Theranostic DNA Repair Inhibitors for PET Diagnosis and Radiotherapy of Ovarian Cancer
Abstract
Rationale and Objective: A women’s lifetime risk of getting ovarian cancer is about 1 in 78. As a result of the fact that there remains no recommended screening test for ovarian cancer and early stage disease often presents vague symptoms, 59% of ovarian cancer patients are first diagnosed with late stage disease, which has a 5-year survival rate of only 29%. These rates have recently benefitted from the initial 2014 United States Food and Drug Administration approval of poly(ADP-ribose) polymerase (PARP) inhibitors, a new class of targeted chemotherapeutic that have dramatically changed the standard of care for recurrent ovarian cancer. However, these drugs are ineffective in some patients, primarily due to genetic biomarker differences in cancer cells’ self-repair mechanisms. The proposed work aims to radioactively tag PARP inhibitors allowing for their use in the positron emission tomography (PET) diagnosis and internal radionuclide therapy of ovarian cancer. With the synergy between the biological mechanism of PARP inhibitors and the nuclear decay properties of the radioactive label, this work aims to increase the efficacy of treatment of recurrent ovarian cancer, regardless of biomarker status. Critical Problem: Despite the success in some patients of chemotherapy with PARP inhibitors, there remains an unmet need of a targeted therapeutic intervention broadly effective in combating ovarian cancer, irrespective of biomarker status. To accomplish this, radical new ideas are necessary to combat late-stage metastatic ovarian cancer where inherently local treatments like surgical resection and external radiation therapy are of limited effect. New Paradigms, Insights, Technologies, and Applications: While PARP inhibitors are effective for some patients, one third of the patient population fail to respond to their chemotherapeutic effects. In addition to their chemotherapeutic function, PARP inhibitors are uniquely suited to target radionuclides to maximize damage to malignant cells. The University of Wisconsin-Madison recently developed new technology for the production of previously unattainable quantities of the medically useful radionuclides of bromine, which are particularly well suited for pairing with PARP inhibitors. In the past year, the development of PARP-inhibitor-targeted radionuclide therapy has been at the forefront of oncologic investigation with laboratory studies beginning in glioblastoma and neuroblastoma. This work aims to utilize this strategy in ovarian cancer, where the clinical use of PARP inhibitors is most prevalent and promising. Relevance to Vision and Mission of OCRP: The Department of Defense Ovarian Cancer Research Program (OCRP) is a congressionally mandated medical research program that has awarded over $300 million in the past 21 years to researchers who share its vision to eliminate ovarian cancer. The proposed cutting-edge research aims to directly fill the unmet need of a therapeutic intervention broadly effective in combating late-stage metastatic ovarian cancer. Additionally, several of the top OCRP research priorities are well met by this proposal. Through the guidance of an experienced ovarian cancer co-investigator, the principal investigator will transition from a background of radiopharmaceutical development into ovarian cancer research, thereby increasing the pool of ovarian cancer scientists. The co-development of a pair of biologically and chemically matched diagnostic and therapeutic agents will allow the use of PET imaging for patient selection and tailoring of radiotherapeutic dosing to optimize outcomes. Of the 2.2 million active and Veteran U.S. Servicewomen, mortality rates indicate that 6,600 will be lost each year from metastatic ovarian cancer that is ineffectively treated with traditional chemotherapeutic PARP inhibitors. The proposed work utilizes a precision nuclear medicine diagnostic-therapeutic approach aims to improve the survival for all
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110351
Entities
People
- Paul A Ellison
Organizations
- United States Army
- University of Wisconsin–Madison