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Open AccessArticle

PARP Theranostic Auger Emitters Are Cytotoxic in BRCA Mutant Ovarian Cancer and Viable Tumors from Ovarian Cancer Patients Enable Ex-Vivo Screening of Tumor Response

1
Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
2
Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
3
Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA
4
Abramson Cancer Center, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Ryuichi Nishii, Shigeki Watanabe and Kazuma Ogawa
Molecules 2020, 25(24), 6029; https://doi.org/10.3390/molecules25246029
Received: 1 December 2020 / Revised: 14 December 2020 / Accepted: 18 December 2020 / Published: 19 December 2020
(This article belongs to the Special Issue Recent Advances in Techniques with Radionuclide for Theranostic Drugs)
Theranostics are emerging as a pillar of cancer therapy that enable the use of single molecule constructs for diagnostic and therapeutic application. As poly adenosine diphosphate (ADP)-ribose polymerase 1 (PARP-1) is overexpressed in various cancer types, and is localized to the nucleus, PARP-1 can be safely targeted with Auger emitters to induce DNA damage in tumors. Here, we investigated a radioiodinated PARP inhibitor, [125I]KX1, and show drug target specific DNA damage and subsequent killing of BRCA1 and non-BRCA mutant ovarian cancer cells at sub-pharmacological concentrations several orders of magnitude lower than traditional PARP inhibitors. Furthermore, we demonstrated that viable tumor tissue from ovarian cancer patients can be used to screen tumor radiosensitivity ex-vivo, enabling the direct assessment of therapeutic efficacy. Finally, we showed tumors can be imaged by single-photon computed tomography (SPECT) with PARP theranostic, [123I]KX1, in a human ovarian cancer xenograft mouse model. These data support the utility of PARP-1 targeted radiopharmaceutical therapy as a theranostic option for PARP-1 overexpressing ovarian cancers. View Full-Text
Keywords: Auger therapy; radiopharmaceutical therapy; theranostic; PARP-1; ovarian cancer; BRCA1; HRD Auger therapy; radiopharmaceutical therapy; theranostic; PARP-1; ovarian cancer; BRCA1; HRD
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MDPI and ACS Style

Riad, A.; Gitto, S.B.; Lee, H.; Winters, H.D.; Martorano, P.M.; Hsieh, C.-J.; Xu, K.; Omran, D.K.; Powell, D.J., Jr.; Mach, R.H.; Makvandi, M. PARP Theranostic Auger Emitters Are Cytotoxic in BRCA Mutant Ovarian Cancer and Viable Tumors from Ovarian Cancer Patients Enable Ex-Vivo Screening of Tumor Response. Molecules 2020, 25, 6029. https://doi.org/10.3390/molecules25246029

AMA Style

Riad A, Gitto SB, Lee H, Winters HD, Martorano PM, Hsieh C-J, Xu K, Omran DK, Powell DJ Jr., Mach RH, Makvandi M. PARP Theranostic Auger Emitters Are Cytotoxic in BRCA Mutant Ovarian Cancer and Viable Tumors from Ovarian Cancer Patients Enable Ex-Vivo Screening of Tumor Response. Molecules. 2020; 25(24):6029. https://doi.org/10.3390/molecules25246029

Chicago/Turabian Style

Riad, Aladdin; Gitto, Sarah B.; Lee, Hwan; Winters, Harrison D.; Martorano, Paul M.; Hsieh, Chia-Ju; Xu, Kuiying; Omran, Dalia K.; Powell, Daniel J., Jr.; Mach, Robert H.; Makvandi, Mehran. 2020. "PARP Theranostic Auger Emitters Are Cytotoxic in BRCA Mutant Ovarian Cancer and Viable Tumors from Ovarian Cancer Patients Enable Ex-Vivo Screening of Tumor Response" Molecules 25, no. 24: 6029. https://doi.org/10.3390/molecules25246029

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