The emerging concept of vascular normalization has changed the paradigm of antiangiogenic treatment in cancer (Jain, Nature Medicine, 2001; Jain, Science, 2005; Willett, Nature Medicine, 2004) and raised many critical, yet unanswered, questions concerning tumor vessel biology. The studies in this Project address two critical questions: 1) how do antiangiogenic agents currently in clinical trials affect delivery of chemotherapeutic agents and 2) which surrogate markers can be used to identify the normalization of the tumor vasculature. To answer these questions we will use our pre-clinical models: breast tumor (MCalV, Tong, Cancer Research, 2004) in a mammary fat pad chamber, and glioma (U87MG, Winkler, Cancer Cell, 2004) in a cranial window.
In Aim 1, we will compare the normalization of blood vessels after treatment with anti-VEGF antibody (B20-4.1, the mouse equivalent of bevacizumab), anti-VEGFR2 antibody (DC101), or three tyrosine kinase inhibitors, all currently in clinical trials. Specifically,we will quantify the enhancement of transvascular pressure gradients and uniformity of drug delivery.
In Aim 2, we will examine vascular basement membrane degradation during vascular normalization by assessing matrix metalloproteinase and tissue inhibitor metalloproteinase levels and their activities in tissue. We will examine the potential ofmatrix metalloproteinases and their degradation products as blood-borne surrogate .markers for vascular normalization.
In Aim 3, we will consider the fate of """"""""excess"""""""" endothelial cells from tumor vessels pruned or reduced in diameter by antiangiogenic therapy. We hypothesize that many of these cells enter the blood stream and are non-viable. We propose to detect them in peripheral blood and use them as a surrogate marker to evaluate vascular normalization during antiangiogenic therapy. The data obtained in this project will complement those obtained in Project 1 and will facilitate rapid translation into the clinic. If one surrogate marker evaluated in this Project is successful, it will help to advance the combined use of antiangiogenic and cytotoxic therapies.
|Ina Ly, K; Vakulenko-Lagun, Bella; Emblem, Kyrre E et al. (2018) Probing tumor microenvironment in patients with newly diagnosed glioblastoma during chemoradiation and adjuvant temozolomide with functional MRI. Sci Rep 8:17062|
|Nowak-Sliwinska, Patrycja; Alitalo, Kari; Allen, Elizabeth et al. (2018) Consensus guidelines for the use and interpretation of angiogenesis assays. Angiogenesis 21:425-532|
|Zhao, Yingchao; Liu, Pinan; Zhang, Na et al. (2018) Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models. Proc Natl Acad Sci U S A 115:E2077-E2084|
|Hong, Theodore S; Grassberger, Clemens; Yeap, Beow Y et al. (2018) Pretreatment plasma HGF as potential biomarker for susceptibility to radiation-induced liver dysfunction after radiotherapy. NPJ Precis Oncol 2:22|
|Pinter, Matthias; Kwanten, Wilhelmus J; Jain, Rakesh K (2018) Renin-Angiotensin System Inhibitors to Mitigate Cancer Treatment-Related Adverse Events. Clin Cancer Res 24:3803-3812|
|Arvanitis, Costas D; Askoxylakis, Vasileios; Guo, Yutong et al. (2018) Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood-tumor barrier disruption. Proc Natl Acad Sci U S A 115:E8717-E8726|
|Khandekar, Melin J; Jain, Rakesh (2018) Smooth sailing for immunotherapy for unresectable stage III non-small cell lung cancer: the PACIFIC study. Transl Cancer Res 7:S16-S20|
|Stylianopoulos, Triantafyllos; Munn, Lance L; Jain, Rakesh K (2018) Reengineering the Tumor Vasculature: Improving Drug Delivery and Efficacy. Trends Cancer 4:258-259|
|Grassberger, Clemens; Hong, Theodore S; Hato, Tai et al. (2018) Differential Association Between Circulating Lymphocyte Populations With Outcome After Radiation Therapy in Subtypes of Liver Cancer. Int J Radiat Oncol Biol Phys 101:1222-1225|
|Zhang, Na; Chen, Jie; Ferraro, Gino B et al. (2018) Anti-VEGF treatment improves neurological function in tumors of the nervous system. Exp Neurol 299:326-333|
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