Therapeutic Targeting of the Disrupted Metabolic State in DIPG
Diffuse intrinsic pontine glioma (DIPG) is the deadliest brainstem cancer in children, and significant therapeutic progress has not been made in decades. DIPG is resistant to pro-apoptotic chemotherapeutics, exhibits a profile of oxidative stress, and has disrupted cellular metabolism. Ferroptosis is an iron-dependent form of cell death mediated by the accumulation of toxic lipid peroxides. The Lyssiotis lab recently found that the disrupted oxidative/metabolic state in DIPG sensitizes these cells to ferroptotic cell death.
The central hypothesis of this project is that Sig15 is abnormally expressed in HM, contributes to immune evasion, and can be inhibited in leukemia and/or lymphoma cells to promote immune clearance. This hypothesis stems from our observations that inhibition of Sig15 prolongs survival in mice with leukemia with an intact immune system, but not in mice with an impaired immune system. Furthermore, Sig15 is expressed at higher levels in HM cells as compared to normal. We will test our hypothesis through the following specific aims: 1) Determine whether inhibition of Sig15 enhances immune-mediated clearance of malignant hematopoietic cells, 2) Determine whether and how Sig15 is overexpressed in malignant hematopoietic cells, and 3) Determine whether Sig15 activation/signaling is required for immune evasion of malignant hematopoietic cells. The project is innovative in that we have identified a novel role for Sig15 as an immune modulating molecule and therapeutic target in HM. The proposed work is significant because it will provide critical data for the design and justification of clinical trials targeting Sig15 in HM.