Most children with acute lymphoblastic leukemia (ALL) can be cured, but the prognosis is dismal for about 20 percent of patients who relapse after treatment.
Now a new study from researchers at Columbia University’s Herbert Irving Comprehensive Cancer Center has found that a mutation that leads to relapse in many ALL patients also causes a weakness that could be exploited to kill the cancer cells in patients experiencing relapse.
The research, led by Adolfo Ferrando, MD, PhD, found that mutations in a gene called NT5C2 make leukemic cells resistant to a common chemotherapy treatment but vulnerable to a class of drugs called IMPDH inhibitors.
“Increased sensitivity to IMPDH inhibition shows proof of principle that the pathway for resistance provides a new therapeutic target,” Dr. Ferrando says. “IMPDH inhibitors could eventually emerge as relevant anti-leukemic drugs, but this would require additional preclinical work before clinical testing.”
NT5C2 mutation emerges during remission
Cancer cells are like moving targets, genetically changing to thrive and multiply. They evolve ways to survive the onslaught of treatment, so patients often stop responding to a particular drug.
Dr. Ferrando’s lab had previously found that cancer cells from relapsed ALL patients frequently have a mutation in a gene called NT5C2 and that these mutations drive resistance to a common chemotherapy treatment, 6-mercaptopurine.
IMPDH inhibitors could eventually emerge as relevant anti-leukemic drugs.How this mutation emerges as cancer recurs after remission was unclear until now. Using samples from patients in remission, the researchers detected the NT5C2 mutation in cancer cells before patients were clinically diagnosed as relapsed. However, the mutation was not detectable in most cases at the time of diagnosis.
What do these findings mean for ALL patients?
The findings suggest that cells with the NT5C2 mutation only multiply in response to treatment, and doctors can be on the lookout for the mutation as an indicator of a patient’s potential to relapse. “This seems to be a late mutation involved in disease progression. Our data support that it may not be present at diagnosis in many cases, and that in cases where it may be present, it represents a very minor population,” says Dr. Ferrando.
The study also paves the way for the discovery of new treatment options. “In this case, by understanding the mechanisms of resistance, we are now positioned to design new strategies to curtail the occurrence of relapse,” says Dr. Ferrando.
About the study
Dr. Ferrando is professor in the Departments of Pediatrics, Pathology & Cell Biology, and Systems Biology and a member of the Institute of Cancer Genetics and the Herbert Irving Comprehensive Cancer Center at Columbia University Irving Medical Center.
The study, published Jan. 17 in Nature, is titled ‘Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia.’
Additional authors: Tzoneva G (CUIMC), Dieck CL (CUIMC), Oshima K (CUIMC), Ambesi-Impiombato A (CUIMC), Sánchez-Martín M (CUIMC), Madubata CJ (CUIMC), Khiabanian H (Rutgers Univ.), Yu J (Princess Maxima Center for Pediatric Oncology and Radboud University Medical Center, the Netherlands), Waanders E (Princess Maxima Center for Pediatric Oncology), Iacobucci I (St. Jude Children’s Research Hospital, Memphis), Sulis ML (CUIMC), Kato M (Saitama Children’s Medical Center, Japan), Koh K (Saitama Children’s Medical Center), Paganin M (Univ. of Padua, Italy), Basso G (Univ. of Padua), Gastier-Foster JM (Nationwide Children’s Hospital and Ohio State University, Columbus, Ohio), Loh ML (UCSF and Children’s Oncology Groups, Arcadia, CA), Kirschner-Schwabe R (UCSF), Mullighan CG (St. Jude Children’s Research Hospital), and Rabadan R (CUIMC).
This work was supported by the National Institutes of Health (grants R35CA210065, R01CA206501, U54CA193313, R01CA185486, U54CA209997, U10CA98543, P30CA013696, U24CA114766, and T32CA09503); the Leukemia & Lymphoma Society; Alex’s Lemonade Stand Foundation; the Chemotherapy Foundation; the Stewart Foundation; the American Lebanese Syrian Associated Charities of St Jude Children’s Research Hospital; an HHMI International Student Research Fellowship; a Rally Foundation fellowship; the China Scholarship Council; the Ter Meulen Grant of the Royal Netherlands Academy of Arts and Sciences; and the Dutch Cancer Society.
The authors declare no competing financial interests.