Photo courtesy of the
Dana-Farber Cancer Institute
A type II JAK2 inhibitor has shown activity against B-cell acute lymphoblastic leukemia (B-ALL) in preclinical experiments.
The inhibitor, known as CHZ868, works by binding JAK2 into a tightly clenched position, which prevents the protein from functioning.
Researchers tested CHZ868 in samples from patients with CRLF2-rearranged B-ALL, in mice with the disease, and in mice implanted with human B-ALL tissue.
“In each case, we saw good activity: leukemia cells died, JAK2 signaling was suspended, and survival rates increased,” said David Weinstock, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.
“When we combined CHZ868 with the steroid dexamethasone, the killing of leukemia cells was much more extensive, and the animals lived longer than they did with CHZ868 alone.”
Dr Weinstock and his colleagues reported these results in Cancer Cell. Some of the researchers involved in this work are employees of, or have received research funding from, Novartis.
The team found that CHZ868 inhibited JAK2 signaling in B-ALL, both in vitro and in vivo. CHZ868 could overcome persistent JAK2 signaling where type I JAK2 inhibitors (BSK805 and BVB808) could not.
However, the researchers also identified a mutation—JAK2 L884P—that conferred resistance to CHZ868 and another type II JAK2 inhibitor, BBT594.
Nevertheless, CHZ868 suppressed the growth of CRLF2-rearranged human B-ALL cells and improved survival in mice with human or murine B-ALL.
CHZ868 worked synergistically with dexamethasone to induce apoptosis in JAK2-dependent B-ALL. The combination also improved survival in mice with B-ALL, when compared to either dexamethasone or CHZ868 alone.
The researchers noted that, when given at 30 mg/kg/day, CHZ868 was tolerated in NSG mice for up to 25 days and in immunocompetent mice for up to 44 days. And the drug had “essentially no effects” on peripheral blood counts.
This result and the tolerability of dexamethasone make CHZ868 and dexamethasone a “particularly attractive” combination that should be investigated in clinical trials, the team said.
They also speculated that CHZ868 or other type II JAK2 inhibitors could prove effective against malignancies other than B-ALL.
“JAK2 abnormalities are found in some cases of triple-negative breast cancer and Hodgkin lymphoma,” Dr Weinstock noted. “The success of CHZ868 in B-ALL suggests that it, or a compound that works by a similar mechanism, may also be effective in these cancers.”
