oHSV therapy increases trametinib access to brain tumors and sensitizes them in vivo
glioblastoma (GBM); oncolytic herpes simplex virus-1 (oHSV); RAS-RAF-MEK-ERK signaling; Trametinib; Tumor necrosis factor α (TNFα)
BACKGROUND: Hyperactivation of the RAS-RAF-MEK-ERK signaling pathway is exploited by glioma cells to promote their growth and evade apoptosis. MEK activation in tumor cells can increase replication of ICP34.5-deleted HSV-1 viruses, but paradoxically its activation in tumor-associated macrophages promotes a pro-inflammatory signaling that can inhibit virus replication and propagation. Here we investigated effect of blocking MEK signaling in conjunction with oncolytic HSV-1 (oHSV) for brain tumors. METHODS: Infected glioma cells co-cultured with microglia or macrophages treated with or without trametinib were used to test trametinib effect on macrophages/microglia. ELISA, western blotting, and flow cytometry were utilized to evaluate the effect of the combination therapy. Pharmacokinetic (PK) analysis of mouse plasma and brain tissue was used to evaluate trametinib delivery to the CNS. Intracranial human and mouse glioma-bearing immune deficient and immune competent mice were used to evaluate the anti-tumor efficacy. RESULT: oHSV treatment rescued trametinib-mediated feed-back reactivation of the MAPK signaling pathway in glioma. In vivo, PK analysis revealed enhanced blood-brain barrier penentration of trametnib after oHSV treatment. Trametinib, a MEK Kinase inhibitor, treatment led to a significant reduction in microglia- and macrophage-derived TNFα secretion in response to oHSV-treatment and increased survival of glioma-bearing mice. Despite the reduced TNFα production observed in vivo, the combination treatment activated CD8+ T cell-mediated immunity, and increased survival in a glioma-bearing immune-competent mouse model. CONCLUSION: This study provides a rationale for combining oHSV with trametinib for the treatment of brain tumors.
Yoo Ji Young; Swanner Jessica; Otani Yoshihiro; Nair Mitra; Park Flora; Banasavadi-Siddegowda Yeshavanth; Liu Joseph; Jaime-Ramirez Alena Cristina; Hong Bangxing; Geng Feng; Guo Deliang; Bystry Darlene; Pelphs Mitch; Quadri Haroon; Lee Tae Jin; Kaur Balveen
Neuro-Oncology
2019
2019-05
<a href="http://doi.org/10.1093/neuonc/noz079" target="_blank" rel="noreferrer noopener">10.1093/neuonc/noz079</a>
Enhancing Therapeutic Efficacy of Oncolytic Herpes Simplex Virus-1 with Integrin beta1 Blocking Antibody OS2966.
Integrin beta1 receptor, expressed on the surface of tumor cells and macrophages in the tumor microenvironment (TME), has been implicated in both tumor progression as well as resistance to multiple modalities of therapy. OS2966 is the first clinical-ready humanized monoclonal antibody to block integrin beta1 and was recently orphan designated by FDA Office of Orphan Products Development (OOPD). Here, we tested therapeutic potential of OS2966-mediated integrin beta1 blockade to enhance the efficacy of oncolytic herpes simplex virus-1 (oHSV) through evaluation of virus replication, tumor cell killing efficiency, effect on the antiviral signaling pathway, co-culture assays of oHSV-infected cells with macrophages, and in vivo bioluminescence imaging on mammary fat pad triple negative breast cancer xenograft and subcutaneous and intracranial glioma xenografts. OS2966 treatment decreased interferon signaling and pro-inflammatory cytokine induction in oHSV-treated tumor cells and inhibited migration of macrophages, resulting in enhanced oHSV replication and cytotoxicity. OS2966 treatment also significantly enhanced oHSV replication and oHSV-mediated anti-tumor efficacy in orthotopic xenograft models including triple negative breast cancer and glioblastoma. The results demonstrated the synergistic potential of the combinatory treatment approach with OS2966 to improve anti-tumor efficacy of conventional oHSV therapy.
Lee Tae Jin; Nair Mitra; Banasavadi-Siddegowda Yeshavanth Kumar; Liu Joseph; Nallanagulagari Tejaswini; Jaime-Ramirez Alena Cristina; Guo Jeffrey Yunhua; Quadri Haroon; Zhang Jianying; Bockhorst Kurt H; Aghi Manish K; Carbonell W Shawn; Kaur Balveen; Yoo Ji Young
Molecular cancer therapeutics
2019
2019-03
<a href="http://doi.org/10.1158/1535-7163.MCT-18-0953" target="_blank" rel="noreferrer noopener">10.1158/1535-7163.MCT-18-0953</a>
MiR-21 enhances melanoma invasiveness via inhibition of tissue inhibitor of metalloproteinases 3 expression: in vivo effects of MiR-21 inhibitor.
Humans; Gene Expression Regulation; Cell Line; MicroRNAs/*genetics/metabolism; Cell Movement/genetics; Cell Proliferation/genetics; Melanoma/*genetics/metabolism/pathology; Neoplasm Invasiveness/*genetics/pathology; Skin Neoplasms/*genetics/metabolism/pathology; Tissue Inhibitor of Metalloproteinase-3/*genetics/metabolism; RNA; Tumor; Neoplastic; Small Interfering
Metastatic melanoma is the most aggressive form of this cancer. It is important to understand factors that increase or decrease metastatic activity in order to more effectively research and implement treatments for melanoma. Increased cell invasion through the extracellular matrix is required for metastasis and is enhanced by matrix metalloproteinases (MMPs). Tissue inhibitor of metalloproteinases 3 (TIMP3) inhibits MMP activity. It was previously shown by our group that miR-21, a potential regulator of TIMP3, is over-expressed in cutaneous melanoma. It was therefore hypothesized that increased levels of miR-21 expression would lead to decreased expression of TIMP3 and thereby enhance the invasiveness of melanoma cells. miR-21 over-expression in the melanoma cell lines WM1552c, WM793b, A375 and MEL 39 was accomplished via transfection with pre-miR-21. Immunoblot analysis of miR-21-overexpressing cell lines revealed reduced expression of TIMP3 as compared to controls. This in turn led to a significant increase in the invasiveness of the radial growth phase cell line WM1552c and the vertical growth phase cell line WM793b (p \textless 0.05), but not in the metastatic cell lines A375 or MEL 39. The proliferation and migration of miR-21 over-expressing cell lines was not affected. Reduced expression of TIMP3 was achieved by siRNA knockdown and significantly enhanced invasion of melanoma cell lines, mimicking the effects of miR-21 over-expression. Treatment of tumor cells with a linked nucleic acid antagomir to miR-21 inhibited tumor growth and increased tumor expression of TIMP3 in vivo in 01B74 Athymic NCr-nu/nu mice. Intra-tumoral injections of anti-miR-21 produced similar effects. This data shows that increased expression of miR-21 enhanced the invasive potential of melanoma cell lines through TIMP3 inhibition. Therefore, inhibition of miR-21 in melanoma may reduce melanoma invasiveness.
Martin del Campo Sara E; Latchana Nicholas; Levine Kala M; Grignol Valerie P; Fairchild Ene T; Jaime-Ramirez Alena Cristina; Dao Thao-Vi; Karpa Volodymyr I; Carson Mary; Ganju Akaansha; Chan Anthony N; Carson William E 3rd
PloS one
2015
2015
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<a href="http://doi.org/10.1371/journal.pone.0115919" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0115919</a>