Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

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
ORCiD logo [1];  [1];  [1];  [1];  [1]; ORCiD logo [1];  [1]; ORCiD logo [1];  [1];  [1]; ORCiD logo [1]
  1. Univ. of Pennsylvania, Philadelphia, PA (United States)
+ Show Author Affiliations

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

References (20)

The PARP Side of the Nucleus: Molecular Actions, Physiological Outcomes, and Clinical Targets journal July 2010
Auger Radiopharmaceutical Therapy Targeting Prostate-Specific Membrane Antigen journal July 2015
Copper-mediated nucleophilic radiobromination of aryl boron precursors: Convenient preparation of a radiobrominated PARP-1 inhibitor journal May 2018
A Radiotracer Strategy to Quantify PARP-1 Expression In Vivo Provides a Biomarker That Can Enable Patient Selection for PARP Inhibitor Therapy journal June 2016
Auger radiation targeted into DNA: a therapy perspective journal August 2006
PARP-1–Targeted Auger Emitters Display High-LET Cytotoxic Properties In Vitro but Show Limited Therapeutic Utility in Solid Tumor Models of Human Neuroblastoma journal November 2019
Direct Imaging of Drug Distribution and Target Engagement of the PARP Inhibitor Rucaparib journal March 2018
Radioimmunotherapy with alpha-emitting nuclides journal September 1998
Lethality of Auger Electrons from the Decay of Bromine-77 in the DNA of Mammalian Cells journal May 1982
Indirect Mechanisms Contribute to Biological Effects Produced by Decay of DNA-Incorporated Iodine- 125 in Mammalian Cells In Vitro: Clonogenic Survival journal February 1998
A PET imaging agent for evaluating PARP-1 expression in ovarian cancer journal April 2018
Targeted Brain Tumor Radiotherapy Using an Auger Emitter journal February 2020
Upregulation of Poly (ADP-Ribose) Polymerase-1 (PARP1) in Triple-Negative Breast Cancer and Other Primary Human Tumor Types journal August 2010
Rapid Cu-Catalyzed [ 211 At]Astatination and [ 125 I]Iodination of Boronic Esters at Room Temperature journal March 2018
PARP inhibitors: Synthetic lethality in the clinic journal March 2017
Therapeutic Radionuclides: Biophysical and Radiobiologic Principles journal September 2008
Evaluation of a bromine-76-labeled progestin 16α,17α-dioxolane for breast tumor imaging and radiotherapy: in vivo biodistribution and metabolic stability studies journal August 2008
MIRD Pamphlet No. 25: MIRDcell V2.0 Software Tool for Dosimetric Analysis of Biologic Response of Multicellular Populations journal July 2014
PARP-1–Targeted Radiotherapy in Mouse Models of Glioblastoma journal March 2018
Improved production of 76Br, 77Br and 80mBr via CoSe cyclotron targets and vertical dry distillation journal January 2020

Similar Records

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
auger therapy
radiopharmaceutical therapy
theranostic
PARP-1
ovarian cancer
BRCA1
HRD