CADD-42. EFFICACY OF MUTANT INTERLEUKIN-13 ALPHA-2 RECEPTOR–TARGETED LIPOSOMAL DOXORUBICIN IN THE INTRACRANIAL BRAIN TUMOR MODEL. (5th November 2018)

• Record Type: Journal Article
• Authors: Nesterova, Darya; Madhankumar, Achuthamangalam; Mrowczynski, Oliver; Sue Webb, Becky; Connor, James
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi282
• Page End: vi282
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.1175
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Glioblastoma (GBM) is the most common primary central nervous system (CNS) tumor in the United States and yet despite aggressive treatment, the median survival remains at 8 months. About 75% of human glioblastoma tumors selectively overexpress the α2 subtype of interleukin 13 (IL-13Rα2 ), considered a "decoy receptor" for GBM, allowing it to evade apoptosis normally induced by IL-13 binding. Our laboratory and others have developed targeting strategies to take advantage of IL-13Rα2 expression on GBMs. We showed that wildtype IL-13 targeted nanoliposomes delivering doxorubicin (WT-IL13-Dox), resulted in over 5-fold reduction of orthotopic tumors, with 60% of mice surviving for >200 days compared to mice treated with unconjugated liposomes. WT-IL13, however, also binds to the shared IL-13/IL-4 receptor α1 subunit found in multiple organs, including the heart and lungs, suggesting potential cross-reactivity with surrounding tissues. To address off-target effects, a mutant version of IL-13 was developed known as Targeted Quadruple Mutant-13 (TQM), which display improved binding affinity to the IL-13Rα2 receptor, and decreased affinity to the IL-13/IL-4 receptor α1 subunit. Twenty mice were normalized by tumor burden into two groups, one treated with WT-IL13-Dox and the other group with TQM-13-conjugated liposomal doxorubicin (TQM-13-Lip-Dox). Each group received 5mg/kg of doxorubicin in the liposomes for 4 weeks. Mice treated with TQM-targeted liposomes had slower tumor growth, smaller tumor burden, and prolonged survival (33 vs 23 days, p=0.009) than those treated with WT-IL13 liposomes. WBC counts in WT-IL13 mice suggested they were immunocompromised in comparison to TQM mice (p=0.02), which may contribute to worse survival. These findings suggest that TQM-13 bound nanoliposomes may enable the development of targeted therapy with a decreased side effect profile for delivery of chemotherapeutic agents to GBMs.