Development of a stress response therapy targeting aggressive prostate cancer

Abstract

Oncogenic lesions up-regulate bioenergetically demanding cellular processes, such as protein synthesis, to drive cancer cell growth and continued proliferation. However, the hijacking of these key processes by oncogenic pathways imposes onerous cell stress that must be mitigated by adaptive responses for cell survival. The mechanism by which these adaptive responses are established, their functional consequences for tumor development, and their implications for therapeutic interventions remain largely unknown. Using murine and humanized models of prostate cancer (PCa), we show that one of the three branches of the unfolded protein response is selectively activated in advanced PCa. This adaptive response activates the phosphorylation of the eukaryotic initiation factor 2–α (P-eIF2α) to reset global protein synthesis to a level that fosters aggressive tumor development and is a marker of poor patient survival upon the acquisition of multiple oncogenic lesions. Using patient-derived xenograft models and an inhibitor of P-eIF2α activity, ISRIB, our data show that targeting this adaptive brake for protein synthesis selectively triggers cytotoxicity against aggressive metastatic PCa, a disease for which presently there is no cure.

The integrated stress response mediates type I interferon driven necrosis in Mycobacterium tuberculosis granulomas

“…ISRIB has demonstrated promising results in prevention of neuronal degeneration, memory enhancement, and reducing tumor growth in certain cancers 79,80 . Further studies in combination with traditional anti-TB drugs may define whether future ISR inhibitors which are being developed for human use may offer therapeutic benefit as a host-directed therapy for TB and related intracellular infections.…”

Targeting genotoxic and proteotoxic stress‐response pathways in human prostate cancer by clinically available PARP inhibitors, vorinostat and disulfiram

“…ERAD malfunction or insufficiency leads to ER stress and activation of the unfolded protein response (UPR) . Several factors of ERAD machinery are upregulated in PCa, and UPR activation in PCa has been recently demonstrated, providing a possible vulnerability exploitable therapeutically . We have recently shown that DSF targets cancer via inhibition of the p97/NPL4 pathway, essential for ERAD .…”

“…As targeting proteotoxic stress pathways represents an emerging promising therapeutic approach for PCa, we also tested DSF that impairs protein degradation . DSF repurposing for cancer treatment is currently tested in at least eight clinical trials (according to http://ClinicalTrials.gov) involving various cancers including PCa.…”

“…22 Several factors of ERAD machinery are upregulated in PCa, 23 and UPR activation in PCa has been recently demonstrated, providing a possible vulnerability exploitable therapeutically. 24 We have recently shown that DSF targets cancer via inhibition of the p97/NPL4 pathway, essential for ERAD. 10 DSF's anticancer activity depends on copper 25 and we showed that in vivo, DSF becomes converted into diethyldithiocarbamate, a strong copper chelator forming a stable (CuET) the ultimate anticancer metabolite of DSF.…”

“…For the first time, we report that vorinostat downregulates also TOPBP1 which is important for Rad51 loading to chromatin during HR. 47 Indeed, pre-treatment with vorinostat resulted in less efficient DNA repair by HR, as documented by lower counts of As targeting proteotoxic stress pathways represents an emerging promising therapeutic approach for PCa, 24 we also tested DSF that impairs protein degradation. 10 29 this study did not combine DSF with copper, which is required for DSF's anticancer activity in vitro 25,49 and potentiates its activity in vivo.…”