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- Title
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.
- Authors
Riad, Aladdin; Gitto, Sarah B.; Lee, Hwan; Winters, Harrison D.; Martorano, Paul M.; Hsieh, Chia-Ju; Xu, Kuiying; Omran, Dalia K.; Powell Jr., Daniel J.; Mach, Robert H.; Makvandi, Mehran; Nishii, Ryuichi; Watanabe, Shigeki; Ogawa, Kazuma
- Abstract
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.
- Subjects
OVARIAN cancer; POLY(ADP-ribose) polymerase; COMPUTED tomography; OVARIAN tumors; CANCER patients; POLY ADP ribose; ADENOSINE diphosphate; CIRCULATING tumor DNA
- Publication
Molecules, 2020, Vol 25, Issue 24, p6029
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules25246029