Novel Therapy for Pediatric Leukemia Patients with NUP98 Translocations
Chromosomal translocations of the nucleoporin 98 (NUP98) genes, which lead to the expression of NUP98 fusion proteins, are often found in patients with various hematologic malignancies, but are particularly prevalent in pediatric acute leukemia, constituting ~10% of all childhood leukemia cases. The presence of NUP98 translocations in pediatric leukemia patients confers very poor clinical outcome, leading to only ~10% of event-free survival three years after diagnosis and <30% four years survival rate. Thus, pediatric leukemia with NUP98 translocations represents an unmet medical need, supporting the requirement for new therapies. The oncogenic activity of NUP98 fusion proteins is dependent on the menin-MLL1 protein-protein interaction, and we have shown that menin inhibitor can effectively eradicate leukemic cells with NUP98 translocations. However, leukemia patients with NUP98 translocations frequently harbor other mutations (e.g. FLT3, FLT3-ITD, RAS), which further promote cancer cell proliferation. This suggests that blocking NUP98 fusion protein complex (e.g. by menin inhibitor as a single agent) might not be sufficient to effectively kill these leukemic cells and combinatorial treatments are needed for effective long-lasting remission of the NUP98-rearranged leukemia.
In this project we will assess rationally designed combinations of our menin inhibitor with selected FDA approved targeted drugs used in Acute Myeloid Leukemia, AML, (e.g. FLT3 inhibitor Gilteritinib, BCL-2 inhibitor Venetoclax) or in other cancers (CDK4/6 inhibitor Palbociclib) in pre-clinical models of the NUP98-rearranged leukemia. The goal of this project is to assess the efficacy and mechanism of action of these combinations to provide a rationale for clinical translation of best combinations to the pediatric leukemia patients with NUP98 translocations. Based on our preliminary data, we expect that at least some of the proposed combinations will outperform the effect of a menin inhibitor as a single agent, resulting in complete, long-lasting remission in vivo in the advanced pre-clinical models of the NUP98-rearranged leukemia, including patient derived xenograft (PDX) models. Since menin inhibitor is currently in clinical trials in AML patients with MLL1 translocations or NPM1 mutations, the outcome of this work should lead immediately to new clinical trials of the most promising combinations in pediatric AML with NUP98 rearrangements. In the long-term, this work should result in new therapies for aggressive pediatric leukemia with translocations of the NUP98 gene, which currently suffer from very poor prognosis.