Exploiting Vulnerability of Impaired DNA Repair Creates New Therapeutic Strategy in Acute Myeloid Leukemia

Novel findings from a study of the PARP inhibitor olaparib are pointing to a new therapeutic strategy in the battle against acute myeloid leukemia (AML). The study, by Jaroslaw Maciejewski, MD, PhD, and colleagues from the Cleveland Clinic, is the first to examine the sensitivity of AML with IDH1 and IDH2 mutations to olaparib, a drug already in use for other cancer types.

The findings were presented at the recent American Society of Hematology (ASH) annual meeting in Atlanta, Georgia. Dr. Maciejewski is chair of Cleveland Clinic’s Department of Translational Hematology and Oncology Research and a recipient of the National Cancer Institute’s (NCI) prestigious Outstanding Investigator Award.

AML is an extremely aggressive malignancy that commonly affects older adults and carries a grim prognosis. The NCI estimated that > 21,000 cases of AML would be diagnosed in 2017, mostly in those ≥ 65 years, a population that has difficulty tolerating intensive chemotherapy regimens, which are today’s standard of care for AML. Given that median age at diagnosis is 68, this population’s inability to tolerate current treatment means that new therapeutic strategies are essential.

The study

A significant proportion of adult patients with AML — nearly 20 percent — present with mutations in isocitrate dehydrogenase (IDH), specifically IDH1/2. These neomorphic mutations result in changes in gene function that can sometimes generate faulty enzymes or protein products that act differently than their precursors. In the case of AML, the IDH1/2MUT cells display an impaired response to DNA damage. Dr. Maciejewski’s team sought to understand the mechanism of this impaired response and the effect of olaparib, PARP inhibitor. PARP contributes to multiple cellular processes, including DNA repair.

“For the first time, we showed that these mutations produce DNA repair vulnerability, which can serve as a new therapeutic target,” explained Dr. Maciejewski, “and we showed that the PARP inhibitor olaparib exploits this feature in AML, creating a novel therapeutic approach.”

Existing drug, new therapeutic avenue

Because olaparib is currently FDA-approved for use in other types of cancers, patients with these AML mutations could receive treatment more rapidly versus waiting for the development of a novel agent. “Our work is critically relevant in the search for customizable therapies in personalized medicine. We believe this drug could be repurposed for selective patients who are going to respond based on these genetic mutations and we don’t have to wait several years for new drug development,” said Dr. Maciejewski.

“Based on our study, we believe that olaparib alone, or most likely in combination with a DNA-damaging agent, may represent a future treatment for specific types of AML with IDH1/2 mutations with less toxic and more tolerable side effects than today’s standard of care.”

A manuscript based on the poster has been accepted for publication in the journal Oncogene.