Kinase inhibitors could provide an effective way to treat high-risk leukaemia

Australian scientists have found a new and effective way to treat a particularly aggressive childhood blood cancer.

Acute lymphoblastic leukemia, or ALL, is the most common cancer in children. Despite dramatic improvements in survival in children with ALL in recent decades, children who develop “high-risk” ALL – subtypes that grow aggressively and often resistant to standard treatments – often relapse, and many of these children die from their disease.

A common type of high-risk ALL that urgently needs new therapies is “Philadelphia chromosome-like ALL” (Ph-like ALL), named for its resemblance to another type, Ph-positive ALL. Shared genetic features of these two types of high-risk ALL have led scientists to hypothesize that they may respond to similar treatments; in particular, a newer class of drugs known as kinase inhibitors.

However, experiments have shown that cases of Ph-like ALL containing a genetic mutation known as CRLF2r — about half of all cases of this subtype — respond poorly to kinase inhibitors when used as a single agent. Scientists have since explored whether kinase inhibitors are more effective when used in combination with other agents.

In new research published this week in the international journal Leukemia, scientists at the Children’s Cancer Institute tested more than 5,000 drugs in combination with the kinase inhibitor ruxolitinib, finding that ruxolitinib worked synergistically with several types of commonly used cancer drugs, including the are the most effective glucocorticoids. , topoisomerase I and II inhibitors, microtubule targeting agents, and antimetabolites.

New therapies are urgently needed for high-risk ALL. We are very encouraged by our results, which suggest that we are on track to develop a more effective way to treat this cancer in some children.”

Richard Lock, Principal Investigator and Professor, Children’s Cancer Institute

Lock is also the head of the Blood Cancer Theme at the Children’s Cancer Institute.

Based on their in vitro findings, the researchers then performed in vivo tests in live disease models known as “patient-derived xenograft models” (PDXs) or “avatars”: mice bred specifically to culture leukemia cells that were taken from individual patients with CRLF2r Ph-like ALL.

The results showed that the addition of ruxolitinib to a general treatment regimen called VXL (consisting of vincristine, 2dexamethasone, and L-asparaginase) improved treatment efficacy in two of the three avatars, suppressing long-term leukemia growth in one of these avatars.

“The enhanced effect of the treatment when ruxolitinib was added, and the variety of drug classes found in our lab to synergize with ruxolitinib, suggest promising potential for kinase inhibitors in the treatment of Ph-like ALL,” said Professor Lock. “We hope this leads to improved treatment options for children with this leukemia in the near future.”

Source:

Children’s Cancer Institute Australia

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