Developing drugs to treat NT5C2 mediated resistance in pediatric ALL
The cure rate for childhood acute lymphoblastic leukemia (ALL) has improved remarkably over the last four decades. However in spite of this improvement 10% to 15% of children will suffer a recurrence and their prognosis is dismal making ALL one of the leading causes of death due to cancer in children. We and others have shown that relapse is due to the outgrowth of a resistant subclone and we have discovered that these subclones contain mutations in genes that regulate response to the drugs used in therapy. This is true for both conventional, as well as, new immunotherapeutic agents. One of the most common mutations occurs in a gene called NT5C2 and results in resistance to 6-mercaptopurine which is a cornerstone of therapy for both childhood and adult ALL. We have already completed a large chemical screen looking for inhibitors of NT5C2 and in this application we propose to optimize their chemical structure so that such compounds can be used to eradicate NT5C2 mutant leukemia cells in patients and therefore prevent relapse. In a parallel group of studies we have developed laboratory tests to screen patients early in treatment to see if their leukemia cells contain NT5C2 mutations. Patients that test positive for the mutation would be ideal candidates for NT5C2 inhibitors.
Our long term goal is to develop the first precision-based clinical trial to prevent relapse rather than waiting for relapse to occur, at which time the leukemia is more difficult to treat.