Robert Hromas, M.D., a blood cancer expert at the University of Florida's College of Medicine, is looking to discover new drugs that will improve the response of elderly AML patients to chemotherapy. His latest research, funded through a Translational Research Program grant from The Leukemia & Lymphoma Society, focuses on inhibiting the DNA repair response.
How would you explain what kind of research you do?
The marrow inside your bones makes white blood cells, which fight infections. Most of these cells must be made new every day, because they only live for less than 24 hours. Once they are made, the bone marrow stops making more. Now imagine if the bone marrow never turned off making these white blood cells, and worse, they lived forever. Then your body would fill up with white blood cells, and this could kill you. This situation is called acute myeloid leukemia (AML). I study ways to kill these immortal leukemia cells in order to prevent them from killing you. Even more importantly, I have come up with some ways to prevent the marrow from making leukemia cells in the first place.
What is novel and innovative about your approach?
There are two novel aspects to our work. First, the most innovative part of what we do is study how to prevent the DNA mutations (called translocations) that cause leukemia.We have found that an FDA-approved ovarian cancer drug called olaparib can prevent translocations when given after a translocation-inducing toxin such as high dose radiation or high dose chemotherapy. The second novel aspect of our work is that we have described a DNA repair protein called Metnase that mediates resistance of leukemia cells to treatment. We have generated a new class of drugs that block Metnase from doing this. These drugs restore the sensitivity of leukemia cells to chemotherapy. Interestingly, these drugs are bi-functional, simultaneously damaging the leukemia cells’ DNA, and then inhibiting Metnase from repairing that DNA.
You note that AML is rarely curable in elderly patients. Why is that?
I wish I knew. There are three main hypotheses. First, it is possible that elderly AML cells are intrinsically better at repairing chemotherapy damage when it occurs than other AML cells. Second, elderly AML cells could mutate at a faster rate, and thereby develop resistance to therapy at a faster rate. Third, they could hide from therapy better, within the bone marrow niche, where they might divide less and thus not be as sensitive to our chemotherapy drugs. Not knowing drives us crazy, and we are hard at work trying to figure out which of the above concepts are true.
What have you learned through your research that could make these patients more responsive to chemotherapy?
It seems that elderly AML cells are less sensitive to our main chemotherapy drug, Ara-C. There are several possible reasons for that, but we have focused on just one. Ara-C stalls the process of DNA replication, which is essential for the AML cells to proliferate, and which ultimately makes patients sick. These AML cells repair these Ara-C-stalled replication forks much better, and we think we know at least one reason why. Proteins called histones surround these stalled replication forks and protect them until the AML cell can repair them. The signal for these histones to surround and protect the replication fork is the transfer of a special tag called a methyl group) to histone 3 by an enzyme.
What are your next steps and how close are you to a clinical trial of a new kind of drug?
We know that this enzyme belongs to the histone methyltransferase family and it adds this signal tag (methyl group) to histone 3 after Ara-C treatment, thus protecting the stalled replication forks in elderly AML cells, allowing the AML cells to stay alive until it can repair the stalled fork. We have designed a drug that can inhibit this histone methyltransferase, and we are testing it in AML models currently.
How do you hope this research will change the outlook or treatment for older people with AML 10 or 20 years from now?
If this methyltransferase inhibitor indeed restores the sensitivity of elderly AML cells to Ara-C, then we would expect that the remission rate and remission duration for these patients would markedly improve. Our goal is to test this new dug that inhibits this methyltransferase in a clinical trial within the next 10 years. The LLS has been a wonderful partner in AML drug development, and without their support such progress could not occur.