Molecular Imaging: PARP-1 and Beyond

Puentes, Laura; Makvandi, Mehran; Mach, Robert H.

doi:10.2967/jnumed.120.243287

Cited by 21 publications

(16 citation statements)

References 34 publications

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“…Most radiopharmaceuticals targeting PARP are structurally similar to small molecules olaparib ([ 18 F]-BO, [ 18 F]-PARPi, [ 18 F]-20, [ 123 I/ 131 I]-PARPi, [ 18 F]-PARPi-FL, [ 64 Cu]-PARPi, [ 18 F]-olaparib, [ 18 F]-AZD2461, [ 18 F]-AZD2281, [ 11 C]-PJ34) or rucaparib ([ 18 F]FTT), [ 18 F]-WC-DZ-F, [ 18 F]FE-LS-75, [ 125 I]-KX1, [ 125 I]-KX-02–019, [ 14 C]-rucaparib, [ 211 At]-MM4) [ 40 , 50 , 53 , 56 , 64 , 69 , 78 , 87 , 188 ]. These radiopharmaceuticals were recently reviewed [ 188 , 237 , 238 ]. Three of these PARP radiopharmaceuticals, namely [ 18 F]-PARPi, [ 18 F]FTT, and [ 14 C]-rucaparib have reached the clinical setting ( Table S2 ) [ 61 , 69 , 76 , 85 ].…”

Section: Ddr (Radio)pharmaceuticalsmentioning

confidence: 99%

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

Everix

Nair

Driver

et al. 2022

Cancers

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Despite numerous innovative treatment strategies, the treatment of glioblastoma (GB) remains challenging. With the current state-of-the-art therapy, most GB patients succumb after about a year. In the evolution of personalized medicine, targeted radionuclide therapy (TRT) is gaining momentum, for example, to stratify patients based on specific biomarkers. One of these biomarkers is deficiencies in DNA damage repair (DDR), which give rise to genomic instability and cancer initiation. However, these deficiencies also provide targets to specifically kill cancer cells following the synthetic lethality principle. This led to the increased interest in targeted drugs that inhibit essential DDR kinases (DDRi), of which multiple are undergoing clinical validation. In this review, the current status of DDRi for the treatment of GB is given for selected targets: ATM/ATR, CHK1/2, DNA-PK, and PARP. Furthermore, this review provides a perspective on the use of radiopharmaceuticals targeting these DDR kinases to (1) evaluate the DNA repair phenotype of GB before treatment decisions are made and (2) induce DNA damage via TRT. Finally, by applying in-house selection criteria and analyzing the structural characteristics of the DDRi, four drugs with the potential to become new therapeutic GB radiopharmaceuticals are suggested.

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Section: Ddr (Radio)pharmaceuticalsmentioning

confidence: 99%

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

Everix

Nair

Driver

et al. 2022

Cancers

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“…While several comprehensive reviews have previously described preclinical development and translational efforts [ 25 , 27 , 28 , 29 , 30 ], the extensive publication of novel radiolabeled PARPi, as well as clinical study results of the translated PARPi ([ 18 F]FTT and [ 18 F]PARPi), just in the last three years, warrants a systematic overview of the current status in the rapidly expanding field of PARP imaging and therapy. We included all existing probes in this analysis to gain an understanding of the effects of the different structural modifications compared to the parent PARPi on affinity, selectivity, cell permeability, and pharmacokinetic properties.…”

Section: Introduction To Radiolabeled Parp Inhibitorsmentioning

confidence: 99%

DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

Nguyen

Pacelli

Nader

et al. 2022

Cancers

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Since it was discovered that many tumor types are vulnerable to inhibition of the DNA repair machinery, research towards efficient and selective inhibitors has accelerated. Amongst other enzymes, poly(ADP-ribose)-polymerase 1 (PARP1) was identified as a key player in this process, which resulted in the development of selective PARP inhibitors (PARPi) as anti-cancer drugs. Most small molecule PARPi’s exhibit high affinity for both PARP1 and PARP2. PARPi are under clinical investigation for mono- and combination therapy in several cancer types and five PARPi are now clinically approved. In parallel, radiolabeled PARPi have emerged for non-invasive imaging of PARP1 expression. PARP imaging agents have been suggested as companion diagnostics, patient selection, and treatment monitoring tools to improve the outcome of PARPi therapy, but also as stand-alone diagnostics. We give a comprehensive overview over the preclinical development of PARP imaging agents, which are mostly based on the PARPi olaparib, rucaparib, and recently also talazoparib. We also report on the current status of clinical translation, which involves a growing number of early phase trials. Additionally, this work provides an insight into promising approaches of PARP-targeted radiotherapy based on Auger and α-emitting isotopes. Furthermore, the review covers synthetic strategies for PARP-targeted imaging and therapy agents that are compatible with large scale production and clinical translation.

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Section: Introductionmentioning

confidence: 99%

“…Several PET radiotracers to image PARP expression have recently been developed [ 13 ]. [ 18 F]FluorThanatrace (FTT), and 18 F-PARPi bind to PARP1, are derived from rucaparib and olaparib, respectively [ 13 ], and are currently being evaluated in breast and ovarian cancers [ 14 , 15 ]. FTT has been developed at our institution, and we have previously reported that FTT has an optimal biodistribution in humans, and the primary route of excretion is through hepatobiliary system [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Pilot Study: PARP1 Imaging in Advanced Prostate Cancer

Dehdashti

Reimers²,

Shoghi

et al. 2022

Mol Imaging Biol

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Purpose PARP inhibitor (PARPi) therapy is approved for patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) genomic aberrations. However, only a fraction of patients with BRCA1/2 mutations respond to PARPi therapy. In this pilot study, we assess PARP-1 expression in prostate cancer patients with and without HRR genomic alternations using a novel PARP-based imaging agent. Procedures Nine advanced prostate cancer patients were studied with PET/CT and [18F]FluorThanatrace (FTT), an analogue of the PARPi rucaparib. Images were analyzed using maximum standardized uptake values (SUVmax). PARP expression was assessed by immunohistochemistry (IHC) when feasible (n = 4). Results We found great variability in FTT uptake (SUVmax range: 2.3–15.4). Patients with HRR mutations had a significantly higher SUVmax (p = 0.0379) than patients with non-HRR mutations although there was an overlap in FTT uptake between groups. Three patients without HRR and one with HRR mutations had similarly high PARP1 IHC expression. Conclusions FTT-PET/CT may serve as an alternate biomarker for PARP1 expression and a potential method for PARPi treatment selection.

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Molecular Imaging: PARP-1 and Beyond

Cited by 21 publications

References 34 publications

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma

DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

Pilot Study: PARP1 Imaging in Advanced Prostate Cancer

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