The role of microenvironment in regulation of cell infiltration and bortezomib-OV therapy in glioblastoma 15:10 Fri 11 Jan, 2019 :: IW 5.57 :: Professor Yangjin Kim :: Konkuk University, South Korea
Tumor microenvironment (TME) plays a critical role in regulation of tumor cell invasion in glioblastoma. Many microenvironmental factors such as extracllular matrix, microglia and astrocytes can either block or enhance this critical infiltration step in brain . Oncolytic viruses such as herpes simplex virus-1 (oHSV) are genetically modified to target and kill cancer cells while not harming healthy normal cells and are currently under multiple clinical trials for safety and efficacy . Bortezomib is a peptide-based proteasome inhibitor and is an FDA-approved drug for myeloma and mantle cell lymphoma. Yoo et al (2) have previously demonstrated that bortezomibinduced unfolded protein response (UPR) in many tumor cell lines (glioma, ovarian, and head and neck) up-regulated expression of heat shock protein 90 (HSP90), which then enhanced viral replication through promotion of nuclear localization of the viral polymerase in vitro. This led to synergistic tumor cell killing in vitro, and a combination treatment of mice with oHSV and bortezomib showed improved anti-tumor efficacy in vivo . This combination therapy also increased the surface expression levels of NK cell activating markers and enhanced pro-inflammatory cytokine secretion. These findings demonstrated that the synergistic interaction between oHSV and bortezomib, a clinically relevant proteasome inhibitor, augments the cancer cell killing and promotes overall therapeutic efficacy. We investigated the role of NK cells in combination therapy with oncolytic virus (OV) and bortezomib. NK cells display rapid and potent immunity to metastasis and hematological cancers, and they overcome immunosuppressive effects of tumor microenvironment. We developed a mathematical model, a system of PDEs, in order to address the question of how the density of NK cells affects the growth of the tumor . We found that the anti-tumor efficacy increases when the endogenous NKs are depleted, and also when exogenous NK cells are injected into the tumor. We also show that the TME plays a significant role in anti-tumor efficacy in OV combination therapy, and illustrate the effect of different spatial patterns of OV injection . The results illustrate a possible phenotypic switch within tumor populations in a given microenvironment, and suggest new anti-invasion therapies. These predictions were validated by our in vivo and in vitro experiments.
1] Â Kanai R, â¦ Rabkin SD, âOncolytic herpes simplex virus vectors and chemotherapy: are combinatorial strategies more effective for cancer?â, Future Oncology, 6(4), 619â634, 2010. â¨
 Â Yoo J, et al., âBortezomib-induced unfolded protein response increases oncolytic hsv-1 replication resulting in synergistic antitumor effectâ, Clin Cancer Res , Vol. 20(14), 2014, pp. 3787-3798. â¨
 Â Yangjin Kim,..Balveen Kaur and Avner Friedman, âComplex role of NK cells in regulation of oncolytic virus-bortezomib therapyâ, PNAS, 115 (19), pp. 4927-4932, 2018. â¨
 Yangjin Kim, ..Sean Lawler, and Mark Chaplain, âRole of extracellular matrix and microenvironment in regulation of tumor growth and LAR-mediated invasion in glioblastomaâ, PLoS One, 13(10):e0204865, 2018. â¨
 Yangjin Kim, â¦, Hans G. Othmer, âSynergistic effects of bortezomib-OV therapy and anti-invasiveâ¨strategies in glioblastoma: A mathematical modelâ, Special issue, submitted, 2018.