Development of Targeted Interleukin‐27 Gene Therapy for Disrupting Malignant Crosstalk in Prostate Cancer Bone Metastases

Although ~90% of prostate cancer patients with advanced disease will exhibit bone metastasis, current therapies focus on one aspect of the disease (either the tumor or the bone), with tumor elimination being the primary goal. Prostate cancer (PCa) cells ‘hijack’ bone homeostasis by disrupting the crosstalk between critical cells within the tumor/bone microenvironment (osteoblasts, osteoclasts, and immune cells), and utilizing this effector‐rich environment for cancer cell survival and growth. Crosstalk pathways primarily involve Interleukins (IL‐6 and IL‐11) and transforming growth factor β (TGFβ). Therefore, a key therapeutic objective in malignant skeletal disease management is to eliminate tumors while restoring bone homeostasis. Current treatments are limited to palliative radiotherapy, chemotherapy, or anti‐RANK treatments, all of which have considerable side effects such as osteonecrosis of the jaw or enhanced tumor invasion. An emerging approach to treating skeletal malignancies, osteoimmunology, investigates new multifunctional immune‐stimulatory agents that can simultaneously combat tumor growth and promote bone repair. Our group is interested in IL‐27, an immunomodulatory cytokine with great potential as a multifunctional cancer therapeutic. Its regulatory roles include antitumor immune responses (promoting Th1 differentiation), inhibition of tumor growth, and direct modification of tumor/bone crosstalk to support bone regeneration. We hypothesize that a secreted tumor‐targeted IL‐27 gene therapy approach would facilitate the accumulation of IL‐27 in the bone/tumor microenvironment, thus eliminating tumors while restoring bone. To test this hypothesis, we created a tumor‐targeted IL‐27 gene by incorporating a novel peptide (LSLITRL); an IL‐6 receptor antagonist known to inhibit angiogenesis and tumor growth; or a scrambled control peptide at the C‐terminus. To detect the expression, secretion, and tumor recognition specificity, IL‐27 constructs were fused to a NanoLuciferase expressing vector modified with a secretion signal at the N‐terminus. We have also assessed the potential for our proposed gene therapy in disrupting malignant characteristics of PCa in vitro in by assessing STAT‐1/‐3 activation and will be assessing bone cell mineralization in PCa/bone co‐cultures. Future studies will examine the therapeutic efficacy of secreted, tumor‐targeted IL‐27 in vivo . Support or Funding Information NCI R01CA196947‐S1