Combinations and collaborations in the fight against cancer: An interview with Dr. Feyruz Rassool and Dr. Stephen Baylin

What happens when scientists collaborate rather than compete? In this case, the result is a combination of two drugs that may be a more effective treatment for acute myeloid leukemia (AML), a blood cancer that claims the lives of more than 10,000 people each year in the U.S. alone.

In a paper published today in Cancer Cell, a team led by Dr. Feyruz Rassool of University of Maryland School of Medicine and Dr. Stephen Baylin of Johns Hopkins University’s Sidney Kimmel Comprehensive Cancer Center and co-leader of the Van Andel Research Institute–Stand Up To Cancer Epigenetic Dream Team describes an exciting new combination therapy that not only combats AML, but holds promise for treating other cancers, such as breast, ovarian and lung cancers.

At the heart of the therapy are two inhibitors—drugs that prevent important cellular processes from occurring—that target two molecules, Poly (ADP-ribose) polymerase  (PARP) and DNA methyltransferases (DNMTs). PARP is an enzyme that plays a crucial role in repairing damaged DNA while DNA methyltransferases are enzymes that transfer special molecules called methyl groups to different parts of the DNA, which aids in gene expression. In short, this combination of inhibitors prevents cancer cells from repairing damage to their DNA, effectively causing the cell to die.

We’ll let Drs. Rassool and Baylin take it from here.

Let’s run through the findings in your own words. What were your results? Why are they so exciting?
FR: A bit of background first. A subset of breast and ovarian cancers are inherited and many of these have mutations in BRCA genes—these cancers are very sensitive to PARP inhibitors. However, the majority of cancers do not have these mutations and, therefore, PARP inhibitors are not effective. So naturally the question arose—how can we enhance PARP inhibitor therapy in cancers without BRCA mutations?

We used the idea that PARP—which is the target of the PARP inhibitors—actually interacts with DNA methyltransferases during DNA damage. DNA methyltransferase inhibitors, called DNMT inhibitors for short—are epigenetic therapy agents already in the clinic and used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

We thought that using these two inhibitors together would potentially enhance the therapy. One recent report demonstrates that PARP inhibitors work in a novel way to create cytotoxity—they trap PARP in DNA and the PARP cannot be removed, so the cell dies. Well, DNMT inhibitors do a similar thing—they trap DMNTs in DNA. Because the DNMTs and PARP interact, we reasoned the two inhibitors together would result in more PARP trapping into damaged DNA and actually enhance the ability to kill the cancer cell. This is a novel strategy and a novel mechanism.

SB: I think as Fey said, there were a couple novel things. Cancer cells have had to adopt ways to survive DNA damage—which is occurring constantly—and these ways are largely dependent on PARP. For PARP to work, it has to go to the DNA damage site and then leave. PARP inhibitors make it so the PARP can’t get away—it gets trapped at DNA damage sites and then ultimately leads to cancer cell killing. Our studies have shown that when you use both inhibitors together, you effectively trap both DNMT and PARP better than either drug alone.

Why AML?
: The standard therapy for AML has not changed in decades—the five-year survival rate with AML is quite poor and novel therapies are needed. Although DNMT inhibitors may be used when the standard AML therapy fails, when they’re used, the responses are not durable, meaning they don’t have a lasting effect. This combination therapy could be a way to increase the effects of DNMT inhibitors, increasing survival of patients with this devastating disease.

What are the implications for other cancers?
FR: We’re hoping to take this therapy into other cancers. In the paper, we include data in triple-negative breast cancer in addition to AML. Remember, the best effect with PARP inhibitors alone was with breast and ovarian cancers that had BRCA mutations. This is a very small subset of inherited breast and ovarian cancers; the majority don’t have this mutation, and therefore aren’t effected by this therapy.

In our study, we used a cell line that had wild-type BRCA, meaning that the gene was not mutated. The results were very promising—we showed that combination therapy increased survival and decreased tumor growth in preclinical models harboring these tumors and worked better than either drug alone. These early findings suggest that this combination could also be a potential therapy for breast and ovarian cancers that don’t have a BRCA mutation. We are also seeing promising preliminary results with lung cancer with this combination therapy.

SB: It’s important to note that breast cancer was studied as a key component of the paper. Leukemia cells are the most sensitive so far but breast cancer without the BRCA mutation is also sensitive. If the leukemia trial is successful, I am sure there will be a real impetus to try this in breast and ovarian cancer, particularly those that don’t have the BRCA mutation. These findings have ramifications beyond AML to multiple other cancers.

What do your findings say about combination therapies? Are they the wave of the future?
FR: I think the whole field of targeted therapy actually is moving toward combination therapy. That is clearly a big movement that goes beyond our study, but the important take-home message from our work is that the intersection of these two pathways—the DNA damage and repair pathway and the epigenetic pathway—opens up a new kind of paradigm.

SB: I agree. In chemotherapy for many, many years, combinations have been a major thing. It’s a newer idea that has really come to the forefront, that in these other types of therapies you’re probably going to have to combine drugs. To be more specific, our VARI–SU2C Epigenetics Dream Team, which is trying to bring new epigenetic therapies to the clinic, realizes that one epigenetic drug may seldom be enough to really accomplish what you need to do. So you can combine epigenetic drugs together and, as Fey suggested, you can put other epigenetic drugs with PARP inhibitors and other sorts of targeted therapy like those that target DNA damage.

How has collaboration played a role in your work?
FR: Without Stand Up To Cancer and the ongoing support of the team from Van Andel Research Institute, I don’t think any of this work would have been possible. This research was started on funds from Stand Up To Cancer’s inaugural Laura Ziskin Prize in Translational Cancer Research several years ago, which really started us thinking in novel ways. Steve comes from an epigenetics background and I come from a DNA damage and repair background and these are considered quite separate fields—but the idea is that DNA damage and DNA methylation and epigenetics actually are very much interacting pathways in cellular biology. So from that point of view, we started thinking that maybe these pathways and the pathways that these inhibitors target may also have a chance to work together.

SB:  The prize gave us the resources to hone the concept, so that’s what we did and we went to work. It’s amazing that in a short span of about four years, all this not only happened in the laboratory but it’s also going to move into a clinical trial. We’re looking forward to the results of the clinical trial and hope that this work represents the start of a new paradigm in cancer treatment.

Read news releases about this study from John Hopkins here and the University of Maryland here. This work was funded in part by the Laura Ziskin Prize in Translational Cancer Research and by the VARI–SU2C Epigenetics Dream Team.