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Melinda L. Telli, MD, is actively involved in clinical research that focuses on DNA repair targeted therapeutics for the treatment of triple-negative and BRCA1/2 mutation-associated breast cancer.
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.
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.
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 or BRCA2. 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.
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.
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 and BRCA2 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 or BRCA2 mutation.
Though there has been significant interest in the development of PARP inhibitors for the treatment of triple-negative breast cancer, it is notable that the efficacy of PARP inhibitors as monotherapy in patients with sporadic triple-negative breast cancer has yet to be demonstrated with any agent, despite the hypothesis that this breast cancer subtype is “BRCA-like.”
There is much that remains to be understood about the optimal use of PARP inhibitors in the clinic. Despite the exciting results of PARP inhibitors in BRCA1/2 mutation-associated cancer, clinical development in this subset has moved slowly, and we do not yet have a PARP inhibitor FDA-approved for mutation carriers with advanced breast or ovarian cancer. To me, this should be one of our highest priorities for the future.
We clearly need to better understand how these drugs are working, an issue highlighted in the clinical development of iniparib. In addition to PARP1, most of the known PARP inhibitors have some effect on at least the PARP2 enzyme. Therefore, there may be “off-target” effects that carry implications both in terms of efficacy and toxicity.
Related to this, another area where much work is needed is determining optimal treatment frequency, dosing, and combination with cytotoxic chemotherapy.
Ultimately, the key for successful PARP inhibitor development lies in biomarker discovery and validation. Our increasing understanding of the mechanism of action of PARP inhibitors suggests that markers indicative of underlying DNA repair defects should be most informative, though whether these are restricted to proteins involved in homologous recombination, like BRCA1 and BRCA2, or include members of additional DNA repair pathways also remains unknown.