For decades, the central paradigm behind the treatment of most tumors has been “get it out”—or, if you can’t, kill it. But note that I said most tumors. For some, the best course isn’t necessarily one that focuses on killing the tumor, but one that also makes it grow up.
The cells of tumors like neuroblastoma or some kinds of acute leukemia aren’t necessarily wildly growing invaders full of murderous mutations. Rather, they’re immature. Instead of following the normal developmental path from stem cell to mature nerve (in the case of neuroblastoma) or white blood cell (in leukemia), something prevents the cells from maturing fully.
Mature or not, the cells can still grow without pause, quickly forming tumors or crowding healthy cells out.
The techniques for making cancer cells mature—or differentiate—differ greatly from those for making cancer cells die. But they hold promise for better, less toxic cures, especially for children with neuroblastoma, which next to brain tumors is the most common solid tumor of children.
“We throw the kitchen sink at neuroblastoma tumors,” says Suzanne Shusterman, MD, an oncologist with Dana-Farber/Boston Children’s Cancer and Blood Disorders Center who specializes in neuroblastoma. “It’s a heterogeneous disease. So we often have to try multiple treatment methods, including surgery, radiation, chemotherapy and immunotherapy, especially in children with high-risk disease.”
That combination does produce cures—some 40 to 50 percent of children with high-risk neuroblastoma survive—but at a price. “Survivors have lots of late effects,” Shusterman explains, citing learning, coordination, vision, growth and skeletal problems. “A major focus in the neuroblastoma community right now is how to cure more children without causing more late effects.”
This is where differentiation therapy comes in. In the 1980s, researchers realized that a drug called 13-cis-retinoic acid (also known as isotretinoin, the active ingredient in the acne medication, Accutane™) could force neuroblastoma cells to mature in a test tube.
“A major focus in the neuroblastoma community right now is how to cure more children without causing more late effects.”
“We’ve since been using cis-retinoic acid in addition to other therapies,” Shusterman notes. “But we still want to know, can we improve differentiation therapy as a way of improving cure rates? In theory, it would have fewer side effects because you wouldn’t need to use so many cytotoxic agents.”
Which is why Shusterman is excited by a recent study led by her Dana-Farber/Boston Children’s colleague, hematologist/oncologist Kimberly Stegmaier, MD, showing that a class of compounds called selective HDAC1/2 inhibitors can trigger neuroblastoma cells to mature, an effect enhanced by isotretinoin.
Screening genes for a cure
Stegmaier’s study, published in the journal Chemistry & Biology, relied on what she calls a chemical genomics approach. Developed with collaborators at the Broad Institute, it circumvents some of the limitations of classic small molecule high-throughput screening surveys.
“Many chemotherapy drugs have been discovered using high-throughput screens that measure simple cellular state changes, such as alive versus dead, or the activity of a single protein target,” Stegmaier explains. “However, for some processes, including neuroblastoma differentiation, we have not yet identified a specific protein to target with drugs. Moreover, for many pediatric cancers, the target we want to hit isn’t one that can easily be ‘drugged.’
Stegmaier and her collaborators realized that they needed a screen that looked at the activity of several genes at once in a way that told them something about more complicated states, like maturity. “We took neuroblastoma and normal nerve cells, looked at their gene expression patterns and developed a high-throughput drug screen for compounds that made a neuroblastoma cell’s gene expression pattern look more like that of a nerve cell.”
After screening a library of 1,916 compounds, they found that a molecule called BRD8430 was quite effective at forcing neuroblastoma cells to differentiate. BRD8430 selectively blocks class 1 and 2 histone deacetylases (HDACs), epigenetic factors that cells use to chemically tag genes and keep them from being expressed. This suggests that the HDACs in neuroblastoma cells are repressing genes that would normally drive maturation; BRD8430 lifts the repression, allowing those genes to function and the cells to differentiate into normal nerve cells.
Stegmaier is quick to note that neither BRD8430 nor other selective HDAC inhibitors that she and her team tested are clinic-ready drugs. “They’re tool compounds,” she cautions. “They need to be optimized using medicinal chemistry techniques.”
But Stegmaier already is seeing some interesting results from combining selective HDAC blockers with other drugs. “BRD8430 increases the activity of cis-retinoic acid,” she says. “It may be that by blocking HDACs, we are making the neuroblastoma cells more sensitive to other forms of differentiation therapy.”
Shusterman also thinks a combinatorial approach could have benefits. “Differentiation therapy seems to put tumors into a kind of stasis,” she explains. “Ideally, we could use something like an HDAC inhibitor to stabilize disease and then use other agents to push a remission with less toxicity.”