Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy

Abstract

Poly-(ADP-ribose) polymerase 1 (PARP1) is commonly known for its vital role in DNA damage response and repair. However, its enzymatic activity has been linked to a plethora of physiological and pathophysiological transactions ranging from cellular proliferation, survival and death. For instance, malignancies with BRCA1/2 mutations heavily rely on PARP activity for survival. Thus, the use of PARP inhibitors is a well-established intervention in these types of tumors. However, recent studies indicate that the therapeutic potential of attenuating PARP1 activity in recalcitrant tumors, especially where PARP1 is aberrantly overexpressed and hyperactivated, may extend its therapeutic utility in wider cancer types beyond BRCA-deficiency. Here, we discuss treatment strategies to expand the tumor-selective therapeutic application of PARP inhibitors and novel approaches with predictive biomarkers to perturb NAD+ levels and hyperPARylation that inactivate PARP in recalcitrant tumors. We also provide an overview of genetic alterations that transform non-BRCA mutant cancers to a state of “BRCAness” as potential biomarkers for synthetic lethality with PARP inhibitors. Finally, we discuss a paradigm shift for the use of novel PARP inhibitors outside of cancer treatment, where it has the potential to rescue normal cells from severe oxidative damage during ischemia-reperfusion injury induced by surgery and radiotherapy.

PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

“…PARP-1 is involved in pathogenesis of oncological diseases in a complex way as described in several excellent comprehensive reviews [ 49 , 50 , 51 , 52 ]. Here we will only briefly describe the effect of PARP-1 on tumor cell metabolism, referring readers to the published reviews for more details.…”

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

“…CPI-613 may also synergistically act with pharmacological inhibitors targeting the DNA damage response proteins poly(ADP-ribose) polymerase-1 (PARP-1) and PARP-2 [ 240 ]. PARP inhibitors, such as Olaparib or Talazoparib, are already approved for the treatment of breast and ovarian cancer [ 241 ]. Interestingly, the GLS inhibitor CB-839 will be tested together with Talazoparib in a clinical Phase I/II trial, which currently recruits patients with solid tumors, including CRC (NCT03875313).…”

Research on the effects of rs1800566 C/T polymorphism of NAD(P)H quinone oxidoreductase 1 gene on cancer risk involves analysis of 43,736 cancer cases and 56,173 controls

“…It is possible to develop a precursor drug that can only be converted into Beta-lapachone in the tumor microenvironment, but also increase the target of Beta-lapachone. The combination β-lap and other therapeutic strategies can also expand clinical application and improve the therapeutic effect ( 34 – 36 ). The role of Beta-lapachone depends on NQO1 activity.…”