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
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.
- Publication Date:
- Research Org.:
- Univ. of Pennsylvania, Philadelphia, PA (United States)
- Sponsoring Org.:
- USDOE; Paul Calabresi K12 Career Development; National Institutes of Health (NIH)
- OSTI Identifier:
- 1737695
- Alternate Identifier(s):
- OSTI ID: 1851646
- Grant/Contract Number:
- SC0012476; 5K12CA076931; TL1TR001880
- Resource Type:
- Published Article
- Journal Name:
- Molecules
- Additional Journal Information:
- Journal Name: Molecules Journal Volume: 25 Journal Issue: 24; Journal ID: ISSN 1420-3049
- Publisher:
- MDPI AG
- Country of Publication:
- Switzerland
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; auger therapy; radiopharmaceutical therapy; theranostic; PARP-1; ovarian cancer; BRCA1; HRD
Citation Formats
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., and Makvandi, Mehran. 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. Switzerland: N. p., 2020.
Web. doi:10.3390/molecules25246029.
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. 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. Switzerland. https://doi.org/10.3390/molecules25246029
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., and Makvandi, Mehran. Sat .
"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". Switzerland. https://doi.org/10.3390/molecules25246029.
@article{osti_1737695,
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},
author = {Riad, Aladdin and Gitto, Sarah B. and Lee, Hwan and Winters, Harrison D. and Martorano, Paul M. and Hsieh, Chia-Ju and Xu, Kuiying and Omran, Dalia K. and Powell, Jr., Daniel J. and Mach, Robert H. and Makvandi, Mehran},
abstractNote = {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.},
doi = {10.3390/molecules25246029},
journal = {Molecules},
number = 24,
volume = 25,
place = {Switzerland},
year = {2020},
month = {12}
}
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