The advances that have been achieved in the management of pediatric cancers all came about as a result of research. Scientists in the Division are working in the laboratory and the clinic — and bridging the two
— to accelerate the pace of such progress. For example, Adolfo Ferrando, MD, PhD, and his team are exploring the molecular mechanisms underlying the growth of acute lymphoblastic leukemia (ALL), particularly leukemias that develop resistance to chemotherapy.

In a paper published in Nature Medicine, they identified a gene called NT5C2 which, when mutated, allows leukemia cells to degrade 6-mercaptopurine, an important backbone of conventional
ALL therapy. “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 explains. His team has also learned
that a protein called AKT1 may be involved in the resistance of leukemia cells
to glucocorticoids, another critical component of ALL treatment. In a paper published in Cancer Cell, Dr. Ferrando’s team demonstrated that inhibiting AKT1 could reverse the resistance of leukemia cells to glucocorticoids.

Translating these basic science discoveries to the clinic is a major priority within the Division, especially using a team-based approach partnering clinical with basic science researchers. Maria Luisa Sulis, MD, is an ideal partner for
Dr. Ferrando, having previously trained in his laboratory and now serving as head of the hematologic malignancies program within the Division.

Over the last ten years, Dr. Sulis has built a leukemia sample bank that has played a vital role in providing the patient samples necessary to empower basic science breakthroughs. In turn, she is now guiding the development of national clinical trials based on the resulting discoveries. “My goal is to be a champion for my patients and to help enable the bidirectional translational research that will improve the outcomes for all patients in the future,” explains Dr. Sulis.

Dr. Ferrando and his team, including Dr. Sulis, previously identified NOTCH1 as a major driver of T-cell ALL (T-ALL). NOTCH inhibitors suppress leukemia cell growth, but cause intestinal toxicity. The Columbia investigators defined the mechanism of action of NOTCH inhibitors and identified a drug combination that maximizes their anticancer effects while minimizing intestinal side effects. Their findings moved the development of NOTCH inhibitors from the lab into clinical trials — which Dr. Sulis is now overseeing — to treat patients with high-risk T-ALL. “We’ve made great strides in raising the cure rate for pediatric ALL to 90 percent,” says Dr. Sulis. “The intent of our work is to help improve the outlook for the remaining 10 percent of children whose cancer is not cured using conventional therapies.”