NU2022-104
INVENTORS
Jaehyuk Choi*
Jay Daniels
Jurgen Ruland
Tim Wartweig
SHORT DESCRIPTION
Targeting PD-1 related mechanisms for treatment of aggressive T-Cell lymphomas
BACKGROUND
T-cell non-Hodgkin lymphomas (T-NHLs) are highly aggressive cancers that can be resistant to chemotherapies. The molecular pathogenesis of these cancers remains ill defined. There are, however, numerous oncogenic alterations within the T-cell antigen receptor (TCR) signaling pathway. For example, the tumor suppressor PDCD1 (PD-1), which encodes for the PD-1 immune checkpoint receptor, is often inactivated, partially explaining the aggressive behavior of T-NHLs. While it is known that inhibitory PD-1 signaling suppresses T-cell malignancies, the mechanisms involved remain largely unknown.
ABSTRACT
In preclinical studies, researchers at Northwestern University demonstrated that PD-1 signaling is a central regulator for energy metabolism and activating protein 1 (AP-1) activity in T-NHLs. They observed that PD-1 restricts glycolysis, glucose- derived acetyl-CoA production, and chromatin remodeling in healthy cells. These results link PD-1 mutations with AP-1 hyperactivation, highlighting the role of this metabolic cascade in aggressive T-cell lymphomas with defective PD-1 function. Pharmacological inhibition of components of this metabolic cascade were toxic to lymphoma cells and prolonged the survival of mice with PD-1 deficient lymphomas. Treatment of human-derived T cell lymphomas with small molecule inhibitors of components within this cascade reduced the proliferation of cancer cells. This work provides a promising avenue for potential therapeutic intervention via a variety of small molecules with versatile targets in aggressive T-cell lymphomas.
APPLICATIONS
ADVANTAGES
Offers first in class therapy for PD-1+ T-cell lymphomas.
Provides multiple targets in an essential pathway for disease progression.
PUBLICATION
Warteweig T. et al. (2023) PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP- 1 activity in T cell lymphoma. Nature Cancer 4: 1508-1525.
IP STATUS
US patent application has been filed.
Survival of PD-1 deficient mice treated with small molecule inhibitor of glycolysis cascade is increased, demonstrating potential as a therapeutic target in T-NHLs.