New therapy for prostate cancer: Enzalutamide "partner" H6PD inhibitor improves survival in mice

Article source: Medical Rubik's Cube Pro

The prostate is part of the male reproductive system, and approximately one in nine men will develop prostate cancer in their lifetime.

The androgen receptor (AR) inhibitor enzalutamide is a standard hormone therapy used in the care of metastatic prostate cancer.

On May 26, in a new study published in Science Translational Medicine, researchers at the Cleveland Medical Center discovered a new target when exploring the mechanism of resistance related to glucocorticoid signal transduction: H6PD, which inhibits H6PD The protein can significantly reduce tumor volume and improve the survival rate of drug-resistant prostate cancer mouse models.

Previous studies have found that the expression of 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2) in drug-resistant tumors is reduced.

The alternative isoenzyme of 11β-HSD2, 11β-HSD1, has the opposite effect to 11β-HSD2, which is reductive.

Cortisol regulation in prostate cancer tissue (Source: Science Translational Medicine)

The interaction of 11β-HSD1 and hexose 6 phosphate dehydrogenase (H6PD) drives 11β reduction, so the researchers hypothesized that blocking H6PD can restore the oxidation direction of glucocorticoid metabolism, normalize the tumor glucocorticoid concentration and reverse Enza Luamine resistance.

In human tumor tissues and cell lines, researchers have observed that enzalutamide treatment induces an up-regulation of the expression of hexose-6 phosphate dehydrogenase (H6PD).

Glucocorticoid metabolism regulation of H6PD and H6PD to enzalutamide resistance (Source: Science Translational Medicine)

Knockout of H6PD significantly enhanced the inhibitory effect of enzalutamide on tumor growth and restored enzalutamide-induced glucocorticoid metabolism disorders, and in the absence of enzalutamide treatment, the absence of H6PD had an effect on tumor growth Or progress has no effect.

Effect of H6PD deletion on enzalutamide treatment sensitivity and tumor corticosterone concentration in mouse xenograft models (Source: Science Translational Medicine)

In view of the fact that there is no related targeted drug for H6PD, the researchers used the PARP inhibitor lukapanib for H6PD targeted inhibition (rukapanib's secondary target is H6PD), proving that lukapanib can specifically bind and inhibit H6PD activity.

In the castration-resistant prostate cancer xenograft model, compared with enzalutamide and lukapanib alone, lukapanib combined with enzalutamide can significantly reduce the tumor volume and prolong the progression-free survival.

Pharmacological inhibition of H6PD and the effect of this inhibition on enzalutamide resistance (Source: Science Translational Medicine)

Although lukapanib can inhibit H6PD, clinical studies must be conducted to determine the effect of lukapanib on the glucocorticoid metabolism of male prostate cancer and the response to enzalutamide.

Reference materials:

[1] Li JN et al.

[2] Cleveland clinic researchers identify new drug target for treating aggressive prostate cancer (Source: Cleveland Medical Center)

[3] Prostate Cancer (Source: Cleveland Medical Center)