Current NIH Funded Grants

Abstract: The University of Utah Synergy Grant Program funded this imaging and diagnostic biomarker study.

This exploratory clinical study is designed to obtain pre-therapeutic imaging assessments using positron emission tomography (PET) imaging in 21 patients with Stage IIIB/IV or recurrent non-small cell lung cancer (NSCLC).

It will also provide an early post therapy assessment after institution of erlotinib (anti-EGFR) (Tarceva) and bevacizumab (anti-VEGF) (Avastin) for first-line treatment of Stage IIIB/IV or recurrent non-squamous NSCLC at baseline and at the following various early time points:

• Two weeks in seven patients
• Four weeks in seven patients
• Six weeks in seven patients

The proposed PET imaging and blood derived biomarkers trial is a companion study to an approved therapeutic trial (IRB# 24377). The therapeutic trial of erlotinib (Tarceva) and bevacizumab (Avastin) for first-line treatment of Stage IIIB/IV or recurrent lung cancer was funded for study at Huntsman Cancer Institute and Huntsman Intermountain Cancer Care Program statewide trial network.

The clinical imaging biomarkers will include an assessment of tumor metabolism (dynamic FDG-PET); tumor proliferation (dynamic FLT-PET); tumor blood flow and perfusion( H215O-PET) in the same patient at baseline and then in the same patient at one of the post therapy time points (two weeks, four weeks, or six weeks). Diagnostic biomarkers assessments include Veristrat— mass spectroscopy of serum as a predictor of patients who will benefit from EGFR therapy.

It is known that rash predicts response with EGFR therapy and we are assessing host reaction by exon-level genome-wide expression profiling obtained from peripheral blood mononuclear cells. We hypothesize that by using a set of imaging derived biomarkers and biomarkers from blood, we can predict response— either a priori, or at an earlier time point than would normally be determined with standard imaging techniques in patients with lung cancer receiving combined bevacizumab and erlotinib.

Abstract: Although there have been many advances in the assessment and treatment of infections responsible for febrile neutropenia in cancer patients, it still remains a common complication of cancer therapy and accounts for the majority of chemotherapy-associated deaths. The ultimate goal of our interdisciplinary group of oncologists, infectious diseases experts, imagers, and biostatisticians is to conduct a large, prospective, multi-center trial to establish the utility and cost-effectiveness of PET/CT using the widely available glucose analogue [18F]fluoro-2-deoxy-D-glucose (FDG) in identifying sites of infection in cancer patients with persistent febrile neutropenia without an obvious identifiable source thus improving targeted therapy. The immediate goal of this Quick-Trials Exploratory Grant application is to conduct a pilot project in a smaller group of these patients to provide critical information that will support the concept, and aid in the design, of a larger multi-center clinical trial. The primary aim of this exploratory study is to perform FDG-PET/CT in approximately 130 cancer patients with persistent febrile neutropenia in whom an obvious source of infection has not been identified. Each suspicious site will be confirmed with pathologic ground truth whenever possible. The data will be evaluated to address the following questions, which are the sub-aims of this proposal:

• How effective is FDG-PET/CT in identifying sites of infection in cancer patients with persistent febrile neutropenia without an obvious cause?
• To what degree does FDG-PET/CT improve detection of sites of infection over CT alone?
• What FDG-PET/CT imaging variables best predict the presence of infection at a specific site (e.g. standardized uptake value [SUV], concomitant abnormality on CT)?
• Can the magnitude of FDG uptake as measured by an SUV at sites of infection predict the identity of the infective agent (bacterial vs. fungal vs. viral)?
• Does the magnitude of uptake at sites of infection correlate with absolute neutrophil count?
• Can a clinical scoring system be developed to identify a population of patients in whom FDG-PET/CT is likely to be most efficacious in identifying sites of infection?
• Is it possible that FDG-PET/CT may be able to significantly change the management of the cancer patient with persistent febrile neutropenia resulting in improved clinical care; decrease the morbidity due to toxicities from certain toxic antibiotics; potentially decrease the cost of medical care by improved targeting of antibiotic therapy; and decrease days of hospitalization for these patients? All of these potential benefits may result in significant cost savings.

Abstract: The human clinical trial and correlative animal studies are funded by the National Comprehensive Cancer Network (NCCN).

The exploratory clinical study is designed to obtain pre-therapeutic imaging assessments in 20 patients with metastatic renal cell cancer (RCC) after institution of standard approved sunitinib therapy at 37.5 mg/day and an early post therapy assessment at baseline and at the following various early time points:

• One week in five patients
• Two weeks in five patients
• Three weeks in five patients
• Four weeks in five patients

The clinical imaging biomarkers will include an assessment of tumor metabolism (dynamic FDG-PET); tumor proliferation (dynamic FLT-PET); tumor blood flow (H215O-PET, DCE MRI), and tumor perfusion (DCE-MRI) in the same patient at baseline and then in the same patient at one of the post therapy time points (one week, two weeks, three weeks or four weeks). We hypothesize that by using this set of imaging assessments it will be possible to determine an individual or more likely a set of imaging derived biomarkers that will accomplish several of the goals of the initiative which is providing funding for the study.

The correlative animal studies in a mouse model of renal cell cancer (RENCA mouse), used a set of imaging derived biomarkers which will be correlated with in vitro indices of the specific physiologic parameters measured by the same imaging biomarkers as in the funded human clinical trial. These correlative studies may suggest that sunitinib (SU11248) therapy may essentially be starving tumor cells of their primary substrate for energy (i.e glucose).

Our proposed correlative study will provide the critically important initial step in credentialing the imaging derived biomarkers against validated in vitro techniques to better explain how sunitinib works and affects the imaging derived biomarkers of interest. This proposed correlative study in a well-validated renal cell mouse model will provide critically important missing basic imaging related biologic information on the effects of Sunitinib therapy that will be difficult, if not impossible, to obtain in human studies.

Abstract: The association between blood clot formation, inflammation, and cancer is strong. Cancer predisposes patients to the development of blood clots, which may complicate therapy and has a higher risk of morbidity and death than in non-cancer patients. The converse is also true, nearly 50% of patients who develop unprovoked venothromboembolic disease (VTE) harbor an occult cancer, yet a search for cancer in these patients is not considered standard of practice. The diagnosis of blood clot formation is compromised when the clot is in the abdomen or pelvis, and/or the patient has a containdication to iodinated contrast. In cancer patients, multiple anatomic abnormalities associated with the cancer or its treatment, and a heightened propensity for intraabdominal or pelvic clot may further complicate the diagnosis of VTE. Further, no current methods exist to identify patients at particularly high risk for cancer-related thrombosis, a critical step in thrombo-prevention. The link between clot, cancer, and inflammation may be due to a host response to cancer resulting in expression of both local and systemic inflammatory cytokines and tissue factors that act on platelets and myeloid leukocytes to produce a cascade of events culminating in blood clot formation. FDG PET imaging has emerged as a powerful tool in the diagnosis, staging, and therapeutic assessment of malignancy. Based on preliminary data and personal observation, we hypothesize that FDG PET may be a useful adjunct in the diagnosis of complicated cases of VTE, in identifying patients with unprovoked VTE that harbor an occult malignancy, and in identifying the systemic state that predisposes many cancer patients to VTE. The specific aims of this project will test these hypotheses in human subjects and also span from benchtop to bedside. In vitro studies complete the molecular imaging loop, by characterizing the relationship between FDG uptake, activation of prothrombotic cells, and expression of known prothrombotic gene products and effectors by these cells.

Abstract: Copper metabolism disease (CMD) is represents a spectrum of abnormalities characterized by abnormal content, distribution or metabolism of copper in the body. These diseases include nutritional, acquired and genetic abnormalities in one or more of the regulatory steps required in copper homeostasis. These diseases can have serious consequences to the patient, affecting multiple organ systems and resulting in abnormalities in the bioavailability of other essential metal ions. The diseases are often difficult to diagnose, and are of great interest to scientists who strive to understand basic metallophysiology and pathophysiology. Copper-related therapies may be of interest in the treatment of cancer and other diseases. Studies of CMD have traditionally been limited by the lack of relevant animal models for many of the diseases, the availability of Cu isotopes for research, and methods to non-invasively, non-destructively and longitudinally assess the kinetics and distribution of copper in the body. Recent developments have provided opportunities to circumvent these limitations, including the characterization of many novel rodent models of specific CMD's, the technology of microPET (positron emission tomography), the availability of Cu-64, a positron emitter with a half life permissive of longitudinal studies from hours to days (provided by an NIH-supported National Research Resource by Washington University, St. Louis). MicroPET imaging, and ex-vivo biodistribution studies of 64-Cu in rodent models of genetically acquired CMD will be utilized to establish whether distinct imaging phenotypes define well-characterized inherited rodent models of CMD's, and whether phenotypic rescue of specific disorders by novel therapies normalizes the imaging phenotype. These pilot data will be used to justify RO1 applications to explore non-invasive methods to diagnose CMD's, to understand the underlying pathophysiology that contributes to these disorders, and to assess the efficacy of novel copper- based therapies. The establishment of the imaging phenotypes of CMD in animal models is also critical to enable non-invasive, non-destructive and longitudinal methods for evaluating novel gene therapies designed to reverse or ameliorate the consequences of lacking or abnormal gene products that contribute to CMD. These imaging tools will be of use to numerous local and regional investigators addressing normal and abnormal copper metabolism, its resultant diseases and treatment of patients with these disorders.

Abstract: This proposal requests funding to acquire a high field-strength small animal magnetic resonance imaging (MRI) scanner, which will form the central component of a comprehensive small animal MRI facility at the University of Utah. The instrument proposed is a Bruker ClinScanZ B-C 70/30 USR (Ultra-Shielded, Refrigerated) high-resolution imaging system. Key technical features of the system include a 7.05 Tesla actively-shielded magnet, 30.2 cm magnetic clear bore size, a 20.1 cm inner-diameter base gradient system capable of 300 mT/m, 8-channel 1H spectrometer electronics, a Siemens MRI console, and in vivo imaging accessories. The University of Utah is a leader in genetic analysis of human disease and has been at the forefront in both generating and studying mice with targeted gene alterations. MRI's noninvasive nature and unparalleled soft-tissue contrast have made it a modality of choice for anatomical and physiological imaging of these genetically engineered animals. MRI imaging in small animals faces technical challenges related to requirements for high-resolution (e.g., SNR and spatial resolution tradeoff) and animal physiological considerations (e.g., high heart rates, motion). Moreover, quantitative interpretation of MR images often necessitates sophisticated post-processing and analysis (e.g., 3D visualization, registration). An innovative aspect of this proposal is that it will take advantage of the novel and innovative MRI technology development and image display/analysis research (largely funded by NIH) ongoing at the University of Utah (U of U). The proposed core MRI facility will leverage the strengths of the Utah Center for Advanced Imaging Research (UCAIR) and Scientific Computing and Imaging Institute (SCI). The integration of these technical resources in the operation and organizational infrastructure of the proposed high-field strength small animal imaging MRI facility will provide significant value-added benefits to its users. There are several NIH funded research projects at the University of Utah that currently utilize limited forms of small animal MRI, and many more NIH funded investigators that have clear but unmet small animal MRI needs. There is currently no dedicated up-to-date small animal MRI scanner in the state of Utah. Consequently, the instrument will have a profound impact on existing NIH funded projects and initiating new research projects at the U of U and beyond.

Abstract: This proposal seeks to improve the accuracy and repeatability of the characterization of ischemic heart disease using MRI. The first two aims focus on dynamic MRI for perfusion: (1) To develop radial k-space acquisition methods to provide rapid measurements of gadolinium concentration to improve the estimation of absolute myocardial perfusion. (2) To improve and automate post-processing analysis of the dynamic data to obtain robust quantitative perfusion estimates. New methods for registration, segmentation, and kinetic modeling will be developed to automatically produce maps of absolute perfusion along with a confidence map. (3) To determine the accuracy and repeatability of the new perfusion methods using 3 Tesla MRI. The repeatability of new methods for strain and scar mapping will also be assessed. (4) To apply the methods to longitudinal studies of patients undergoing bone marrow stem cell therapy as an adjunct to coronary artery bypass grafting. Methods: Development of radial perfusion sequences to provide accurate gadolinium concentrations from high dose dynamic MRI studies will be pursued using realistic computer simulations, phantoms, and human studies. Slice tracking acquisitions and combined registration/segmentation methods will be developed for robust automated processing of the data. Different physiological models will be developed and compared in their ability to provide absolute perfusion values. Mathematical methods for improving input functions by jointly estimating tissue and arterial input function model fits will be developed and tested. The new radial slice-tracking acquisition and processing methods will be validated by comparison in the same patients to quantitative perfusion from dynamic PET, along with comparison to a Cartesian acquisition. The repeatability of the perfusion methods and the strain and scar mapping techniques will be characterized in 20 subjects, each imaged twice. The new methods will then be applied to generate new insights into the myocardial response to stem cell therapy. The outcome of this project will be validated imaging protocols and software for use with cardiac MRI studies, improved methods for longitudinal assessment of myocardial perfusion, strain, and scar in vivo, and new information regarding the effect of stem cells on cardiac perfusion, strain, and scar. Such methods will be invaluable for evaluating novel therapies and for the detection and characterization of ischemic heart disease.

Abstract: Positron emission tomography (PET) is undergoing a period of tremendous growth, and the continued development of new tracers and applications for oncology, cardiology, and neurology ensures that this modality will expand for many years to come. Technological advances are pushing PET toward fully-3D imaging with advanced statistical-based reconstruction algorithms. There is a significant need for improved iterative algorithms which are fast enough for routine use with fully-3D PET, and which take the guesswork out of choosing reconstruction parameters and regularization schemes. The objective of this project is to investigate new paradigms for statistical PET reconstruction which are specifically targeted and separately optimized for estimation and detection tasks. Two (2) complementary reconstruction frameworks are proposed: (Aim 1) direct reconstruction from raw LOR histograms using comprehensive modeling of the system transfer matrix, which achieves true maximum-likelihood estimation with exact Poisson statistics to produce lower-noise, higher spatial resolution images; and (Aim 2) statistically-regulated expectation-maximization (StatREM) algorithms, which adapt to the statistical quality of the dataset being reconstructed. The StatREM framework provides a means for selecting subsets and acceleration in a statistically-meaningful way, offering more robust acceleration than current algorithms. It also provides an iterative stopping criterion which may be optimized specifically for estimation and detection tasks. Moreover, StatREM provides spatially-adaptive regularizations which offer high resolution for high statistics regions, while at the same time regularizing low count background regions. We hypothesize that StatREM provides better lesion detection performance than current algorithms. Aims 3 and 4 will evaluate in detail the quantitation and lesion detection performance, respectively, of the new algorithms using experimentally acquired data of a highly-reproducible whole-body phantom. Each algorithm will be optimized with respect to these tasks. Lesion detectability will be evaluated using a detailed human observer study with a multi-slice display and localization receiver operating characteristic (LROC) analysis. The improvements in image quality offered by this research will broadly impact all applications of PET imaging, with specific benefit for tumor detection and quantitation.

Abstract: One of the greatest strengths of positron emission tomography (PET) is the ability to image any of a number of molecular or physiologic targets using different radiotracers. The clinical utility of PET is well- established for cancer detection and staging. The development of new tracers for imaging metabolism, proliferation, blood flow and numerous other molecular targets offers almost unlimited potential for image- guided personalized medicine. However, much of this potential remains unrealized because current technology permits only one PET tracer to be imaged at a time-multiple scanning sessions need to be scheduled, often on different days, resulting in high costs, image alignment issues, and a long and onerous experience for the patient. Recent advances have shown that it is technically feasible to image 2-3 PET tracers in a single scan using staggered injections and dynamic imaging. Measures of each tracer can be recovered using "signal-separation" algorithms based on kinetic constraints for each tracer. This project will continue development of such rapid multi-tracer imaging technologies, with emphasis on developing specific methods of immediate value and translation to clinical patient imaging. Four tracers will be studied: 18F-fluorodeoxyglucose (FDG) as a marker for glucose metabolism; 18F-fluorothymidine (FLT) for proliferation; 11C-acetate (ACE) for lipid synthesis and related growth; and 15O-water (H2O) for blood flow and volume of distribution. Aim 1 will develop and test methods for rapid dual- and triple-tracer imaging of FDG, FLT, and ACE in a single scan, targeting total scan times of ~70 min. for dual-tracer, and 90-120 min. for triple-tracer imaging. These methods will be evaluated in large animal tumor models and in patients with primary brain tumors. Aim 2 will develop improved multi-tracer algorithms, emphasizing robust algorithms suitable for routine use. Rapid multi-tracer imaging also provides unique opportunities for determining inter-linked physiologic parameters. Aim 3 will investigate methods of measuring tumor blood from derived from the first-pass uptake of all tracers present, using H2O PET as the standard measure of flow. This will potentially provide reliable measures of blood flow without the need for a focused blood flow tracer. The overall project is designed to translate multi-tracer PET technologies to clinical tumor imaging, which will be expressly accomplished through Aim 4. Twenty patients with primary brain tumors will undergo multi-tracer PET imaging prior to any therapy, after 6 weeks chemoradiotherapy, and at the time of tumor recurrence. These data will validate the new methods of Aims 1-3, and will begin to explore the clinical value of multi-tracer PET biomarkers for predicting tumor aggressiveness, assigning patients to personalized treatment regimens, and assessing response to therapy. PUBLIC HEALTH RELEVANCE: Advances in cancer treatment have provided a host of therapeutic drugs, radiation treatments, and targeted agents that provide a vast array of weapons for treating cancer. Rational methods are needed for selecting which treatment will be the best for each individual patient, such as tumor imaging with positron emission tomography (PET). This project will develop new and improved methods of characterizing tumors by PET imaging with multiple tracers, providing a new and greatly improved means of selecting the best treatment option for individual patients.