Adolfo A. Ferrando, MD, PhD
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Enormous progress has been made in the treatment of ALL, raising the cure rate to more than 80 percent in children. However, there remains a subset of patients whose leukemia comes back, posing a clinical challenge to their physicians. Adolfo Ferrando, MD, PhD is a researcher whose investigations are exploring the molecular mechanisms underlying the growth of ALL, particularly leukemias that develop resistance to chemotherapy drugs.
He and colleagues are conducting laboratory studies to determine how and why some leukemia cells escape the damaging effects of chemotherapy. The researchers identified a gene called NT5C2 which, when mutated, activates other genes that help leukemia cells clear themselves of chemotherapy drugs, enabling them to continue to survive and grow. This genetic mutation may serve as a target for new therapies that could work by inactivating mutant NT5C2, restoring the sensitivity of leukemia cells to anticancer drugs.
The team has also learned that a protein called AKT1 may be involved in the resistance of leukemia cells to another component of treatment, a class of drugs called glucocorticoids. AKT1 is in a pathway called the PI3 kinase pathway, and there are many drugs in development now that target these molecules. It is hoped that inhibiting AKT1 could reverse the resistance of leukemia cells to glucocorticoids.
In past work, his team in pathology identified a protein called NOTCH1 as a major driver of ALL that develops from white blood cells, called T cells (T-ALL). Drugs that inhibit NOTCH suppress leukemia cell growth, but cause intestinal toxicity. Dr. Ferrando and his team defined the mechanism of action of NOTCH inhibitors and identified a drug combination that maximizes their anticancer effects while minimizing intestinal side effects. The findings moved the development of NOTCH inhibitors into clinical trials for the treatment of patients with high-risk T-ALL.