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
- Univ. of Pennsylvania, Philadelphia, PA (United States)
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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