inhibitors and external beam radiation has been demonstrated in the clinic, and several phase I clinical trials based on this approach have been completed at the time of writing (NCT00770471, NCT00649207, NCT01264432, NCT01477489, NCT01514201, NCT01657799), with results being available for some of them (Russo et al, 2009; Tangutoori et al, 2015; Dréan et al, 2016). Several clinical trials of PARPinhibitor-based diagnostic imaging agents are currently in progress or have been completed ([18F]FluorThanatrace (Michel et al, 2017), PARPi-FL (Kossatz et al, 2019)), and [18F]PARPi (Schöder et al, 2019)) and a number of therapeutic radiopharmaceuticals based on PARP inhibitors have been employed in preclinical animal models (Kossatz et al, 2016; Michel et al, 2017; Sander Effron et al, 2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
