Deciphering the Genetic Drivers of Leukemia

March 9, 2021
portrait of Dr. Adolfo Ferrando

Adolfo Ferrando, MD, PhD

Medical progress is made as researchers gradually illuminate the unknown. For the past 16 years Adolfo Ferrando MD, PhD, has been uncovering the mysteries of leukemia, and showing why, despite huge gains in outcomes for most children with the disease, some still do less well and their disease recurs. Dr. Ferrando is Associate Director for Shared Resources at the Herbert Irving Comprehensive Cancer Center, and heads up a 10-member lab in CUIMC’s Institute for Cancer Genetics. 

Using a combination of genomic and systems biology approaches, biochemical analyses, structural biology, chemical biology, and experimental therapeutics, he and members of his lab are exploring the molecular mechanisms underlying acute lymphoblastic leukemia (ALL), the most common cancer in children. 

Dr. Ferrando and his lab members focus primarily on deciphering the mechanisms that lead to chemotherapy resistance and relapse in ALL—important questions given the poor prognosis and limited therapeutic options for patients who experience a relapse. 

“Relapsed lymphoblastic leukemia, the fourth most common cancer in children, is very aggressive and very difficult to treat, and resistance to chemotherapy is a major challenge,” Dr. Ferrando says. “We are exploring the genomes of tumors at diagnosis and at relapse, analyzing mutation and gene expression signatures to find ways to directly target the mechanisms leading to leukemia persistence, disease progression, and resistant relapse.”

Pediatric oncologists currently treat ALL with complex multiagent chemotherapy protocols, developed over the last three decades through laboratory and clinical research. As understanding of ALL has deepened, Dr. Ferrando says, “we now know that the most effective drug combinations succeed because of specific drug-gene interactions.” But, he adds, “exposure to therapeutic agents also imposes major genetic selection bottlenecks, and can propel leukemia cells down a complex evolutionary path leading to disease progression and relapse. Drugs that narrow that path work better.” 

One gene commonly found to be mutated in patients with relapsed ALL is NT5C2. Dr. Ferrando and his team have shown that specific mutations of this gene can increase its activity and production of a protein that helps cells clear themselves of chemotherapy drugs, thereby inducing resistance to chemotherapy. The Ferrando lab has developed NT5C2 inhibitors, and showed proof of principle that these inhibitors would curtail the emergence cells capable of initiating leukemia relapse and chemotherapy resistance.

Dr. Ferrando is also exploring the mechanisms of mutant genes responsible for leukemia initiation. He has shown that a gene called PHF6 is commonly mutated in ALL and promotes leukemia cells’ self-renewal, a property normally restricted to stem cells. “PHF6 is at the crossroads of central cellular functions that govern stem cell self-renewal. Genetic loss of PHF6 accelerated leukemia development in animal models and confers leukemia cells increased stem cell properties.” 

Dr. Ferrando’s deep explorations of the machinery that drives leukemia—the genes that play a role in initiating the disease, how they work, where are the mutations that cause the disease—may soon pay off, as he and colleagues identify specific vulnerabilities and therapeutic targets. 

“The accelerated pace of discovery is transforming the therapeutic landscape of pediatric leukemias. Many of the most promising targeted drugs and immunotherapies that we use today to treat this disease were at a preconceptual stage only 10 years ago,” Dr. Ferrando says. “I expect that the next ten years will bring paradigm changes in the therapy of most pediatric cancers, and that we will see improved outcomes and markedly reduced toxicities.”