PHILADELPHIA (August 31, 2020)—In a recent study, researchers at Fox Chase Cancer Center identified agents that can specifically target the histone-dependent route of PARP-1 activation. This novel approach appears to be able to target cancer cells better than traditional NAD-like PARP-1 inhibitors and could have potential for developing new treatments for urologic tumors.
Histones are basic proteins found on cells that help pack and order DNA into specific structures. PARP-1 inhibitors are substances used to treat a variety of inheritable cancers that block an enzyme in cells called poly (ADP-ribose) polymerase 1 (PARP-1). Clinical interest in PARP-1 inhibitors has increased over the last 10 years because of their role in the processes of DNA repair, transcription regulation, epigenetic bookmarking, and chromatin restructuring.
“PARP-1 can be activated by binding to DNA, histones, or nicotinamide adenine dinucleotide, also known as NAD⁺, which can activate a number of enzymes and proteins in the human body, resulting in certain off-target effects,” said Vladimir Kolenko, MD, PhD, lead author of the paper and an associate research professor in the Cancer Biology Research program at Fox Chase.
Other Fox Chase co-authors include Peter Makhov, MD, PhD, a research assistant professor, and Robert G. Uzzo, MD, MBA, FACS, chair of the Department of Surgical Oncology. Alexei Tulin, PhD, a former associate professor at Fox Chase, developed the idea of targeting PARP-1 via non-NAD-dependent mechanism and was another co-author on the study. Tulin is now a professor at the University of North Dakota.
Most standard PARP-1 inhibitors are designed to mimic NAD+, which plays an important role in a variety of cellular reactions. However, because NAD+ can activate a number of enzymes and proteins in the human body, NAD⁺ competitors tend to produce certain off-target effects.
Researchers addressed that issue by developing a new type of PARP-1 inhibitor with more specific mechanism of action. “Our mechanism of activation targets only PARP-1. Our inhibitors prevent binding of PARP-1 to histones, and by doing so can specifically target PARP-1 in tumor cells,” said Kolenko.
According to the study authors, “The new non-NAD⁺-like PARP-1 inhibitors demonstrate higher efficacy in in vitro and in vivo settings against prostate and renal tumors compared with the classical NAD-like PARP-1 inhibitors. Taken together, our findings suggest that non-NAD⁺-like PARP-1 inhibitors have strong therapeutic potential for the treatment of urologic tumors.”
Kolenko said researchers are now focusing on finding more specific and effective PARP-1 inhibitors. Currently, over 50 clinical studies are ongoing to evaluate PARP-1 inhibitors for solid and hematological tumors, according to the authors. Fox Chase researchers are among those currently working to study the efficacy of using these inhibitors to treat patients with prostate cancer and kidney cancer.
The study, “Histone-Dependent PARP-1 Inhibitors: A Novel Therapeutic Modality for the Treatment of Prostate and Renal Cancers,” was published in the journal Urologic Oncology: Seminars and Original Investigations.