Melinda L. Telli, MD
Assistant Professor, Department of Medicine, Stanford School of Medicine, Stanford University, Stanford, CA
Melinda L. Telli, MD, is actively involved in clinical research that focuses on DNA repair targeted therapeutics, including PARP inhibitors, for the treatment of triple-negative and BRCA1/2
mutation-associated breast cancer.
What are PARP proteins, and what is their role in a normal cell?
Poly(ADP-ribose) polymerase (PARP) proteins comprise a large family of proteins that possess ADP-ribosyl transferase enzymatic activity. These PARP proteins are involved in the poly(ADP-ribosyl)ation of target proteins, and in doing so, regulate a diverse spectrum of normal cellular processes, including DNA repair, telomere maintenance, transcriptional regulation, mitochondrial function, and cellular stress responses, among others.
What are PARP inhibitors, and how are they implicated in the treatment of cancer?
Thus far in cancer drug development, much of the action has focused on PARP1, a nuclear enzyme that is activated by and recruited to sites of DNA base damage. PARP1 binds to the damaged DNA and results in the formation of poly(ADP-ribose) polymers that are important for recruitment of the base excision repair machinery to the site of the DNA damage.
Since many effective cytotoxic chemotherapies and ionizing radiotherapy exert their antitumor effect through production of DNA damage, early on it was hypothesized that interference with cellular DNA repair using PARP inhibitors may mitigate repair of this damage, resulting in enhanced therapeutic efficacy. Based on this rationale, increasingly potent chemical inhibitors of PARP1 were developed in the 1990s and evaluated preclinically for their potential as chemotherapy or radiation sensitizers.
In 2005, a pair of pivotal papers suggested a novel application of PARP inhibitors in the treatment of human cancers. The use of PARP inhibitors in cells deficient in BRCA1 and BRCA2 function resulted in selective cytotoxicity, compared to cells wild-type or heterozygous for BRCA1
. This concept of “chemical synthetic lethality” generated tremendous enthusiasm and fueled the rapid development of clinical investigation in this area.
In addition, the hypothesis emerged that certain sporadic cancers like triple-negative breast cancer and high-grade serous ovarian cancer, among others, may possess similar DNA repair deficiencies and exhibit similar chemosensitivities as BRCA1/2
mutation-associated tumors, including sensitivity to PARP inhibition.
What PARP inhibitors are currently available?
The current PARP inhibitors in clinical development are based on the chemical structure of nicotinamide and are competitive inhibitors of NAD+ [oxidized nicotinamide adenine dinucleotide]. Compared to the early PARP inhibitor 3-aminobenzamide, newer PARP inhibitors such as olaparib, veliparib, and rucaparib have improved potency and specificity.
Iniparib, initially investigated as a PARP1 inhibitor, moved forward quickly in clinical development in combination with chemotherapy in triple-negative breast cancer, but it was subsequently observed that iniparib does not possess characteristics typical of the PARP inhibitor class. The exact mechanism of action has not yet been fully elucidated; however, in preclinical experiments, iniparib induces gamma-H2AX (a marker of DNA damage) and potentiates the cell cycle effects of DNA-damaging drugs in tumor cell lines. Investigation into potential targets of iniparib and its metabolites are ongoing.
What has been the most significant development relating to PARP inhibitor research in recent years?
The most significant clinical development in PARP inhibitor research to date has been the initial proof-ofconcept demonstration that monotherapy with olaparib, a potent oral PARP inhibitor, led to objective tumor responses in 41% and 33% of BRCA1
mutation carriers with heavily pretreated advanced breast and ovarian cancers, respectively.
Another noteworthy study demonstrated the activity of olaparib as monotherapy in women with advanced high-grade serous ovarian cancer who lack a germline BRCA1