Prostate cancer is a principal cause of cancer-associated morbidity in men. Although 5-year survival of patients with localized prostate cancer approaches 100%, survival decreases precipitously after metastasis. Bone is the preferred site for disseminated prostate cancer cell colonization, altering the equilibrium of bone homeostasis resulting in weak and fragile bones. Currently, no curative options are available for prostate cancer bone metastasis. Melanoma differentiation associated gene-7 (MDA-7)/IL24 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 anticancer properties of MDA-7/IL24 delivered as a recombinant protein. Using bone metastasis experimental models, animals treated with recombinant MDA-7/IL24 had significantly less metastatic lesions in their femurs as compared with controls. The inhibitory effects of MDA-7/IL24 on bone metastasis resulted from prostate cancer–selective killing and inhibition of osteoclast differentiation, which is necessary for bone resorption. Gain- and loss-of-function genetic approaches document that prosurvival Akt and Mcl-1 pathways are critically important in the antibone metastatic activity of MDA-7/IL24. Our previous findings showed that MDA-7/IL24 gene therapy plus Mcl-1 inhibitors cooperate synergistically. Similarly, an Mcl-1 small-molecule inhibitor synergized with MDA-7/IL24 and induced robust antibone metastatic activity. These results expand the potential applications of MDA-7/IL24 as an anticancer molecule and demonstrate that purified recombinant protein is nontoxic in preclinical animal models and has profound inhibitory effects on bone metastasis, which can be enhanced further when combined with an Mcl-1 inhibitory small molecule. Mol Cancer Ther; 17(9); 1951–60. ©2018 AACR.

中文翻译：

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重组 MDA-7/IL-24 通过下调 Akt/Mcl-1 通路抑制前列腺癌骨转移

前列腺癌是男性癌症相关发病率的主要原因。尽管局限性前列腺癌患者的 5 年生存率接近 100%，但转移后生存率急剧下降。骨骼是播散性前列腺癌细胞定植的首选部位，改变了骨骼体内平衡的平衡，导致骨骼脆弱易碎。目前，前列腺癌骨转移尚无治愈选择。黑色素瘤分化相关基因 7 (MDA-7)/IL24 是一种经过充分研究的细胞因子，作为基因治疗递送后，已被确定为多种癌症的治疗剂。在这项研究中，我们探索了作为重组蛋白递送的 MDA-7/IL24 的潜在抗癌特性。使用骨转移实验模型，与对照组相比，用重组 MDA-7/IL24 治疗的动物股骨中的转移病灶明显减少。MDA-7/IL24 对骨转移的抑制作用源于前列腺癌选择性杀伤和抑制破骨细胞分化，这是骨吸收所必需的。功能获得和功能丧失的遗传方法证明，促存活 Akt 和 Mcl-1 通路在 MDA-7/IL24 的抗骨转移活性中至关重要。我们之前的研究结果表明，MDA-7/IL24 基因治疗与 Mcl-1 抑制剂协同合作。同样，Mcl-1 小分子抑制剂与 MDA-7/IL24 协同作用并诱导强大的抗骨转移活性。这些结果扩大了 MDA-7/IL24 作为抗癌分子的潜在应用，并证明纯化的重组蛋白在临床前动物模型中是无毒的，并且对骨转移具有深远的抑制作用，当与 Mcl-1 抑制剂联合使用时可以进一步增强小分子。摩尔癌症治疗; 17(9); 1951-60。©2018 AACR。