Car-T therapy's new partner, PAK4 inhibitors

In a new study published November 30 in Nature Cancer, a team of researchers from Sun Yat-sen University and the University of Pennsylvania found that the absence of PAK4 in glioblastoma (GBM) endoblasts "normalizes" tumor micro-environmental blood vessels and inhibits PAK4 to improve the effectiveness of CAR-T cell therapy in GBM, both of which can significantly improve survival in mice.
: Nature Cancer GBM is one of the most common and invasive malignant primary brain tumors and one of the deadliest human malignancies.
there are complex immune resistance mechanisms, although traditional treatment can extend the life of GBM patients, but the quality of life of patients after treatment is reduced, survival is often short, so GBM urgently needs new therapies.
In a previous study, PAK4 (p21-activatedkinase 4) has been shown to be a driver of solid tumor growth, and in this new study, the team analyzed and identified more than 500 kinases from endoblast cells in GBM patients and found that PAK4 ranked first.
source: Nature Cancer and PAK4 in silent GBM endothor cells, cell proliferation, migration, and invasion in GBM endothor cells are inhibited, but do not inhibit cell proliferation and migration in normal endothor cells in the brain.
Source: Nature Cancer It is worth noting that after PAK4 was silenced, the form of GBM endoskin cells changed from spindle-shaped to characteristic pebble-like, indicating that the formation of blood vessels was less chaotic, meaning that the microenn environment was "normalized".
: Nature Cancer In a GBM mouse model, researchers found that knocking out PAK4 reduced hypoxia and vascular abnormalities in mouse tumors, improved T-cell immersion, and inhibited tumor growth.
about 80 percent of PAK4 knock-out mice survived more than 60 days after the end of the experiment, while all wild mice died within 40 days of tumor implantation.
PAK4 deficiency inhibits vascular abnormalities and enhances T-cell immersion (Source: Nature Cancer) Researchers then studied the effects of PAK4 pharmacological inhibition on GBM endodertic cell function and vascular morphology.
they observed that the selective PAK4 inhibitor KPT9274 specifically inhibited the proliferation of GBM endotent cells, but not normal endotyte cells in the brain.
source: Nature Cancer and the use of KPT9274, the chaotic form of blood vessels (with spatial heterogeneity of twists and turns and non-continuous blood vessels) significantly changed, the tumor vein system formed a continuous blood vessels.
addition, the treatment of KPT9274 significantly reduced hypoxia in the tumor, indicating that the tumor microencology was repaired.
in another EGFRvIII CAR-T cell therapy and PAK4 inhibitor experiment using changes in the tumor microenvironour vein system after KPT9274 (Source: Nature Cancer), separate KPT9274 and CAR-T cell therapy did not significantly affect tumor growth and mouse survival.
but after five days of CAR-T cell infusion, the combination of KPT9274 and CAR-T cell therapy reduced tumor growth by nearly 80 percent compared to mice that received only CAR-T therapy.
note that all mice in the other group died 33 days after the tumor was implanted, and nearly 40 percent of the mice in the combined treatment group survived.
PAK4 inhibition in combination with CAR-T cell therapy (Source: Nature Cancer) "For the first time, we have shown that PAK4 inhibitors can reconstruct the entire vascular microenvironment and promote cell therapy, and importantly, almost all solid tumors have vascular abnormalities, so this finding may also be used on other tumors, including breast and pancreatic cancer.
Fan, author of the paper, concludes.
: 1 s Ma, W., Wang, Y., Zhang, R. et al. Targeting PAK4 to reprogram the vascular microenvironment and improve CAR-T immunotherapy for glioblastoma. Nature Cancer (2020). 2 s researchers the door to tumor microenvironment for CAR T cells (Source: MedicalXpress) 3 s exclusive depth! Progress in the development of new drugs for the most difficult tumors ,glioblastoma" (Source: Pharmaceutical Rubik's Cube)