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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

Journal Article · · Molecules

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.

Research Organization:
Univ. of Pennsylvania, Philadelphia, PA (United States)
Sponsoring Organization:
USDOE; Paul Calabresi K12 Career Development; National Institutes of Health (NIH)
Grant/Contract Number:
SC0012476; 5K12CA076931; TL1TR001880
OSTI ID:
1737695
Alternate ID(s):
OSTI ID: 1851646
Journal Information:
Molecules, Vol. 25, Issue 24; ISSN 1420-3049
Publisher:
MDPICopyright Statement
Country of Publication:
United States
Language:
English

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