Date of Degree

2-2020

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor

Brian M. Zeglis

Advisor

Thomas Reiner

Committee Members

Jill Bargonetti

Akira Kawamura

Rein V. Ulijn

Subject Categories

Biochemistry | Medicinal Chemistry and Pharmaceutics | Translational Medical Research

Keywords

glioblastoma, PARP, olaparib, Auger, radiotherapy, theranostic

Abstract

Poly-ADP-ribosylation reactions were first reported by Chambon in 1963 as enzymatic activity that increases incorporation of ATP in the presence of nicotinamide mononucleotide. In the decades since that publication, Poly(ADP-ribose)polymerase 1 (PARP1) and the PARP family enzymes have been widely studied. PARP enzymes are currently known to play various roles in mammals, including anti-aging processes, interactions with Breast Cancer Suppressor Protein-1 (BRCA1), and DNA damage repair. A significant focus of PARP1 research has been elucidating its role in DNA damage repair. PARP1 is recruited to repair single strand DNA (ssDNA) breaks, which can become double stranded DNA (dsDNA) breaks if PARP1 is not present. It is now known to be overexpressed in various cancers, as well as being linked to survival in gliomas.

The increased presence of PARP1 in cancer cells and the increased radio-sensitivity of the cells when PARP1 is inhibited make it an exceptional target for therapies and imaging agents. Naturally, several PARP inhibitors have since been developed and approved by the FDA. PARP1 expression in gliomas can be leveraged to design a radiotherapeutic that would be highly specific for cancer cells while sparing surrounding healthy tissue in gliomas. Using one of these FDA approved PARP inhibitors; several PARP imaging agents for fluorescent, PET, and SPECT modalities that retain specificity for PARP1 have been developed. The next step in the PARPi imaging suite is to develop PARP-targeted radiotherapeutics and theranostics. A toolbox of imaging and therapeutic agents with the same highly targeted specificity would provide a valuable advantage when diagnosing patients, treating them, and even monitoring patient response or disease progression.

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