When oncologists talk about cancer targets, they’re usually referring to mutated genes that can be thwarted with drugs. Researchers at the University of Pennsylvania used gene-editing technology CRISPR to elucidate a different sort of target in acute myeloid leukemia (AML)—and to uncover a way to target it with drugs.
A team at Penn’s medical school discovered that an epigenetic regulatory protein called ZMYND8 governs the expression of genes that are critical for the growth and survival of AML cells. Inhibiting ZMYND8 in mouse models shrank tumors. The researchers also found a biomarker that they believe could predict which patients are likely to respond to ZMYND8 inhibition, they reported in the journal Molecular Cell.
AML is one of the hardest leukemias to treat, with a five-year survival rate of about 27% in adults. The Penn team had been searching for precision medicine approaches that could improve the prognosis for adults with AML, and they turned to CRISPR for help.
ZMYND8 is known as a “histone reader” in cancer that can recognize epigenetic changes and influence gene expression involved in metastasis.
Using CRISPR, the Penn team disrupted various functions of proteins in cancer cells and mapped their functions on a molecular level. When they blocked the epigenetic reader function of ZMYND8 in mouse models, it not only caused tumors to shrink, but also improved survival, they said in a statement. With CRISPR, they were able to pinpoint a “pocket” on ZMYND8 that they believe could be targeted with drugs.
Several efforts to develop new treatments for AML have hit roadblocks of late. The FDA placed a hold on trials of Aprea Therapeutics’ eprenetapopt in AML after worrisome side effects appeared in a trial of the drug in myelodysplastic syndrome. Amgen had been developing a bispecific antibody for AML, AMG 427, but stopped a phase 1 trial after some patients developed the dangerous side effect cytokine release syndrome. The company is now investigating ways to optimize the treatment approach, a spokesperson said earlier this month.
Several immuno-oncology approaches to AML are under development, including engineered natural killer cell therapies, and researchers are investigating a range of targeted approaches such as combining MDM2 and BET blockers.
The Penn researchers wanted to see whether they could predict how sensitive AML cells might be to ZMYND8 inhibition, so they turned to blood samples from patients treated at Penn Medicine. They found that high expression of a particular gene in those cells, IRF8, could serve as a biomarker of response to ZMYND8 inhibition.
“CRISPR revealed here, for the time, an unexpected epigenetic-linked molecular circuity that AML is dependent on, and one that we can potentially manipulate,” said co-author Shelley Berger, Ph.D., professor at the Perelman School of Medicine and director of the Penn Epigenetics Institute, in the statement. “It opens a new door toward better treatments for these patients using next-generation epigenetic inhibitors.”