The Trustees of Columbia University in the City of New York, Columbia University Medical Center
Project Term: October 1, 2021 - September 30, 2023
Acute lymphoblastic leukemia (ALL) represents the most frequent type of cancer in children and displays high rates of relapse. In this context, mutations in NT5C2 act as major drivers of resistance to chemotherapy with 6-mercaptopurine and are associated with early relapse and progression. Our project aims to investigate the regulation of this protein and design NT5C2 inhibitors that would prevent and improve the treatment of relapsed leukemia patients.
Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy that requires treatment with intensive chemotherapy. ALL represents the most frequent type of cancer in children and young adults, accounting for 30% of all diagnosis, and currently stands as the leading cause of cancer-related death in children. Protocols have increased the overall survival rates of newly diagnosed pediatric acute ALL to over 80%. However, a high percentage of patients relapse after intensified chemotherapy. Notably, relapsed ALL is associated with higher risk of therapeutic failure and poor prognosis, with unsatisfactorily low cure rates of less than 40%. In this context, understanding the mechanisms of resistance to therapy, identifying therapeutic targets capable of overcoming resistance, and implementing therapeutic regimens that curtail the development of relapse are top priorities in the field. Our project seeks to characterize and target the molecular mechanisms driving resistance to 6-mercaptopurine (6-MP), an essential drug widely used in the treatment of ALL. Specifically, we will use genomic profiling, genetically engineered mouse models, and biochemical and structural analyses to investigate the regulation of NT5C2, a protein mutated in relapsed ALL. NT5C2 mutations hyperactivate the protein and inactivate 6-mercaptopurine anti-leukemia effects, leading to chemotherapy resistance in these patients. Afterwards, we will use this knowledge to design specific NT5C2 inhibitors that, used in combination with 6-MP chemotherapy, would prevent and improve the treatment of relapsed leukemia patients. The identification of new mechanisms of ALL relapse is key to develop new markers and improve early diagnosis. An important corollary of these findings is that NT5C2 inhibitors could reverse resistance to 6-MP not only in patients with NT5C2 mutations, but also more broadly in relapsed ALL. These studies will enhance our understanding of the mechanisms responsible for leukemia relapse and pave the way for the development of new targeted therapies for the treatment of high-risk leukemia patients.