Abstract SY42-01: MRI/MRS of tumor microenvironment
Authors: Bhujwalla Zaver M. 
Published: August 2012

Abstract
Multi-modality and multi-parametric molecular and functional imaging provide windows into the tumor microenvironment (TME) and into the interactions between cancer cells and stromal cells. Tumors have abnormal physiological environments such as hypoxia and acidic extracellular pH that influence the cancer cell-stromal cell interaction, generate a more aggressive phenotype, and play a major role in the response to treatment. The influence of hypoxia and acidic extracellular pH on the cancer cell phenotype has justifiably received significant attention. Magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and MR spectroscopic imaging (MRSI) techniques have been used for several decades to characterize physiologic parameters such as tumor vasculature, oxygenation, and necrosis, pH and metabolism. The bench to bedside span of noninvasive MR methods to characterize cancer makes them an attractive choice for clinically translatable applications. Recent advances in the development of molecular targeted contrast agents have expanded the traditional strengths of MRI and MRS of characterizing functional tumor parameters such as pH, vascularization, metabolism and cell death, to include visualization of stromal cells, cell surface receptors, molecular pathways, degradative enzyme activity, and the extracellular matrix integrity in preclinical models.
The TME is rich with targets to exploit for therapy that can be used in combination with imaging for ‘theranostic’ imaging agents. The use of MR biomarkers such as total choline and perfusion are already being explored clinically for characterizing tumors and following treatment response. The elevation of choline compounds presents a unique target to exploit for molecular targeting; such targeting can be imaged noninvasively with MRS. We are developing molecular and molecular imaging based approaches to target choline metabolism, specifically choline kinase activity, which is the first step in choline phospholipid biosynthesis. New areas that are being developed in our program include targeting choline kinase using siRNA delivered using lentiviral vectors, and performing image-guided targeting of choline kinase using siRNA in combination with a prodrug enzyme cytosine deaminase using a multi-modal imaging platform. The interaction between cancer cells and the tumor microenvironment is providing new insights into the etiology and progression of cancer. Using combined MR and optical imaging of human breast and prostate cancer xenografts engineered to express green fluorescent protein (GFP) or red fluorescent protein (RFP) under hypoxia, we have obtained useful insights into the dynamics between hypoxia and the tumor extracellular matrix (ECM), vascularization, extracellular pH, interstitial fluid transport, and metabolism. MRI and MRSI were used to obtain co-localized maps of vascular volume, permeability, interstitial fluid transport, total choline and lactate/lipid, while optical imaging was used to obtain co-localized maps of hypoxia and ECM fiber distribution. These insights can be exploited to find effective treatment strategies.
Tumor recurrence and metastasis continue to be the leading causes of morbidity and mortality from cancer and, despite the tremendous advances in cancer research and treatment, even in the twenty-first century cancer continues to evade cure and frequently control. The discovery of cancer initiating cells or cancer stem cells is generating tremendous excitement and is offering new paradigms for understanding and treating cancer recurrence and metastasis. These stem-like cancer cell populations can form tumors in immune suppressed mice from low cell number inoculums, are more drug resistant, more invasive, and more likely to metastasize. Identifying biomarkers associated with cancer stem cells, and imaging and targeting permissive or preventive microenvironmental niches for cancer stem cells is another area that will have significant impact on cancer research and treatment.
A major direction for the future will be to translate preclinical molecular imaging developments for use in the clinic. Exciting new areas that should rapidly develop in the future include targeting specific microenvironments or stromal compartments with theranostic agents. Unlike radiopharmaceuticals, the inherent insensitivity of MR methods will require that most molecular contrast agents be used at concentrations that will be subject to much more stringent FDA control. Challenges for the future will be to increase the sensitivity of detection of such agents through novel chemistry, or instrumentation and the incorporation of multi-modality imaging.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY42-01. doi:1538-7445.AM2012-SY42-01