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

Abstract

Aneustat (OMN54) is a multivalent, botanical anticancer candidate therapeutic. A recent Phase-I clinical trial has indicated that it is well tolerated by patients and has immunomodulatory activity. In our study, using in vitro and in vivo prostate cancer models, we investigated Aneustat with regard to effects on (i) cancer-generated immunosuppression based on aerobic glycolysis leading to acidification of the tumor microenvironment, and (ii) immune-related processes such as macrophage differentiation and shifts in the intratumoral levels of host immune cells. Aneustat markedly reduced glucose consumption, lactic acid secretion, glycolysis-related gene expressions and proliferation of human LNCaP prostate cancer cells. In addition, Aneustat induced differentiation of RAW264.7 macrophages to the M1 anticancer phenotype. Treatment of LNCaP xenografts and first-generation patient-derived prostate cancer tissue xenografts with Aneustat in both cases led to a marked shift in intratumoral host (mouse/patient) immune cell levels: a higher ratio of cytotoxic CD8+ T/Treg cells, higher numbers of NK cells, lower numbers of Treg cells and MDSCs, i.e. changes favoring the host anticancer immune response. Taken together, the data indicate that Aneustat has immunomodulatory activity based on inhibition of aerobic glycolysis which in patients may lead to reduction of cancer-induced immunosuppression. Furthermore, first-generation patient-derived cancer tissue xenograft models may be used for screening compounds for immunomodulatory activity.

• Authors: Sifeng Qu, Hui Xue, Xin Dong, Dong Lin, Rebecca Wu, Noushin Nabavi, Colin C Collins, Martin E Gleave, Peter W Gout, Yuzhuo Wang
• Journal: International journal of cancer (Int J Cancer) Vol. 143 Issue 2 Pg. 419-429 (07 15 2018) ISSN: 1097-0215 [Electronic] United States
• PMID: 29441566 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Chemical References

• Immunologic Factors
• Small Molecule Libraries
• Lactic Acid

Topics

• Aerobiosis
• Animals
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glycolysis (drug effects)
• Humans
• Immunologic Factors (administration & dosage, pharmacology)
• Lactic Acid (metabolism)
• Macrophages (cytology, drug effects)
• Male
• Mice
• Prostatic Neoplasms (drug therapy, genetics, immunology)
• RAW 264.7 Cells
• Small Molecule Libraries (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays