Therapy of prostate carcinoma by immunoproteasome inhibition

• Applicant: Professor Dr. Michael Basler, since 12/2022
• Subject Area: Reproductive Medicine, Urology ; Hematology, Oncology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433663351

For hormone refractory, metastasizing prostate carcinoma (CaP) there are only moderately effective and no curative treatments available. Due to inflammation, CaP tissues express high levels of the immunoproteasome i.e. a cytokine-inducible variant of the constitutive proteasome expressing the catalytically active subunits LMP2 (beta1i), MECL-1 (beta2i), and LMP7 (beta5i). Previously, we have shown that during the treatment of autoimmune diseases and interference with transplant rejection, the potent immunoproteasome inhibitor ONX 0914 achieved suppression of the pro-inflammatory cytokines IL-6, IL-23, TNF, and IL-17, which strongly promote autoimmunity but also CaP growth. Moreover, we showed in a recent publication that ONX 0914 suppressed colon carcinoma development and progression in pre-clinical models. Since this carcinoma also relies on IL-6, IL-23, TNF and IL-17, we want to investigate in this project whether immunoproteasome inhibition may likewise be effective in CaP therapy. In preliminary work we could show that ONX 0914 induced apoptosis and blocked proliferation in a human CaP cell line in vitro. First we will test if this is true in other CaP lines from mouse and human as well, whether ONX 0914 causes accumulation of poly-ubiquitin conjugates, the induction of the unfolded protein response, blockage of Nrf1 activation, and the preferential accumulation of specific proteins or degradation intermediates. Then we will investigate whether combinations of subunit-selective immunoproteasome inhibitors potentiate these effects. In two clinically relevant spontaneous and autochthonous transgenic mouse models of CaP (the TRAMP and prostate specific Pten-/- models) we will test if ONX 0914 treatment can block the development and progression of CaP. We will examine the effect on changing the cytokine environment of the tumor, on apoptosis induction, and proliferative arrest. Finally, we will assess the expression levels of immunoproteasome subunits in human CaP tissues from patients before and after hormone ablation therapy. Immunoproteasome inhibitors, in contrast to general proteasome inhibitors, can be applied far below the maximally tolerated dose and show no obvious adverse side effects in rodents and humans in a recent clinical phase I trial. Hence, we hope that our study will pave the way for testing immunoproteasome inhibitors, the first of which is already in phase 2 clinical testing in autoimmunity, for the treatment of hormone refractory CaP.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Dr. Marcus Groettrup, until 12/2022 (†)