Rational therapeutic targeting of oncogenic immune signaling states in myeloid malignancies

Daniel Starczynowski

PhD

Cincinnati Children's Hospital Medical Center

Project Term: July 1, 2020 - June 30, 2024

Project Summary

Myeloid malignancies, such as acute myeloid leukemia (AML), are heterogeneous hematopoietic malignancies typically characterized by suppression of normal blood formation, and overproduction of immature myeloid blood cells (blasts) associated with a differentiation block. Despite significant effort, patients with AML continue to have poor outcomes, with a five-year relative survival of 25%. AML originates in hematopoietic stem and progenitor cells referred to as leukemic stem/progenitor cells (LSPC) that acquire genetic or epigenetic abnormalities. Due to the heterogeneity and plasticity of myeloid malignancies, the ideal molecular target(s) is broadly dysregulated and requisite for multiple signaling pathways in leukemic stem/progenitor cells (LSPC). We observed that patient-derived LSPC across various myeloid malignancy subtypes exhibit a higher than previously appreciated frequency of dysregulated immune and inflammatory pathways (referred as “oncogenic immune signaling states”). Despite efforts to interfere with oncogenic immune signaling states in cancer, including AML, targeting one (or two) of these pathways will have limited therapeutic benefit. The lack of therapeutic effectiveness is due to the redundancy of pathways that converge on oncogenic immune signaling states. We propose an alternative strategy by targeting a convergent signaling node essential for oncogenic immune signaling states in LSPC. Through functional studies, we found that oncogenic immune signaling states in LSPC require the activity of a ubiquitin-conjugating enzyme, UBE2N. Based on our preliminary data, we propose that inhibiting UBE2N will selectively eliminate LSPC with oncogenic immune signaling states, while permitting outgrowth of residual normal blood-forming cells. In this proposal we hypothesize that inhibition of UBE2N will target oncogenic immune signaling states and suppress LSPC while sparing normal hematopoietic cells, and thus such a strategy may have therapeutic applicability in myeloid malignancies. To test this theory, we propose to identify optimized UBE2N inhibitors, evaluate the efficacy of UBE2N inhibitors in AML, and establish the requirement of UBE2N catalytic function on normal and malignant hematopoiesis.

This Discovery award is sponsored through a partnership between LLS, the Mark Foundation for Cancer Research and The Paul G. Allen Frontiers Group.