Preclinical and first-in-human-brain-cancer applications of [18F]poly-(ADP-ribose) polymerase inhibitor PET/MR

Young, Robert J.; França, Paula Demétrio De Souza; Pirovano, Giacomo; Piotrowski, Anna F.; Nicklin, Philip J.; Riedl, Christopher C.; Schwartz, Jazmin; Bale, Tejus; Donabedian, Patrick L.; Kossatz, Susanne; Burnaz, Eva M; Roberts, Sheryl; Lyashchenko, Serge K.; Miller, Alexandra; Fiasconaro, Megan; Zhang, Zhigang; Mauguen, Audrey; Reiner, Thomas; Dunphy, Mark

doi:10.1101/2020.07.13.20141036

Cited by 5 publications

(3 citation statements)

References 44 publications

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“…2C). Furthermore, recent clinical data has shown that the utility of [ 18 F]PARPi can be potentially expanded to image brain cancer in patients for treatment monitoring (68). In addition to applying radiolabeled-PARPi in patients for cancer detection, a fluorescent-labeled PARPi, PARPi-FL, was also subjected to clinical studies for the detection of oral carcinoma, and potentially serve as the surgical-margin assessment of epithelial cancer of the upper intestinal tract (69).…”

Section: Radiolabeled Parp Inhibitors: Imaging and Therapymentioning

confidence: 99%

PARP Inhibitors in Cancer Diagnosis and Therapy

Chan

Tan

Cornelissen

2020

Clinical Cancer Research

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Targeting of poly(ADP-ribose)polymerase (PARP) enzymes has emerged as an effective therapeutic strategy to selectively target cancer cells with deficiencies in homologous recombination (HR) signaling. Currently used to treat BRCA-mutated cancers, PARP inhibitors (PARPi) have demonstrated improved outcome in various cancer types as single agents. Ongoing efforts have seen the exploitation of PARPi combination therapies, boosting patient responses as a result of drug synergisms.Despite great successes using PARPi therapy, selecting those patients who will benefit from single agent or combination therapy remains one of the major challenges.Numerous reports have demonstrated that the presence of a BRCA mutation does not always result in synthetic lethality with PARPi therapy in treatment-naïve tumors.Cancer cells can also develop resistance to PARPi therapy. Hence, combination therapy may significantly affect the treatment outcomes. In this review, we discuss the development and utilization of PARPi in different cancer types from preclinical models to clinical trials, provide a current overview of the potential uses of PARP imaging agents in cancer therapy, and discuss the use of radiolabeled PARPi as radionuclide therapies.

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Section: Radiolabeled Parp Inhibitors: Imaging and Therapymentioning

confidence: 99%

PARP Inhibitors in Cancer Diagnosis and Therapy

Chan

Tan

Cornelissen

2020

Clinical Cancer Research

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“…25 PARP imaging has proven its exceptional clinical merit in several scenarios, specifically for the detection and delineation of oral, brain, pancreatic, and liver cancers, as well as target engagement imaging of different PARP inhibitors. [26][27][28][29][30][31][32] Several PARP1-targeted imaging probes have been developed, with the most prominent among these being PARPi-FL, a fluorescently labeled olaparib analog; [ 18 F]FTT, the first clinically applied PARP radiotracer based on rucaparib. 33 To fully exploit PARP as an imaging biomarker, the development of novel PARP imaging probes with further improved pharmacological profiles is warranted.…”

Section: -23mentioning

confidence: 99%

DoE Optimization Empowers the Automated Preparation of Enantiomerically Pure [18F]Talazoparib and its In Vivo Evaluation as a PARP Radiotracer.

Bowden¹,

Stotz²,

Kinzler³

et al. 2021

Preprint

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PARP inhibitors are proven chemotherapeutics and serve as lead structures for the development of PARP-targeted in vivo imaging probes. Given the clinical potential of PARP imaging for the detection and stratification of various cancers, the development of novel PARP imaging probes with improved pharmacologi-cal profiles over established PARP imaging agents is warranted. Here, we present a novel 18F-labeled PARP radiotracer based on the clinically superior PARP inhibitor talazoparib. An automated radiosynthesis of [18F]talazoparib (RCY: 13 ± 3.4 %; n = 4; molar radioactivity 52 – 176 GBq/μmol) was achieved using a “Design of Experiments” (DoE) optimized copper-mediated radiofluorination reaction. The chiral product was isolated from the reaction mixture using 2D reversed-phase/chiral radio-HPLC (>99% ee). (8S, 9R)-[18F]Talazoparib demonstrated PARP binding in HCC1937 cells in vitro and showed an excellent tumor-to-blood ratio in xeno-graft-bearing mice (10.2 ± 1.5). Despite expected uptake into muscle, bone, and abdominal tissue, a favorable pharmacological profile in terms of excretion, blood half-life, and target engagement was observed in the pilot in vivo study. This synthesis of [18F]talazoparib exemplifies how a DoE based tracer development pipeline can enable the radiosyntheses of clinically relevant but synthetically challenging radiolabeled compounds of high interest to the imaging community.

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“…The structure of [ 18 F]PARPi is derived from the scaffold of Olaparib, an FDA-approved PARP1 inhibitor widely used as a therapeutic agent in gynecological malignancies [ 23 ]. [ 18 F]PARPi has been previously shown to bind specifically to tumor areas with a minimal off-target uptake [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

[¹⁸F]PARPi Imaging Is Not Affected by HPV Status In Vitro

et al. 2021

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Background. Human papillomavirus- (HPV-) associated oropharyngeal squamous cell carcinomas (OPSCCs) are clinically and pathologically distinct from HPV-negative tumors. Here, we explore whether HPV affects functional biomarkers, including γH2AX, RAD51, and PARP1. Moreover, the role of [18F]PARPi as a broadly applicable imaging tool for head and neck carcinomas is investigated. Methods. HPV-positive and HPV-negative cell lines were used to evaluate the γH2AX, RAD51, and PARP1 expression with immunoblotting and immunofluorescence. Effects of external beam ionizing radiation were investigated in vitro, and survival was investigated via colony-formation assay. [18F]PARPi uptake experiments were performed on HPV-negative and HPV-positive cell lines to quantify PARP1 expression. PARP1 IHC and γH2AX foci were quantified using patient-derived oropharyngeal tumor specimens. Results. Differences in DNA repair were detected, showing higher RAD51 and γH2AX expression in HPV-positive cell lines. Clonogenic assays confirm HPV-positive cell lines to be significantly more radiosensitive. PARP1 expression levels were similar, irrespective of HPV status. Consequently, [18F]PARPi uptake assays demonstrated that this tracer is internalized in cell lines independently from their HPV status. Conclusion. The HPV status, often used clinically to stratify patients, did not affect PARP1 levels, suggesting that PARP imaging can be performed in both HPV-positive and HPV-negative patients. This study confirms that the PET imaging agent [18F]PARPi could serve as a general clinical tool for oropharyngeal cancer patients.

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Preclinical and first-in-human-brain-cancer applications of [18F]poly-(ADP-ribose) polymerase inhibitor PET/MR

Cited by 5 publications

References 44 publications

PARP Inhibitors in Cancer Diagnosis and Therapy

PARP Inhibitors in Cancer Diagnosis and Therapy

DoE Optimization Empowers the Automated Preparation of Enantiomerically Pure [18F]Talazoparib and its In Vivo Evaluation as a PARP Radiotracer.

[¹⁸F]PARPi Imaging Is Not Affected by HPV Status In Vitro

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Preclinical and first-in-human-brain-cancer applications of [18F]poly-(ADP-ribose) polymerase inhibitor PET/MR

Cited by 5 publications

References 44 publications

PARP Inhibitors in Cancer Diagnosis and Therapy

PARP Inhibitors in Cancer Diagnosis and Therapy

DoE Optimization Empowers the Automated Preparation of Enantiomerically Pure [18F]Talazoparib and its In Vivo Evaluation as a PARP Radiotracer.

[18F]PARPi Imaging Is Not Affected by HPV Status In Vitro

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[¹⁸F]PARPi Imaging Is Not Affected by HPV Status In Vitro