Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. It causes the bone marrow to produce abnormal blood cells, white blood cells in particular. About 20,000 people develop AML in the United States every year and about 10,000 die from it. While treatment has improved in recent years, the five-year life expectancy for people diagnosed with AML is only about 27 percent.

Better treatments are urgently needed. Some teams of researchers are currently using epigenetics to develop treatments for AML, among other cancers. Epigenetics is the study of biological mechanisms that change the way DNA is packaged in our cells to help determine which genes are on, or need to become active, or are switched off.

A one-two punch

We are developing means to combine changing these epigenetic parameters with approaches that attack fundamental processes that the cancer cells need to survive and grow and specifically how cancer cells repair damage to their DNA. 

In terms of DNA damage, drugs called PARP-enzyme inhibitors (PARPi) block key pathways for DNA repair. When we add drugs that change cancer epigenetic abnormalities, DNMT inhibitors (DNMTi), which are not typically combined with PARPi, this enhances the effects of the PARPi such that more DNA damage accumulates.

 Thus, poisonous PARP “traps” on the DNA also accumulate. Eventually the cancerous cell will self-destruct. We’ve shown that combining these drugs at low doses causes massive damage to the cancer. It’s not just a matter of combining two drugs, each with its own benefit to the patient — it’s using two drugs that work together to deal a fatal blow to the cancer cells.

“... it attacks the cancer at a very basic cellular level that is common to many cancers.”

Recent breakthroughs

Researchers are testing PARPi to treat a number of cancers. Research suggests that the new drug combination could also help patients with triple-negative breast cancer and also possibly lung, prostate and ovarian cancers. The reason it could be so broadly effective is that it attacks the cancer at a very basic cellular level that is common to many cancers.

For AML, it’s especially encouraging that, based on preliminary data, patients with subtypes of AML with a poor prognosis are likely to be sensitive to the combined PARPi-DNMTi approach. That’s potentially good news for people for whom other therapies haven’t worked well.

While our data are encouraging, they are also preliminary, and more definite information is needed. A VARI-SU2C Phase 1/2 clinical trial is underway at the University of Maryland led by Dr. Maria Baer, Director of Hematologic malignancies. The trial will test whether a DNMTi called decitabine and an investigational PARPi called talazoparib can be safely combined in patients and whether the combination is effective in fighting the disease. There is special interest in patients who can’t take intensive chemotherapy, whose leukemia is resistant to treatment or who have had treatment but experienced a relapse. These are the people who need new treatment the most.

Staying ahead of cancer

In other research, Ross Levine, M.D., leader of the SU2C Convergence Research Team, which is studying how cancer can evolve, found a previously unknown mechanism of chemo-resistance in AML that is driven by a specific mutation in an epigenetic regulator. That study, recently published in the journal “Nature Medicine” provides insight into treating a common, high-risk AML subtype by targeting DNA damage pathways.

This subtype of AML is characterized by a specific mutation in the gene DNMT3A, which is involved in the process of physically restructuring DNA to help turn genes on or off, known as epigenetic regulation. Patients with mutations in this gene have a higher risk of the cancer becoming malignant, and do not respond as well to the standard chemotherapies compared to those who do not carry the mutation. 

Dr. Levine’s work describes the molecular mechanisms by which the DNMT3A mutations lead to increased resistance to chemotherapy and an increased likelihood of metastatic disease. Understanding this process provides direction for new epigenetic approaches to treating AML.

These are very exciting times in cancer research. We’re unlocking some of the secrets of cancer at the most fundamental biological level and bringing forth promising new treatments. We are not going to cure cancer tomorrow, but we are making great progress towards the day when that goal will no longer seem impossible.