Recently there has been great interest in brain tumor therapies that suppress growth factors generated by cancer cells for the generation of new blood vessels (angiogenesis). However, while frequently successful in the short term, all current anti- angiogenic therapies eventually fail. This failure has been attributed to invasive cancer cell growth along existing normal vasculature, termed vessel co-option. Indeed, anti- angiogenic therapies in rodent brain tumor models have recently been shown to accelerate tumor invasion by vessel co-option, leading to escape from anti-angiogenic therapy. New combination therapies that target both tumor angiogenesis and invasion are therefore urgently needed. However, detecting invasive tumor regions and assessing their response to potential therapies is complicated by the lack of methods for detecting such invasive cancer cells. Conventional Magnetic Resonance Imaging (MRI) methods detect the elevated vascular permeability and edema that are characteristic of angiogenesis driven tumor growth. Invasive cancer cells that co-opt normal vasculature, however, do not display elevated permeability or edema, thereby rendering them invisible to MRI. New methods are therefore urgently needed for detecting such invasive tumor regions. We propose to investigate and validate the use of novel MRI vascular biomarkers that are sensitive to vascular changes induced by invasive cancer cells in the absence of angiogenesis and its associated elevated edema and vascular permeability. We will also investigate the sensitivity of these new MRI biomarkers to changes induced by anti- tumor therapy. These studies will be performed in invasive mouse brain tumor models that closely mimic tumor growth patterns observed clinically. We hypothesize that these novel MRI vascular biomarkers will provide highly sensitive measures of vascular changes and vessel co-option in invasive brain tumor regions that are not detectable by current methods.
No clinical methods are currently available for the detection of invasive tumor regions that grow by vessel co-option. The development of MRI biomarkers of tumor invasion is therefore critical for (1) the detection of invasive tumor borders, thereby improving tumor resection, (2) the detection of escape from anti-angiogenic therapy, and (3) monitoring the response of invasive cancer cells to new tumor therapies that target both tumor angiogenesis and invasion.
|Emblem, Kyrre E; Farrar, Christian T; Gerstner, Elizabeth R et al. (2014) Vessel caliber--a potential MRI biomarker of tumour response in clinical trials. Nat Rev Clin Oncol 11:566-84|
|Snuderl, Matija; Batista, Ana; Kirkpatrick, Nathaniel D et al. (2013) Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152:1065-76|
|Kodack, David P; Chung, Euiheon; Yamashita, Hiroshi et al. (2012) Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases. Proc Natl Acad Sci U S A 109:E3119-27|
|Huang, Shuning; Liu, Christina; Dai, Guangping et al. (2009) Manipulation of tissue contrast using contrast agents for enhanced MR microscopy in ex vivo mouse brain. Neuroimage 46:589-99|