B-cell acute lymphoblastic leukemia (B-ALL), the most common form of cin children and young adults, is vulnerable to an existing class of drugs that was previously developed for Alzheimer’s and Parkinson’s diseases. The findings, meaningful to all patients with leukemia but especially those who have relapsed, were published Jan. 8 in the journal Nature Cancer.
A central finding of the study, led by Yale’s Center of Molecular and Cellular Oncology (CMCO), regards an unusual characteristic of B-ALL. The study found that, unlike most other cancers which have high levels of a protein called β-catenin, B-ALL cells use a unique mechanism to break down the β-catenin protein. It is barely detectable in B-ALL cells and immediately removed by an efficient clearance mechanism.
“Because B-ALL cells are extremely sensitive to β-catenin accumulation, we tested if disrupting the β-catenin protein removal machinery can overcome drug resistance and prevent relapse in B-ALL.”
Markus Müschen, MD, PhD, director of CMCO
Markus Müschen, MD, PhD, director of CMCO and Arthur H. and Isabel Bunker Professor of Internal Medicine (Hematology) at Yale School of Medicine (YSM) and a member of the Yale Cancer Center.
The high-efficiency clearance mechanism of β-catenin protein depends on the enzyme GSK3B, the study found. To treat neurological diseases including Alzheimer's and Parkinson’s diseases, several inhibitors of GSK3B were previously developed. In multiple clinical trials, GSK3B inhibitors drugs were found to be safe and well-tolerated by the patients.
Studying patient-derived xenograft models, including from patients with B-ALL relapse, GSK3B-inhibitors effectively induced B-ALL cell death and overcame conventional drug-resistance.
Importantly, researchers found, GSK3B inhibitors eradicated B-ALL cells at much lower concentrations than the doses used in previous clinical trials, forecasting lower side effects and greater efficacy in the treatment of patients with B-ALL.
While treatment of B-ALL has improved markedly in recent years, children and teenagers who relapse with the disease still face poor outcomes. Even those who are considered cured often experience long-term side effects from toxic high-dose chemotherapy treatments, including problems with their hearts, central nervous systems, and bone growth.
“Since several GSK3B-inhibitors achieved favorable safety profiles in clinical trials, our results provide a rationale for repurposing these drugs for patients with refractory B-cell malignancies,” says Müschen, who leads the international study consortium.
(Newswise/HG)
