Recombinant MDA-7/IL-24 suppresses prostate cancer bone metastasis through down regulation of the Akt/Mcl-1 pathway

Prostate cancer (PC) is a principal cause of cancer-associated morbidity in men. Although 5-year survival of patients with localized PC approaches 100 percent, survival decreases precipitously after metastasis.

Bone is the preferred site for disseminated PC cell colonization, altering the equilibrium of bone homeostasis resulting in weak and fragile bones. Currently, no curative options are available for PC bone metastasis. MDA-7/IL-24 is a well-studied cytokine established as a therapeutic in a wide-array of cancers upon delivery as a gene therapy. In this study, we explored the potential anti-cancer properties of MDA-7/IL-24 delivered as a recombinant protein. Using bone metastasis experimental models, animals treated with recombinant MDA-7/IL-24 had significantly less metastatic lesions in their femurs as compared to controls. The inhibitory effects of MDA-7/IL-24 on bone metastasis resulted from PC-selective killing and inhibition of osteoclast differentiation, which is necessary for bone resorption. Gain- and loss-of-function genetic approaches document that pro-survival Akt and Mcl-1 pathways are critically important in the anti-bone metastatic activity of MDA-7/IL-24. Our previous findings showed that MDA-7/IL-24 gene therapy plus Mcl-1 inhibitors cooperate synergistically. Similarly, an Mcl-1 small molecule inhibitor synergized with MDA-7/IL-24 and induced robust anti-bone metastatic activity. These results expand the potential applications of MDA-7/IL-24 as an anti-cancer molecule and demonstrate that purified recombinant protein is non-toxic in pre-clinical animal models and has profound inhibitory effects on bone metastasis, which can be enhanced further when combined with an Mcl-1 inhibitory small molecule.

Molecular cancer therapeutics. 2018 Jun 22 [Epub ahead of print]

Anjan K Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xue-Ning Shen, Luni Emdad, Swadesh K Das, Devanand Sarkar, Paul B Fisher

Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine., VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine., VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine., Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine .