Enhanced anticancer activity of a combination of docetaxel and Aneustat (OMN54) in a patient‐derived, advanced prostate cancer tissue xenograft model

Abstract

The current first‐line treatment for advanced metastatic prostate cancer, i.e. docetaxel‐based therapy, is only marginally effective. The aim of the present study was to determine whether such therapy can be improved by combining docetaxel with Aneustat (OMN54), a multivalent botanical drug candidate shown to have anti‐prostate cancer activity in preliminary in vitro experiments, which is currently undergoing a Phase‐I Clinical Trial. Human metastatic, androgen‐independent C4‐2 prostate cancer cells and NOD‐SCID mice bearing PTEN‐deficient, metastatic and PSA‐secreting, patient‐derived subrenal capsule LTL‐313H prostate cancer tissue xenografts were treated with docetaxel and Aneustat, alone and in combination. In vitro, Aneustat markedly inhibited C4‐2 cell replication in a dose‐dependent manner. When Aneustat was combined with docetaxel, the growth inhibitions of the drugs were essentially additive. In vivo, however, the combination of docetaxel and Aneustat enhanced anti‐tumor activity synergistically and very markedly, without inducing major host toxicity. Complete growth inhibition and shrinkage of the xenografts could be obtained with the combined drugs as distinct from the drugs on their own. Analysis of the gene expression of the xenografts using microarray indicated that docetaxel + Aneustat led to expanded anticancer activity, in particular to targeting of cancer hallmarks that were not affected by the single drugs. Our findings, obtained with a highly clinically relevant prostate cancer model, suggest, for the first time, that docetaxel‐based therapy of advanced human prostate cancer may be improved by combining docetaxel with Aneustat.

Aneustat (OMN54) has aerobic glycolysis‐inhibitory activity and also immunomodulatory activity as indicated by a first‐generation PDX prostate cancer model

“…In our study, we showed that a 3‐week treatment with Aneustat (1,652 mg/kg) of male athymic nude mice bearing subcutaneous LNCaP tumors markedly inhibited the growth of the tumors; there was no major host toxicity, as assessed by animal body weights and behavior 18. Using preserved tissue sections of this experiment, the effect of Aneustat on the relative levels of mouse host NK cells and myeloid‐derived suppressor cells (MDSCs) were determined by IHC, using NK1.131 and Ly6G32 markers, respectively.…”

“…Microarray data, obtained in a previous study of LTL‐313H patient‐derived prostate cancer xenografts treated with Aneustat (GSE48667), were filtered by removal of probes without corresponding gene annotations and probes without detectable expression levels (<4 in log2 scale) as previously described 18. The gene enrichment was analyzed using GSEA hallmark gene‐set signatures.…”

“…To this end, the xenograft‐bearing mice were treated, 10 days after grafting, for 3 weeks with vehicle control or Aneustat (1,652 mg/kg), an effective, non‐toxic dosage determined in our study 18. No major host toxicity was observed.…”

“…First-generation patient-derived prostate cancer xenograft model, treatment with Aneustat Fresh patient metastatic prostate cancer lymph node tissues (obtained from the Vancouver General Hospital with proper patients' consent and approved biosafety certificates and animal protocols) were grafted under renal capsules of male NOD/ SCID-IL-2R-gc-KO (NOG or NSG) mice supplemented with testosterone as previously described. 18 After 10 days, the mice were randomly divided into two groups (3 mice/group; 4 grafts/mouse), and treated with Aneustat (1,652 mg/kg; orally; Q1d 3 5/3) or vehicle control (orally; Q1d 3 5/3). The health of the mice was monitored daily.…”

“…17 We have recently demonstrated, using a patient-derived prostate cancer xenograft model, that combining docetaxel (used in first-line treatment of advanced prostate cancer) with Aneustat led to much higher antitumor activity than the combined activities of the individual drugs, with indications that inhibition of aerobic glycolysis was involved. 18 In our study, we investigated Aneustat with regard to effects on (i) aerobic glycolysis of LNCaP prostate cancer cells, a process underlying cancer-generated lactic acid-induced immunosuppression and (ii) immune system-related processes such as macrophage differentiation and shifts in the levels of intratumoral host immune cells using LNCaP xenografts and firstgeneration patient-derived prostate cancer tissue xenografts.…”