Research Team in Canada Explores PARP's Complex Role in DNA Repair

Girish M. Shah, PhD

Professor, Faculty of Medicine

Senior Researcher and Head

Laboratory for Skin Cancer Research

Laval University Medical Research Center

Quebec, Canada

Girish M. Shah, PhD, is a professor in the Faculty of Medicine at Laval University, Quebec, Canada, and head of the Laboratory for Skin Cancer Research at the Laval University Medical Research Center. Research in his laboratory focuses on carcinoid neuroendocrine tumors and solar ultraviolet (UV) radiation-induced skin cancers with a specific emphasis on DNA damage, DNA repair, and cell death processes. Recently, his team has been using cellular and murine models to examine various therapeutic options, including inhibitor and gene knockout approaches against the DNA damage-responsive enzyme poly(ADP-ribose) polymerase 1 (PARP-1). He is the author of many peer-reviewed publications and the recipient of various awards, including an Outstanding Achievement in Carcinoid/Neuroendocrine Tumor Research award in 2006 from the Carcinoid Cancer Foundation in White Plains, New York.

Please briefly describe your research as it relates to PARP biology.

Our focus is to identify the different roles of PARP, specifically PARP-1, in DNA repair and cell death in mammalian cells responding to DNA damage. While the role of PARP-1 in the base excision repair (BER) pathway is targeted by the current PARP inhibitors in cancer therapy, our most recent studies have revealed a novel role of PARP-1 in the nucleotide excision repair pathway, which is implicated in the repair of DNA damage induced by UV [rays] or anticancer drugs such as cisplatin. In addition, we are also examining the therapeutic potential of PARP inhibitors in chemotherapy-resistant cancers using preclinical animal models.

What are your thoughts on the revival of olaparib development for the treatment of ovarian cancer?

When AstraZeneca announced that they were halting clinical trials with their PARP inhibitor olaparib, my first impression, similar to many of my colleagues in the PARP field, was that we were “throwing out the baby with the bathwater.” In other words, all good competitive PARP inhibitors are being blindsided by adverse publicity related to iniparib. This supposedly “noncompetitive PARP inhibitor” turned out to be a general cysteine-binding poison and not much of a PARP inhibitor. In contrast, the competitive inhibitors of PARPs have consistently shown positive results in cellular or animal studies and in clinical trials.

Therefore, a revised decision by AstraZeneca to invest even more money and energy to proceed to phase III clinical trials with olaparib for selected cancers strongly indicates: (1) the strength of their existing data for progression-free survival in ovarian cancers; and (2) their vision that PARP inhibitors have a strong future as anticancer agents. Personally, I am confident that PARP inhibitors will eventually take their rightful place in the anticancer arsenal.

What do you feel is the most promising recent finding relating to the use of PARP inhibitors in oncology?

While the synthetic lethal effect of PARP inhibitors as monotherapy in specific cancers with BRCA-ness initiated the whole concept of PARP inhibitors in cancer therapy, the following emerging trends for other uses of PARP inhibitors will be equally interesting. Firstly, the consistent success of PARP inhibitors in combination therapy with anticancer drugs such as cisplatin, which cause DNA damage that is not repaired via BER, indicates that the usefulness of PARP inhibitors extends beyond narrow earlier interpretations. Secondly, there are increased levels of effort to understand the exact mechanism by which PARP inhibition kills cancer cells, which will allow better targeting of PARP inhibitors. Finally, there is the recognition that there are other cellular factors that can modulate PARP inhibitor function in cancers, and efforts to identify the complex molecular signatures that will determine the sensitivity or resistance of specific cancers to PARP inhibition will greatly rationalize their use in cancer therapy.

What are the implications of the broad specificity of PARP inhibitors that are currently in development, and are we likely to see more specific agents emerging in the near future?

I see two fundamental issues with the broad specificity of the current agents. Firstly, there are 18 members of the PARP family, and all of them can split the substrate NAD+ to liberate ADP-ribose, nicotinamide, and a proton. Since the product nicotinamide is a very weak inhibitor of PARP-1, chemicals that mimic nicotinamide and compete with NAD+ for binding to the active site of PARP-1 have been used as PARP inhibitors. PARP inhibitors therefore have the potential to inhibit all PARPs in cells, and could end up acting as a “bazooka” rather than a “magic bullet.” Hence, while we presume that the anticancer effect of PARP inhibition is due to suppression of our hypothesized target, PARP-1, we can’t be sure that only a PARP-1-inhibiting dosage will reach the tumor and nothing higher that could inhibit other PARPs. Indeed, this might explain the success and failure or differing extent of side effects of PARP inhibitor therapy sometimes observed in a given cohort of patients suffering from the same cancer.

Secondly, even if we were able to fine-tune the delivery of a precise dosage to specifically inhibit only one target PARP, we face another problem—PARPs are multifunctional proteins and we can’t be sure that PARP inhibition will affect only a single function. For example, PARP-1, the principal target of PARP inhibitors in cancer therapy, is implicated not only in BER (the presumed function that is targeted for therapeutic effect), but also in other pathways of DNA repair, including nonhomologous end-joining, homologous recombination, and nucleotide excision repair. PARP-1 is also implicated in death of cells exposed to pathophysiological levels of DNA damage as well as in transcription control, chromatin remodeling, differentiation, and other functions. Thus, while we hope that PARP inhibition will affect only the DNA repair role of PARP-1, we do not have a rational basis to assume that PARP inhibition will not suppress other PARP-1 functions that could confound the anticipated outcome. Similar arguments can be made for PARP-2, another multifunctional PARP that is inhibited equally well by many of the current PARP inhibitors.

Girish M. Shah, PhD, far left, heads the Laboratory for Skin Cancer Research at the Laval University Medical Research Center in Quebec. Team members include, front from left, Febitha Kandan-Kulangara, a PhD student, and Rashmi Shah, a research professional; back row, from left, Alicia Montoni, postdoctoral fellow/research associate; Véronique Richard, MSc student; Mihaela Robu, a PhD student, and Nancy Petitclerc, MSc student. Nupur Purohit, a PhD student, is not pictured.

That being said, research is being done to try to overcome these issues. Researchers are focusing on a new paradigm: one PARP inhibitor for one PARP. New PARP inhibitors are being developed that would mimic the adenine moiety rather than the nicotinamide moiety. Other approaches being examined include identification and targeting of a specific structural region or amino acid residues that are unique to the interaction between a given PARP and its substrate. The hope is that we will find unique PARP inhibitors for each PARP. In addition, siRNA against PARP-1, delivered as a nanodrug to animal tumors in animals, has shown promising results and could be the future of PARP-specific therapy.

We will need to think outside the box to solve the trickier problem of how to specifically affect a given function of PARP-1 without affecting other functions of the same enzyme. A parallel effort must be made to identify the subset of cancers that are more amenable to current PARP inhibitors, such as large-scale molecular cataloging of the tumor in The Cancer Genome Atlas project to identify the molecular signature of the subset of cancers that are susceptible to PARP inhibition. Our ability to resolve these issues in the future could very well dictate the widespread use of PARP inhibitors in anticancer or any other therapy.