Kinetic and Static Analysis of Poly-(Adenosine Diphosphate-Ribose) Polymerase-1–Targeted <sup>18</sup>F-Fluorthanatrace PET Images of Ovarian Cancer

Young, Anthony J.; Pantel, Austin R.; Viswanath, Varsha; Dominguez, Tiffany; Makvandi, Mehran; Lee, Hsiaoju; Li, Shihong; Schubert, Erin K.; Pryma, Daniel A.; Farwell, Michael D.; Mach, Robert H.; Simpkins, Fiona; Lin, Lilie L.; Mankoff, David A.; Doot, Robert K.

doi:10.2967/jnumed.121.261894

Cited by 13 publications

(8 citation statements)

References 18 publications

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“…We could estimate [ 211 At]PTT SUVmax in neuroblastoma tumors to reach approximately 10, although in clinical settings SUVmax would be highly variable among different patients and even within a patient. Furthermore, we are unable to accurately estimate absorbed tumor dose from the prior [ 18 F]FTT study as the imaging window of up to 200 minutes from injection failed to reveal a washout pattern 14 . By using the biological half-life seen in mice in the present study (5.1 hr) for [ 211 At]PTT and then applying the SUVmax of 10, we can make a rough estimate of the absorbed tumor dose in a 1year-old patient to be 0.17 Gy per MBq/kg.…”

Section: Discussionmentioning

confidence: 93%

“…Therefore, it is expected that both agents would exhibit similar kinetics in vivo. In ovarian cancer patients, [ 18 F]FTT displayed rapid tumor uptake kinetics between 60-180 minutes post injection with minimal wash-out 14 . Considering [ 18 F]FTT as a surrogate for PARPi, We envisioned the rapid tumor targeting kinetics, slow target off-rate, and deep tumor penetration of a small molecule PARPi to be perfectly matched for the half-life of 211 At (7.2 h).…”

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confidence: 99%

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Pre-clinical investigation of astatine-211-parthanatine for high-risk neuroblastoma

et al. 2022

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Astatine-211-parthanatine ([211At]PTT) is an alpha-emitting radiopharmaceutical therapeutic that targets poly(adenosine-diphosphate-ribose) polymerase 1 (PARP1) in cancer cells. High-risk neuroblastomas exhibit among the highest PARP1 expression across solid tumors. In this study, we evaluated the efficacy of [211At]PTT using 11 patient-derived xenograft (PDX) mouse models of high-risk neuroblastoma, and assessed hematological and marrow toxicity in a CB57/BL6 healthy mouse model. We observed broad efficacy in PDX models treated with [211At]PTT at the maximum tolerated dose (MTD 36 MBq/kg/fraction x4) administered as a fractionated regimen. For the MTD, complete tumor response was observed in 81.8% (18 of 22) of tumors and the median event free survival was 72 days with 30% (6/20) of mice showing no measurable tumor >95 days. Reversible hematological and marrow toxicity was observed 72 hours post-treatment at the MTD, however full recovery was evident by 4 weeks post-therapy. These data support clinical development of [211At]PTT for high-risk neuroblastoma.

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Section: Discussionmentioning

confidence: 93%

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confidence: 99%

Pre-clinical investigation of astatine-211-parthanatine for high-risk neuroblastoma

et al. 2022

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“…Its performance compared to screening for BRCA1/2 mutations in predicting and selecting patients for PARP inhibitor therapy warrants further evaluation [ 63 ]. Young et al studied the pharmacokinetics of [ 18 F]FTT and concluded that imaging at 60 min post-injection is optimal, and whole-body SUV is a robust metric for noninvasively quantifying PARP1 expression in vivo [ 73 ]. McDonald et al conducted a two-single-arm prospective non-randomized clinical trial evaluating PARP expression in breast cancer [ 74 ].…”

Section: [ 18 F]f-radiolabeled Molecular Probes Fo...mentioning

confidence: 99%

[18F]F-Poly(ADP-Ribose) Polymerase Inhibitor Radiotracers for Imaging PARP Expression and Their Potential Clinical Applications in Oncology

Ndlovu,

Lawal,

Mdanda

et al. 2024

JCM

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Including poly(ADP-ribose) polymerase (PARP) inhibitors in managing patients with inoperable tumors has significantly improved outcomes. The PARP inhibitors hamper single-strand deoxyribonucleic acid (DNA) repair by trapping poly(ADP-ribose)polymerase (PARP) at sites of DNA damage, forming a non-functional “PARP enzyme–inhibitor complex” leading to cell cytotoxicity. The effect is more pronounced in the presence of PARP upregulation and homologous recombination (HR) deficiencies such as breast cancer-associated gene (BRCA1/2). Hence, identifying HR-deficiencies by genomic analysis—for instance, BRCA1/2 used in triple-negative breast cancer—should be a part of the selection process for PARP inhibitor therapy. Published data suggest BRCA1/2 germline mutations do not consistently predict favorable responses to PARP inhibitors, suggesting that other factors beyond tumor mutation status may be at play. A variety of factors, including tumor heterogeneity in PARP expression and intrinsic and/or acquired resistance to PARP inhibitors, may be contributing factors. This justifies the use of an additional tool for appropriate patient selection, which is noninvasive, and capable of assessing whole-body in vivo PARP expression and evaluating PARP inhibitor pharmacokinetics as complementary to the currently available BRCA1/2 analysis. In this review, we discuss [18F]Fluorine PARP inhibitor radiotracers and their potential in the imaging of PARP expression and PARP inhibitor pharmacokinetics. To provide context we also briefly discuss possible causes of PARP inhibitor resistance or ineffectiveness. The discussion focuses on TNBC, which is a tumor type where PARP inhibitors are used as part of the standard-of-care treatment strategy.

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“…PET images from this study showed visible [ 18 F]FTT uptake in tumor regions from one out five patients with measurable tumors who had a biphenotypic hepatocellular carcinoma/cholangiocarcinoma [ 82 ]. An erratum to the study corrected that a patient with pancreatic ductal adenocarcinoma, who was originally reported to show [ 18 F]FTT uptake, did not demonstrate [ 18 F]FTT uptake above the background activity [ 83 ]. The effective dose was estimated at 6.9 mSv, which is in a similar range of a [ 18 F]FDG PET scan.…”

Section: Clinical Evaluation Of Parp Imaging Agentsmentioning

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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Kinetic and Static Analysis of Poly-(Adenosine Diphosphate-Ribose) Polymerase-1–Targeted ¹⁸F-Fluorthanatrace PET Images of Ovarian Cancer

Abstract: Kinetic and static analysis of poly-(adenosine diphosphate-ribose) polymerase-1 (PARP-1) targeted 18 F-FluorThanatrace ( 18 F-FTT) PET images of ovarian cancer

Cited by 13 publications

References 18 publications

Pre-clinical investigation of astatine-211-parthanatine for high-risk neuroblastoma

Pre-clinical investigation of astatine-211-parthanatine for high-risk neuroblastoma

[18F]F-Poly(ADP-Ribose) Polymerase Inhibitor Radiotracers for Imaging PARP Expression and Their Potential Clinical Applications in Oncology

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

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Kinetic and Static Analysis of Poly-(Adenosine Diphosphate-Ribose) Polymerase-1–Targeted 18F-Fluorthanatrace PET Images of Ovarian Cancer

Abstract: Kinetic and static analysis of poly-(adenosine diphosphate-ribose) polymerase-1 (PARP-1) targeted 18 F-FluorThanatrace ( 18 F-FTT) PET images of ovarian cancer

Cited by 13 publications

References 18 publications

Pre-clinical investigation of astatine-211-parthanatine for high-risk neuroblastoma

Pre-clinical investigation of astatine-211-parthanatine for high-risk neuroblastoma

[18F]F-Poly(ADP-Ribose) Polymerase Inhibitor Radiotracers for Imaging PARP Expression and Their Potential Clinical Applications in Oncology

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

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Product

Resources

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Kinetic and Static Analysis of Poly-(Adenosine Diphosphate-Ribose) Polymerase-1–Targeted ¹⁸F-Fluorthanatrace PET Images of Ovarian Cancer