Lab mouse
Researchers have found the NOTCH1 pathway “hijacks” heat shock transcription factor 1 (HSF1) signaling in T-cell acute lymphoblastic leukemia (T-ALL).
Therefore, blocking one or more genes in the HSF1 pathway could represent a new approach to treating T-ALL.
An experimental drug, PU-H71, is already in development against one of these targets, heat shock protein 90 (HSP90).
The researchers found that PU-H71 was active against T-ALL in vitro and in vivo.
The team recounted these findings in Nature Medicine.
“Our study shows how the NOTCH1 pathway hijacks the heat shock transcription factor 1 pathway to promote tumor growth,” said study author Iannis Aifantis, PhD, of NYU School of Medicine in New York, New York.
“The cancer cells are sending into overdrive a system that helps healthy cells respond to stress.”
Dr Aifantis and his colleagues found that HSF1 is involved in the pathogenesis of T-ALL. When they knocked down HSF1 in T-ALL cell lines, the researchers observed an increase in apoptosis, defective proteostasis, and a decrease in the growth of leukemic cells.
Similarly, HSF1 was deemed necessary for disease progression in mouse models of T-ALL. When the researchers deleted HSF1, mice experienced “striking” reductions in leukemic burden and “dramatic” improvements in survival. However, HSF1 deletion did not affect normal hematopoiesis.
Dr Aifantis and his colleagues also showed that NOTCH1 regulates the epichaperome in T-ALL. The team said previous studies have shown that, in the presence of oncogenic stress, heat shock proteins participate in a network nucleated by HSP90 and HSP70 chaperones—the epichaperome.
The researchers found that an intact epichaperome was critical for T-ALL by showing that pharmacologic inhibition of HSP90 and HSP70 significantly hindered the growth of human T-ALL in vitro. The team also found the HSP90 inhibitor PU-H71 reduced leukemic burden and extended survival in a NOTCH1-inducible T-ALL mouse model.
Then, the researchers found NOTCH1 levels could predict response to HSP90 inhibition in vitro. T-ALL patient samples expressing high levels of nuclear NOTCH1 and high levels of epichaperome were significantly more sensitive to treatment with PU-H71.
PU-H71 is already in early clinical trials of patients with breast cancer. If further testing proves successful, PU-H71 could be quickly adapted for trials in T-ALL patients, according to Dr Aifantis.
In the meantime, he and his colleagues plan to evaluate the effects of another 8 proteins produced by genes active in the HSF1 pathway to see if any show promising anticancer activity in T-ALL.