Kelly McCann, MD, PhD
PARP inhibitors have made a substantial impact on the treatment of ovarian cancer in recent years. The DNA damage sensor PARP has wide-reaching roles in several pathways and processes of DNA repair, said Kelly McCann, MD, PhD. However, ovarian tumors continue to develop resistance to these therapies.
State of the Science Summit™ on Ovarian Cancer, McCann, a medical oncologist in the Breast Cancer Research Group at the University of California, Los Angeles, discussed the process of DNA damage and repair, resistance to PARP inhibitors, and rational combination strategies to overcome resistance.
Understanding DNA Damage
PARP1 and PARP2 both bind DNA at sites of damage, and they undergo a conformational change to activate their catalytic activity, McCann explained. The types of damage recognized are single-strand DNA breaks, DNA double-strand breaks, and DNA crosslinks, supercoils and stalled replication forks. When they bind to this kind of DNA damage, they use nicotinamide adenine dinucleotide (NAD+) as a substrate in order to add ADP ribose moieties onto the target proteins, added McCann. They add these in a linear fashion, as well as in chains in a process called PARylation.
, other methods can identify homologous recombination deficiency (HRD). Mechanisms include gene sequencing, defects in double-strand break repair, a patient’s clinical history, and response to platinum agents—which can predict response to PARP inhibitors, said McCann.
Trials Designed to Overcome PARP Resistance
There are multiple clinical trials assessing combinations with PARP inhibitors in order to expand their use in the treatment of ovarian cancer. These trials are addressing multiple questions, including the ability to cause and inhibit DNA damage repair, forced apoptosis through dual DNA repair blockade, inducing BRCA
-ness, and overcoming PARP inhibitor resistance.
The current strategies that clinical trials of combinations with PARP inhibitors are implementing are meant to cause DNA damage with chemotherapy, target HRD, interfere with multiple DNA repair processes, or abrogate possible PARP inhibitor resistance mechanisms, according to McCann.
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