For the first time, researchers have discovered a link between a pathway that activates a protein called heat shock transcription factor 1 (HSF1) and leukemia. Blocking even just a single gene in this pathway could offer a new way of treating an aggressive form of the disease called T cell acute lymphoblastic leukemia (T-ALL), they believe.
What’s more, there’s already a drug in development that does just that, and it’s currently in clinical trials for breast cancer. Boston startup Samus Therapeutics is leading the research.
The researchers, led by the New York University School of Medicine, discovered that HSF1 signaling is “hijacked” by a pathway called NOTCH1. HSF1 normally produces other proteins that help healthy cells respond to stress. So when NOTCH1 takes control of HSF1, tumor cells grow out of control.
In mouse models of T-ALL, the researchers used genetic engineering to block HSF1. That killed all the cancer cells without affecting healthy tissues, they discovered. Removing HSF1 did not interrupt the production of normal blood cells, they said, nor could they find any other adverse effects. They published their research in the journal Nature Medicine.
HSF1 produces other proteins that promote the growth of leukemia, including heat shock protein 90 (HSP90), a well-known target among cancer researchers. The drug that’s in clinical trials for breast cancer, called PU-H71, blocks HSP90 and could be adapted for trials in T-ALL patients, too, NYU said in a statement.
"Having a targeted therapy that kills only cancer cells could really boost our efforts to treat T cell acute lymphoblastic leukemia, which affects mostly children," said Nikos Kourtis, Ph.D., a postdoctoral fellow at NYU and lead author of the study.
Drugs targeting HSP90 have been studied in cancer before, but they’ve proven largely disappointing so far. Infinity Pharmaceuticals, for example, dropped its HSP90 blocker for lung cancer, retaspimycin hydrochloride, after it failed a midstage clinical trial in 2013. Infinity has since shifted its focus to other oncology targets.
The HSP90 blocker that’s of interest to the NYU researchers, PU-H71, is currently in a phase 1/2 trial at Memorial Sloan Kettering Cancer Center in New York. The drug is being investigated in combination with chemotherapy to treat patients with HER2 negative metastatic breast cancer. Researchers involved in that trial also contributed to the NYU study in leukemia.
After they observed the effectiveness of blocking HSF1 in mouse models, they went on to silence the gene that produces HSP90 in both mouse and human cells. That proved to be an efficient way to kill T-ALL cells, especially those with high HSP90 and NOTCH1 activity, they reported.
The next step for the NYU team is to study eight other proteins in the HSF1 pathway to determine if they might be effective in fighting T-ALL. They are also hoping to plan clinical trials of HSP90 blockers in the disease.