Targeting NOX2 in cancer – a translational approach

This program comprises studies of the potential impact of the myeloid cell NADPH oxidase 2 (NOX2) and NOX2-derived reactive oxygen species (ROS) for the expansion and metastatic spread of malignant cells, along with attempts to target NOX2 for therapeutic purposes.

In the past grant period, we have developed murine models of NOX2+ myeloid leukemia (including triple transgenic Nox2-/- × LSL-KrasG12D × Mx1-Cre mice) and utilized Nox2-/- leukemic cells to demonstrated that genetic or pharmacologic targeting of NOX2 reduces the expansion of NOX2+ myeloid leukemic cells in vivo.

These models will be utilized in studies of combinatory immunotherapies.We develop murine models of metastatic cancer, including models where metastasis is enhanced by surgery-induced inflammation and immunosuppression.

Our initial results imply that genetic or pharmacological inhibition of NOX2 reduces metastasis formation and abolishes the enhanced metastasis that entails surgery-induced inflammation.

In addition, animal experiments imply that NOX2 inhibition ameliorates the anti-tumor efficacy of inhibitors of the PD-1/PD-L1 pathway.

In parallel with these murine studies, we cooperate with leading hematologists, oncologist and surgeons aiming at validating these findings in patients undergoing immunotherapy.

The proposed studies may point towards novel strategies for improved cancer immunotherapy, including inhibition of NOX2 in conjunction with anti-PD1 therapy.