non-invasive-petmr-imaging-an-orthotopic-mouse-model-hepatocellular

Non-Invasive PET/MR Imaging in an Orthotopic Mouse Model of Hepatocellular Carcinoma

Preclinical experimental models of hepatocellular carcinoma (HCC) that recapitulate human disease represent an important tool to study tumorigenesis and ...

University of Oxford

Targeting of PARP enzymes has emerged as an effective therapeutic strategy to selectively target cancer cells with deficiencies in homologous recombination signaling. Currently used to treat -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  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.

PARP Inhibitors in Cancer Diagnosis and Therapy.

The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib is used in the clinic to treat -mutated cancers. Herein, we report two strategies to access the F-isotopologue of rucaparib by applying a copper-mediated nucleophilic F-fluorodeboronation. The most successful approach features an aldehydic boronic ester precursor that is subjected to reductive amination post-F-labeling and affords [F]rucaparib with an activity yield of 11% ± 3% ( = 3) and a molar activity () up to 30 GBq/μmol. Preliminary  studies are presented.

Copper-Mediated Radiosynthesis of [F]Rucaparib.

Rucaparib, an FDA-approved PARP inhibitor, is used as a single agent in maintenance therapy to provide promising treatment efficacy with an acceptable safety profile in various types of BRCA-mutated cancers. However, not all patients receive the same benefit from rucaparib-maintenance therapy. A predictive biomarker to help with patient selection for rucaparib treatment and predict clinical benefit is therefore warranted. With this aim, we developed [F]rucaparib, an F-labelled isotopologue of rucaparib, and employed it as a PARP-targeting agent for cancer imaging with PET. Here, we report the in vitro and in vivo evaluation of [F]rucaparib in human pancreatic cancer models.

Article	Year
PARP Inhibitors in Cancer Diagnosis and Therapy. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 33082213	2021
Copper-Mediated Radiosynthesis of [F]Rucaparib. Organic letters\| PubMed ID: 34459606	2021
Imaging PARP with [F]rucaparib in pancreatic cancer models. European journal of nuclear medicine and molecular imaging\| PubMed ID: 35614267	2022

Chung Ying Chan

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