I imagine a game of poker in which the dealer refuses to reveal whether the house rules are Texas hold ’em or seven-card stud. For decades, there was a similar story for molecular biologists investigating the mechanisms of leukemia.
“What we were doing before, it’s as if we were playing a game without knowing the rules,” says Adolfo Ferrando, MD, PhD, professor of pediatrics and of pathology & cell biology in Columbia’s Institute for Cancer Genetics and director of the Lymphoid Malignancies and Development Program at the Herbert Irving Comprehensive Cancer Center. “Not so long ago, when we had a patient with leukemia coming through the door, the pathologist could tell you what the leukemia cells joked like, but we didn’t know what was driving the disease, why one patient would be different from another, and why one would be cured and another wouldn’t be.”
Dr. Ferrando has dedicated his research to unlocking the genetic secrets f T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematologic tumor that strikes predominantly in young people, hijacking the precursors that generate T-cells. Current cure rates hover at 75 percent »r children and 50 percent for adults. Clinicians have long known that patients whose leukemias do not respond promptly to chemotherapeutic treatment have a worse prognosis than those for whom the treatment starts working immediately, but they did not know how to detect who would fall into each group or understand the mechanisms of resistance and relapse.
In February 2013, Nature Medicine published findings of a team led by Dr. Ferrando that implicated mutations to a gene known as NTC52 in resistance to two nucleoside analogs, drugs at the core of conventional chemotherapy treatment for T-ALL. “We hope that this might translate into new therapies that will convert people from poor prognosis into a more favorable outcome,” says Dr. Ferrando, who collected blood samples from children at diagnosis, treatment, and relapse stages, then used high-throughput parallel exome sequencing to identify mutations common to those who relapsed. “Now we can start, in a rational way, to intervene in the pathways that are most clinically relevant.”
By deploying the same genomic techniques that revealed the role of NTC52 mutations in some cases of relapse, Dr. Ferrando hopes to identify additional mutations at play in adults with T-ALL. Beyond the immediate therapeutic value of such studies for people with T-ALL, the scientific techniques his lab develops might be applied to other forms of cancer. “The study of leukemia is a step ahead of the broader field of cancer research, because getting relapse samples from a leukemia patient is much easier – than biopsying a solid tumor,” says Dr. Ferrando, whose early work on the role of the NOTCH1 gene in T-ALL has since become pertinent in the | development of new drugs to treat more common forms of leukemia.
Source: the 2013 annual report of the Columbia University College of Physicians & Surgeons