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.
His team in at the Institute for Cancer Genetics 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. In addition, his team has also learned that a protein called AKT1 may interact with NOTCH1 and promote the resistance of leukemia cells to a class of drugs central in the treatment of ALL, 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.
Recently much of the efforts in the Ferrando lab are directed 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.
Dr. Ferrando has served PI or co-Investigator on several previous grants funded by the NIH, the Leukemia and Lymphoma Society and other private foundations. He has built a highly trained and well-coordinated team with specific expertise in genomics, bioinformatics, protein biochemistry, genetically manipulated mouse models of leukemia and experimental therapeutics. His labâ€™s research projects have produced numerous peer-reviewed publications, including Nature, Nature Medicine, Nature Genetics, Cancer Cell, and Cancer Discovery. He has been recognized for his contributions to the field with several awards, including the Pershing Square Sohn Prize in Cancer Research and induction into the American Society of Clinical Investigation membership.