Oncolytic virotherapy is a promising approach because the efficient transduction and cancer cell-specific viral replication can boost therapeutic efficacy. However, the large size of oncolytic viruses hinders their transvascular and interstitial movement, thus significantly limiting their delivery to cancer cells and anti- tumor efficacy. Our findings from the current funding period showed that cancer cell apoptosis produced void spaces and channel-like structures, which enhanced the initial delivery, viral spread and therapeutic efficacy of oncolytic herpes-simplex-virus (HSV) after intratumor injection. But in order to improve the systemic efficacy of oncolytic virotherapy targeted both at primary and metastatic tumors, it is essential to identify agents (e.g., cytotoxic agents) or strategies that will improve the vascular extravasation and intratumoral distribution of viral particles injected intravenously. In the proposed studies we will test the hypothesis that targeting tumor blood vessels will improve the delivery of viral vectors and the anti-tumor efficacy of oncolytic HSV. The tumor vasculature will be targeted with endothelial cell targeting agents (anti-integrin 14 or 15 blocking antibodies) or cytotoxics (cyclophosphamide, docetaxel) that target both endothelial and cancer cells. The agents selected are known to induce endothelial cell apoptosis and remodel the tumor vasculature. We will use multiphoton laser scanning microscopy to measure the vascular pore cutoff size of large particles, vascular remodeling (e.g. vessel density, diameter, perfusion), and virus extravasation and spread in human mammary carcinoma cells implanted in mammary fat pad windows in immunodeficient mice. Because of the short-half life of virus in blood (HSV ~ 3 hours), we will determine for each agent the peak-time of large particle extravasation. Based on the peak-time of particle extravasation, oncolytic HSV will be injected systemically and the fraction of vessels associated with infected cells will be determined. The correlation between endothelial apoptosis and particle extravasation will be assessed in tumor sections. We will test if the administration of endothelial targeting agents or cytotoxics before the intravenous injection of oncolytic virus will produce a longer tumor growth delay in mammary fat pad tumors and reduce spontaneous metastasis formation in the lung. We will also determine if the repeated administration (cycling) of cytotoxics or endothelial targeting agents with oncolytic HSV will improve the intratumoral distribution of large particles and the spread and therapeutic efficacy of oncolytic HSV. We expect that the results of these translational studies will identify single agents and / or approaches that will enhance the vascular extravasation and intratumoral spread of virus, and the efficacy of oncolytic virotherapy targeted at tumors.
The clinical efficacy of oncolytic virotherapy is limited by the large size of virus particles, which prevents their movement across the endothelial wall of tumor vessels and between cancer cells. Our results demonstrate that the induction of cancer cell apoptosis improves the tumor penetration and therapeutic efficacy of oncolytic virus injected intratumorally. In the proposed studies we will determine if the targeting of tumor blood vessels with clinically available cytotoxics or endothelial targeting agents will improve the intratumoral dispersion and efficacy of oncolytic virus injected intravenously.
|Jain, Rakesh K; Martin, John D; Stylianopoulos, Triantafyllos (2014) The role of mechanical forces in tumor growth and therapy. Annu Rev Biomed Eng 16:321-46|
|Chauhan, Vikash P; Martin, John D; Liu, Hao et al. (2013) Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun 4:2516|
|Stylianopoulos, Triantafyllos; Soteriou, Konstantinos; Fukumura, Dai et al. (2013) Cationic nanoparticles have superior transvascular flux into solid tumors: insights from a mathematical model. Ann Biomed Eng 41:68-77|
|Stylianopoulos, Triantafyllos; Jain, Rakesh K (2013) Combining two strategies to improve perfusion and drug delivery in solid tumors. Proc Natl Acad Sci U S A 110:18632-7|
|Chauhan, Vikash P; Stylianopoulos, Triantafyllos; Martin, John D et al. (2012) Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat Nanotechnol 7:383-8|
|Perentes, Jean Y; Kirkpatrick, Nathaniel D; Nagano, Satoshi et al. (2011) Cancer cell-associated MT1-MMP promotes blood vessel invasion and distant metastasis in triple-negative mammary tumors. Cancer Res 71:4527-38|
|Diop-Frimpong, Benjamin; Chauhan, Vikash P; Krane, Stephen et al. (2011) Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci U S A 108:2909-14|
|Perentes, Jean Y; McKee, Trevor D; Ley, Carsten D et al. (2009) In vivo imaging of extracellular matrix remodeling by tumor-associated fibroblasts. Nat Methods 6:143-5|
|Nagano, Satoshi; Perentes, Jean Yannis; Jain, Rakesh K et al. (2008) Cancer cell death enhances the penetration and efficacy of oncolytic herpes simplex virus in tumors. Cancer Res 68:3795-802|
|Kozin, Sergey V; Winkler, Frank; Garkavtsev, Igor et al. (2007) Human tumor xenografts recurring after radiotherapy are more sensitive to anti-vascular endothelial growth factor receptor-2 treatment than treatment-naive tumors. Cancer Res 67:5076-82|
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