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Current Advances in PARP1-Targeted Theranostics
Jie Tong1, Baosheng Chen1, Tommaso Volpi1
1Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut, USA.
Abstract:
Poly (ADP-ribose) polymerase 1 (PARP1) plays critical roles in DNA repair, chromatin regulation, and cellular equilibrium, positioning it as a pivotal target for therapeutic interventions in cancer and central nervous system (CNS) disorders. PARP1 responds to oxidative stress and DNA damage through PARylation, influencing energy depletion, survival, inflammation, and genomic regulation in many biological scenarios. PARP inhibitors (PARPis) have demonstrated efficacy against cancers harboring defective homologous recombination repair pathways, notably those linked to BRCA mutations. PARP1-targeted PET imaging enables patient stratification, treatment assessment, and PARPi pharmacodynamic evaluation in cancers and other pathophysiological conditions. Importantly, PARP1-targeted theranostics have emerged for both diagnostic imaging and therapeutic applications in multiple types of cancers, representing a pivotal advancement in personalized oncology. However, its application in brain tumors is limited by the heterogeneous integrity of the blood brain barrier (BBB) and the blood-tumor barrier. Thus, the development of BBB-penetrant PARP1 tracers remains an unmet need for imaging brain cancers. This review summarizes the current landscape of radiopharmaceuticals and radioligands targeting PARP1, detailing their pharmacological characteristics and potential clinical uses. Furthermore, this review discusses PARP1 tracers that can cross the BBB, underscoring their potential applications in neurooncology and other neurological disorders.
Insights
Poly (ADP-ribose) polymerase 1 (PARP1) is crucial for DNA repair and targeted by cancer therapies. New PARP1 imaging agents that cross the blood-brain barrier are needed for brain cancer diagnosis and treatment.
Area of Science:
- Biochemistry and Molecular Biology
- Oncology
- Radiopharmaceutical Science
Background:
- Poly (ADP-ribose) polymerase 1 (PARP1) is vital for DNA repair, chromatin regulation, and cellular homeostasis.
- PARP1 activity, through PARylation, impacts cellular responses to oxidative stress and DNA damage, influencing survival and inflammation.
- PARP inhibitors (PARPis) show efficacy in cancers with homologous recombination repair defects, such as BRCA-mutated cancers.
Purpose of the Study:
- To review radiopharmaceuticals and radioligands targeting PARP1 for diagnostic and therapeutic applications.
- To highlight the need for blood-brain barrier (BBB)-penetrant PARP1 tracers for neurooncology.
- To discuss the potential of BBB-penetrant PARP1 tracers in diagnosing and treating brain cancers and other neurological disorders.
Main Methods:
- Literature review of PARP1-targeted radiopharmaceuticals and radioligands.
- Analysis of pharmacological characteristics and clinical utility of existing PARP1 tracers.
- Evaluation of PARP1 tracers capable of crossing the BBB.
Main Results:
- PARP1 is a validated therapeutic target in oncology and CNS disorders.
- PARP1-targeted PET imaging aids in patient stratification and treatment monitoring.
- Development of BBB-penetrant PARP1 tracers is crucial for advancing neuro-oncology.
Conclusions:
- PARP1-targeted theranostics represent a significant step in personalized oncology.
- Limited BBB penetration restricts current PARP1 imaging applications in brain tumors.
- BBB-penetrant PARP1 tracers hold promise for neuroimaging and neurological disorder management.
