Inadequate delivery and tumor spread after systemic administration remains a major -unsolved- obstacle that limits the efficacy of systemically administered oncolytic viruses for the treatment of cancer. This is a significant, rate limiting step for the pre-clinical and clinical development of these agents. The tumor stroma (tumor endothelium, tumor fibroblasts, and extracellular matrix) contributes to the poor efficacy of oncolytic agents, as it creates a "barrier" for viral entry and replication in tumor cells in vivo. Our long term goal is to improve the efficacy of systemically administered oncolytic viruses by understanding the interactions among virus, tumor and stroma, and exploiting them therapeutically. The overall objective of this application, which is the next step in the pursuit of that goal, is to characterize the specificity and therapeutic effects of tumor stromal and vascular targeting of oncolytic measles viruses via the urokinase receptor (with a virus called MV- uPA), a critical tumor/stromal cell surface glycoprotein. The central hypothesis of this application is that selective viral uPAR targeting of tumor stroma/vasculature will significantly enhance the virus'effects against primary tumors and metastases. The rationale for the proposed research is that understanding of how oncolytic viruses interact with important components of the tumor stroma will help create "smarter", safer oncolytic viral vectors with a better therapeutic window. The proposed research is relevant to NIH's mission, in that it pertains to developing safer, more effective biological agents for the fight against cancer. Guided by strong preliminary data, the central hypothesis will be tested by pursuing three specific aims: 1) Characterize MV-uPA's tumor selectivity and virus-host interactions in syngeneic murine cancer models;2) to further characterize the in vivo effects of tumor and stromal urokinase receptor targeting by MV-uPA in breast cancer models;and 3) to characterize the tumor vascular targeting abilities of MV-uPA and its contribution to the virus'overall anti-tumor effects.
Aim 1 will investigate the tumor selectivity, viral replication and organ biodistribution, of uPAR retargeted measles viruses, after systemic administration, using molecular and immunohistochemical techniques. In addition, we will characterize the safety and efficacy dose response to the virus in immunocompetent mammary and colon cancer models.
In aim 2, we will characterize the antimetastatic activity of uPA retargeted measles virus using, in vivo imaging techniques. We will also characterize MV-uPA's ability to target stromal cells, and its consequences in regards to antitumor efficacy.
In aim 3, we will characterize the kinetics of virus/endothelial interactions as they pertain to the virus'potential antiangiogenic effects, and the ability of the uPAR targeted viruses to enhance viral delivery into breast tumor in vivo via tumor endothelium. The approach is innovative and significant, because it will bring new knowledge on in vivo interactions between virus and stroma, which will translate into the development of better oncolytic viral agents for the benefit of patients with cancer.
The proposed studies are of an important area of cancer research that has potential applicability to all aspects of targeted cancer therapeutics. The proposed research has relevance to public health, because further development of antitumor viral agents retargeted against tumor stroma is expected to significantly improve the quality and quantity of life of thousands of cancer patients.
|KovÃ¡cs, Krisztina; Decatur, Christina; Toro, Marcela et al. (2016) 2-Deoxy-Glucose Downregulates Endothelial AKT and ERK via Interference with N-Linked Glycosylation, Induction of Endoplasmic Reticulum Stress, and GSK3Î² Activation. Mol Cancer Ther 15:264-75|
|Jing, Yuqi; Bejarano, Marcela Toro; Zaias, Julia et al. (2015) In vivo anti-metastatic effects of uPAR retargeted measles virus in syngeneic and xenograft models of mammary cancer. Breast Cancer Res Treat 149:99-108|
|Kurisetty, Vittal V S; Heiber, Joshua; Myers, Rae et al. (2014) Preclinical safety and activity of recombinant VSV-IFN-Î² in an immunocompetent model of squamous cell carcinoma of the head and neck. Head Neck 36:1619-27|
|Jing, Y; Zaias, J; Duncan, R et al. (2014) In vivo safety, biodistribution and antitumor effects of uPAR retargeted oncolytic measles virus in syngeneic cancer models. Gene Ther 21:289-97|
|Jing, Yuqi; Kovacs, Krisztina; Kurisetty, Vittal et al. (2012) Role of plasminogen activator inhibitor-1 in urokinase's paradoxical in vivo tumor suppressing or promoting effects. Mol Cancer Res 10:1271-81|