Research Plan

Cancer Research

 

Attacking cancer with basic, pre-clinical and clinical MRI & MRS

 

Tumor Metabolomics and Biomarkers

 

Goal: The goal of this work is to discover and measure the effectiveness of pharmaceutical treatments that suppress tumor growth.

 

Specific Aim 1: to use MRS to quantify metabolic biomarkers in tumors and normal tissue from rodent models of cancer.

 

Metabolomics: Using NMR spectroscopy and principal component analysis (PCA) it is now possible to distinguish between the metabolic profiles of tumor and normal tissue. We have demonstrated this for liver cancer and further work will establish the metabolic signatures that characterize various types and stages of cancer. The main value of this approach is that it can expedite the drug discovery process. Preclinical and clinical pharmaceutical tests for the treatment of cancer can also be non-invasively monitored by quantitation of metabolites.

 

Methods and Preliminary Results:

Using a rodent model of liver tumor, tissue extracts have been prepared using perchloric acid or a mixture of methanol and water. NMR spectra have been obtained for normal and cancerous tissue. Spectra have been subjected to principal component analysis (PCA) and quantification of individual metabolites. The figure below shows: a schematic diagram of the experimental model populations included in the study, the scores plot of the results of PCA which show that the three types of tissue can be clearly distinguished, and a bar graph showing the ratios of concentrations of key metabolites from the 1D NMR spectra indicating changes in metabolism of tumors.

 

Figures: (TOP) Experimental Model of sample populations of tissue extract for which NMR spectra will be obtained; (CENTER) Scores plot of the results of principal component analysis from tissue extracts from liver tumor, contol and normal rats; (BOTTOM) ratio of metabolites from tumor and control rat liver.

 

Specific Aim 2: to use MRI to characterize the growth cancerous tumors and to monitor the growth response to pharmaceutical treatment in rodent models of cancer.

 

Imaging: Using MRI it is possible to measure the physical and physiological changes in tumors and image molecular processes in cancerous tissue. Three dimensional (3D) MRI and MRS, along with dynamic contrast enhanced (DCE) and dynamic susceptibility contrast enhanced (DSCE) MRI have been used to monitor changes in tumor size, metabolism and perfusion. The importance of these methods is that they provide accurate non-invasive measurements of the response of tumors to pharmaceutical treatment in pre-clinical and clinical settings.

 

 

The following basic, pre-clinical and clinical research goals are also part of the research program for the application of magnetic resonance in medicine.

 

Basic Cancer Research

Structural Biology: The goal of this work is to determine the structures of DNA molecules and small proteins that are parts of the puzzle that constitute the DNA repair pathways. The determination of DNA and protein structures remains a vital part of the effort to establish the mechanisms that lead to the development of cancers at the cellular level. DNA mutations, and mis-repair of certain configurations of DNA damage, have been linked to cancer. But the selective repair of DNA damage raises the question of differential recognition by repair enzymes. The mechanisms of differential recognition and repair are still unanswered. Some answers are forthcoming from studies of DNA and protein structures. NMR Spectroscopy and molecular dynamics modeling continue to be important tools for determining the structures of small biological molecules.

 

Computational Cancer Research

Beyond Structure: The goal of this work is to bridge the gap between basic science and clinical practice. The availability of an ample number of protein and DNA structures now makes it possible to proceed beyond structure to deduce the functional relationships. This information coupled with energetics studies can lead to the elucidation of the mechanisms of enzyme activity that pertain to the relationship between the DNA repair and cancer. The goal of this work is to develop software simulations that would both explain known function and predict functional outcomes in DNA repair processes.

 

Cell Tracking in Cancer Research

Translational Research: The goal of this work is to find new ways to monitor the growth and treatment of cancer cells and stem cells. Cell tracking promises to be an important tool in the effort to understand the spread and treatment of certain cancers, and other diseases. The use of digital imaging coupled with in vivo magnetic resonance spectroscopy (MRS) is one way to track cells non-invasively. Metabolic signatures unique to specialized cells can be used to identify and track them. Thus, the goal of this work is to develop sensitive detection systems such as MRS for identifying and tracking specific cells such as stem cells and cancer cells by their unique signatures.

 







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