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Targeted Interleukin‐27 Gene Therapy Development for Disrupting Key Malignant Crosstalk between Metastatic Prostate Cancer and Bone
Author(s) -
Salameh Janelle W.,
Figueiredo Marxa L.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.491.5
Subject(s) - cancer research , prostate cancer , tumor microenvironment , medicine , crosstalk , osteoimmunology , immune system , cytokine , cancer , immunology , receptor , rankl , activator (genetics) , physics , optics
Prostate cancer (PCa) bone metastases have been reported in up to 90% of patients with advanced disease. Prostate cancer 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 regeneration. IL‐27 is an immunomodulatory cytokine with a 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. Thus, we hypothesize that a tumor‐targeted IL‐27 gene therapy approach would facilitate the accumulation of IL‐27 in the bone/tumor microenvironment and enhance its therapeutic efficacy . 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. We have also assessed the potential for tumor‐targeted IL‐27 expression in disrupting malignant characteristics of PCa in vitro in terms of viability and invasiveness following transfection. Future studies will examine the expression and therapeutic efficacy of tumor‐targeted IL‐27 in vivo in a TRAMP‐C2 tibial implantation model. Support or Funding Information NIH‐NCI R01CA196947‐S1 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .