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Research
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John Kurhanewicz
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John Kurhanewicz, Ph.D. johnk@mrsc.ucsf.edu Professor of Radiology and Pharmaceutical Chemistry Director of the Prostate Imaging Group and Biomedical NMR Lab |
Research Program
The accurate characterization of prostate cancer is a major problem in the management of individual prostate cancer patients and in monitoring treatment effects. To address this pressing need, we (Drs. Kurhanewicz, Vigneron and Nelson) have developed over the past 15 years a large research program at UCSF to develop new anatomic and metabolic (MR spectroscopic imaging, MRSI) methods to provide an improved assessment of human prostate cancer. I have directed the UCSF Prostate Imaging Program over the last ten years and we have applied these advanced imaging techniques in over 4700 research and clinical exams. This has been a truly translational, multidisciplinary research project that has ranged from basic MR development to now routine clinical usage of these magnetic resonance imaging tools in the clinic. In conjunction with GE Healthcare we have developed a commercial MRI/MRSI staging exam (“PROSE”) for prostate cancer patients, and have provided the leadership and training for a NIH funded multi-center trial of this commercial exam (ACRIN 6659). In a number of ongoing grants, we are investigating the ability of combined MRI/MRSI to detect and characterize the extent and aggressiveness of prostate cancer prior to therapy, to improve radiation treatment planning, and to determine it’s ability to detect residual disease early after therapy and predict clinical outcome. Another focus of the UCSF prostate imaging program is the investigation of other imaging sequences that can provide additional functional information within the same MR staging exam. Currently, single-shot fast spin echo diffusion weighted imaging and dynamic contrast enhanced imaging techniques are being optimized and incorporated into a multi-parametric 1 hour prostate MRI/MRSI exam in order to provide the most accurate diagnosis and characterization of prostate cancer in individual patients.
We are also currently using multi-parametric in vivo imaging data to target cancer tissues in prostate cancer patients who undergo biopsy and/or radical prostatectomy for prostate cancer. 1H HR-MAS is a non-destructive ex vivo technique that can enhance spectral resolution in spectroscopic examinations of intact biological tissues prior to the pathologic, immunohistochemical and gene micro-array analysis of the same tissue sample. As part of two ongoing NIH grants we are establishing a database correlating metabolic profiles associated with specific prostate tissue types, grades of prostate cancer, response to therapy and to begin correlating pre- and post-therapy metabolic profiles with gene expression profiles. The initial success of this project has resulted in the establishment of the Biomedical NMR lab that I direct. The laboratory houses the 11.7T HR-MAS NMR spectrometer and other equipment necessary to perform the subsequent pathologic and genetic analysis of the ex vivo tissues. This facility has resulted in the expansion of my research program beyond prostate cancer to include; (1) the identification of chemical changes associated with disc degeneration, (2) the identification of metabolic profiles associated with dense breast and breast cancer, and (3) the metabolic profiles associated varying types and grades of brain tumors.
A new direction for the UCSF Prostate Imaging Program is the development of high field MR imaging and multi-nuclear (31P and 13C) spectroscopy techniques. One project involves the translation of the 1.5T PROSE package to 3T scanners. There are also several studies investigating the possibilities of multinuclear MRS using the higher sensitivity and spectral resolution associated with the higher field MR scanners (3 and 7T) and the increased sensitivity gained by hyperpolarized NMR spectroscopy of 13C labeled substrates. Specifically, we are using human prostate cell lines cultured with 13C labeled substrates, and transgenic mice injected with 13C labeled substrate to; (1) determine the key 13C labeled metabolites that best identify the presence of prostate cancer and characterize its aggressiveness, and (2) determine the kinetics of incorporation of 13C labels into the key metabolites as well as the T1 and T2 relaxation times of the 13C labeled metabolites. This data will be combined with specialized rf detectors, fast 13C spectroscopic imaging pulse sequences, and data reconstruction and analysis protocols to detect hyperpolarized 13C labeled metabolites in the first clinical trial of the use of hyperpolarized 13C labeled pyruvate to image prostate cancer patients (collaborative effort with GE healthcare).
Current Research Grants
NIH R21EB005363 “Hyperpolarized 13C NMR Studies of Prostate Cancer”
NIH R01 CA102751 “MR Based Molecular Imaging of Prostate Cancer”
Accurate characterization of prostate cancer remains a major problem in the clinical management of individual prostate cancer patients and in monitoring clinical trials of emerging therapies. High Resolution - Magic Angle Spinning (HR-MAS) spectroscopy is a non-destructive ex vivo technique that can provide a full chemical analysis of intact prostate tissues prior to a complete histopathologic, immunohistochemical and genetic analysis of the exact same tissue. In this project we will use the high specificity of combined in vivo MRI/MRSI for identifying prostate cancer to target prostate biopsy and surgical tissues in 250 patients prior to therapy and 125 patients demonstrating biochemical failure (rising PSA) and MRI/MRSI evidence of recurrent disease after hormone deprivation therapy for subsequent ex-vivo analyses. The goal of this proposal is to establish a database correlating metabolic profiles associated with specific prostate tissue types, grades of prostate cancer, and response to hormone deprivation therapy and to begin correlating pre-therapy metabolic profiles with gene expression profiles. Using this correlative data we wish to test the following hypotheses: (1) That distinctive metabolic profiles can be associated with the following pathologic prostate tissue types predominantly glandular and stromal healthy peripheral zone tissues, predominantly glandular and stromal benign prostatic hyperplasia, cancers of increasing Gleason score, prostatic intraepithelial neoplasia (PIN), prostatic inflammatory atrophy (PIA) and prostatitis. (2) The dramatic decreases in prostate citrate levels with prostate cancer evolution, progression, and in response to hormone deprivation therapy are associated with changes in morphology (reduction in glandular tissue), prostatic Zn concentration, and/or expression of key Kreb cycle enzymes. (3) Elevated concentrations of phospholipid metabolites (glycerophosphocholine, phosphocholine and choline) in prostate cancer prior to and after therapy are associated with changes in morphology (increased malignant epithelial cell density) and/or changes in cellular proliferation and apoptosis. (4) The dramatic decrease in prostatic spermine concentration with prostate cancer evolution, progression and in response to hormone deprivation therapy is associated with changes in its secretion (reduction in glandular tissue), and/or changes in cellular proliferation and apoptosis. (5) That distinctive metabolic profiles can be associated with the over- and/or under-expression of specific genes categorized by the following pathologic criteria, predominantly stromal versus predominantly glandular healthy tissue, healthy tissue versus prostate cancer, and cancer having Gleason Score ≤ 6 versus cancer having a Gleason Score ≥7. This work should result in improved interpretation of patient MRSI data, and provide data on how HR-MAS metabolic profiles can compliment the pathologic and genetic assessment of prostate cancer prior to and after hormone deprivation therapy.
R01 CA079980-06 “Monitoring Radiation Therapy of Prostate Cancer by MRSI”
This is a renewal of a very successful project in which we demonstrated for the first time: 1) the feasibility of obtaining 3D MRSI data before and serially following prostate cancer patients receiving external beam radiation therapy (EBRT) and brachytherapy, 3) that the degree and spatial extent of elevated choline, and reduced citrate and polyamine levels prior to therapy correlated with pathologic tumor volume and grade, and predicted short-term (<1yr) PSA response; 3) the ability to detect the presence of biopsy proven prostate cancer after therapy based on elevated choline-to-creatine ratios; 3) that “metabolic atrophy” occurred earlier after treatment than PSA nadir; and 4) differences in the time course of metabolic changes for EBRT versus brachytherapy. The motivation for this renewal project is that these exciting findings need to be further validated through longer follow-up studies since treatment failure normally occurs 3 to 10 years after radiation therapy. Additionally, a larger patient population stratified for both risk and treatment type needs to be studied since both the time course of metabolic response and clinical outcome are influenced by these factors. This renewal will be a prospective MRI/MRSI study of patients prior to and serially following EBRT and brachytherapy at UCSF. We will obtain 3 to 5 year clinical outcome data from a sufficient number of patients to determine whether the pre-treatment degree and spatial extent of the metabolic abnormalities and the radiation dose delivered are prognostic of therapeutic outcome. We will also test the hypotheses that: “metabolic atrophy” and elevated choline-to-creatine are early predictors of therapeutic outcome, and that there are radiation dose dependent differences in the time course of metabolic response for EBRT versus brachytherapy. Finally, ex-vivo HR-MAS spectroscopy will be applied to biopsy samples of patients with biochemical failure in order to better define the metabolic profile of residual/recurrent cancer and its relationship with cellular proliferation and apoptosis. This is a translational project intended to provide both new biochemical information about prostate cancer before and after radiation therapy and to aid in the translation of this technology into clinical practice.
NIH R01CA59897 - Metabolic Imaging of the Prostate Using 3-D MRSI [PDF]
Abstract
Prostate cancer is presently the second leading cause of cancer death in American men. Several variables in the occurrence and natural history of prostate cancer make it especially difficult to treat. Statistics indicate that less than 1 percent of prostate cancers cause clinical disease. Yet when they do, the average survival time of patients with metastases is less than two years. Currently there is no reliable way of predicting which cancers will be indolent versus those that will metastasize and result in death. Also as screening for these diseases improves, more and earlier stage tumors will be detected increasing the difficulties in managing these patients. A variety of treatment options exist and no consensus has been reached on what constitutes the best therapy and how to assess early treatment
response, which is only poorly addressed by conventional imaging techniques. A noninvasive method such as Magnetic Resonance Spectroscopic Imaging (MRSI) to characterize prostate cancers based on cellular function and metabolism would be an extremely valuable tool for the clinical management of prostate cancer. In this project, we will develop new techniques to greatly improve prostate MRSI studies. They include: 1) New endorectal coils with a 2+fold improvement in sensitivity allowing increased spectral and spatial resolution, reduced motion artifacts, and improved Bo homogeneity over prostate (reduced magnetic susceptibility effects; 2) New rf pulses for better controlled water/lipid suppression, improved conformal spatial selection with 2.7 fold improvement in selectivity; 3) Absolute quantitation using
electronic referencing to provide accurate measurements of metabolite levels (especially critical following hormonal therapy). 4) New 2d J-resolved MRS sequences for detection of additional metabolites (polyamines, lipid, lactate) and accurate T2 information; 5) MRI/MRSI guided tissue sample collection for accurate correlation of high resolution magic angle spinning (HR MAS) NMR spectra with outstanding spectral resolution from small (5-20 mg) tissue samples which then will be correlated to conventional histology and new molecular marker assays of the same sample. In this renewal research project, we will apply these new techniques to characterize the metabolic differences between prostate cancers with varying biologic aggressiveness and hormone responsiveness. While these technical developments are specifically
designed for this research project, they will greatly improve the quality, reliability, applicability of this method for future clinical studies both at our institution and others.
This grant is in its 13th year of funding and has provided the technical support for the UCSF Prostate Cancer Imaging Program. I am the co-principle investigator and my colleague Daniel Vigneron is the principle investigator on this grant. A Bioengineering Research Partnerships (BRP) grant is close to being funded and will provide future funding for technical development and translation of new prostate imaging techniques in the future.
NIH R01 103934 “MR Diffusion Tensor Imaging of Prostate Cancer”
I am co-principle investigator (PI-Dr. Daniel Vigneron) on this grant that is focused on improving the characterization of prostate cancer through the addition of Diffusion-tensor imaging to the clinical prostate MRI/MRSI exam. Although combined MRI/MRSI has demonstrated a great improvement in the radio logic assessment of prostate cancer, an additional method with higher spatial resolution than MRSI could benefit measures of tumor extent prior to and especially following therapy when anatomic MRI is less accurate. Our recent preliminary data have indicated that Diffusion-tensor imaging (DTI) of the prostate using a single-shot fast spin-echo sequence (SSFSE; also called single-shot RARE or HASTE) can provide high quality water diffusion parameter images with negligible spatial distortions (unlike EPI images of the prostate). The DTI-SSFSE preliminary results have demonstrated significant differences in mean diffusivity between cancer and normal tissues both before and following therapy. The proposed project builds on the exciting initial results and includes the technical improvements, normal age-matched control studies and patient exams necessary to translate these exciting preliminary findings into a valuable tool for prostate cancer imaging.
Lsit01-10107 “Development of High Field MR Imaging and Spectroscopy Techniques”
Abstract
I am a co-investigator (PI- Dr. Sarah Nelson) on this high field technology development grant with a focus on Specific aim 2. As advances in molecular and cellular biology provide an increased understanding of the genetic basis of human diseases, the development of non-invasive imaging modalities that are sensitive and specific to changes in the properties of different tissues have become critical for basic and disease oriented research. Improvements in the hardware and software associated with whole body Magnetic Resonance (MR) scanners have made possible the development and practical implementation of a whole new range of imaging and spectroscopy techniques. While these
have shown promising results at the standard clinical field strength of 1.5T, the increase in signal to noise and spectral resolution associated with higher field strengths are critical for developing new functional and metabolic imaging techniques with the best possible sensitivity and specificity. The objective of this proposal is to support collaborative research between the California based research and development group of General Electric Medical Systems (GEMS) and
scientists at the Institute for Quantitative Biomedical Research (QB3), which is one of the four California Institutes for Science and Innovation. The focus of the project will be the optimization of 3T and 7T whole body scanners for biological and medical research. Specific Aim 1 will address the optimization of translational research on the 3T system. This will be an extension of previous research performed at UCSF in high resolution MRI and MRSI that has resulted in several
important applications such as the evaluation of pediatric epilepsy, osteoporosis and prostate cancer. Specific Aim 2 will provide a validation of in vivo MR parameters and will identify new targets for high field MR spectroscopy by performing ex vivo MR spectroscopy and immunohistochemistry of tissue samples obtained under well-controlled conditions from uniform populations of patients participating in clinical trials. Specific Aim 3 will address the use of the 7T whole
body magnet and will require a much higher degree of engineering development associated with optimizing gradient and radiofrequency coils, the design of new pulse sequences and the design of algorithms for data reconstruction and analysis. Specific Aim 4 will provide training in both practical and theoretical aspects of high field MR for
students and postdoctoral fellows from UCSF, UCB and UCSC. This collaboration will provide critical resources for the researchers participating in QB3, as well as other many other academic and industrial partners in California.
NIH R21 AR51048 “Spectroscopic Markers of Disc Degeneration”
Abstract
I am a co-investigator (PI- Dr. Sharmila Majumdar) on this grant applies ex-vivo High Resolution Magic Angle Spinning Spectroscopy for the identification of metabolic biomarkers of disc degeneration and back pain. Degeneration of the intervertebral disc is a common ailment in working-age adults, affecting between 65% and 80% of the population
at least once in their lifetime. The intervertebral disc is thought to be a primary source of pain in these individuals and therefore disc pathophysiology is well studied. Intervertebral discs are complex spinal structures consisting of three tissues: nucleus pulposus, cartilaginous end-plate, and annulus fibrosis. The process of disc degeneration is characterized by a loss of cellularity; degradation of the extracellular matrix; and as a result, alterations in physiochemical properties. The most consistent chemical change observed with aging is loss of proteoglycan and associated loss of water. In
normal discs, large proteoglycans consist primarily of an aggrecan core protein with chondroitin and keratin sulfate side chains. Electron microscope studies suggest that with degeneration, the length of the chondroitin sulfate regions of aggrecan decreases. Also, age-related decreases in chondroitin sulfate correlate with decreases in water content. It has also been reported that prolapsed discs contain less keratin sulfate and chondroitin sulfate than age-matched controls.
Magnetic resonance (MR) imaging methods have been used to study disc degeneration by observing the changes in water content, relaxation and diffusion, which are an indirect by-product of alterations in biochemistry and proteoglycan changes in degenerative disc. High resolution magic angle spinning (HRMAS) NMR spectroscopy is a non-destructive technique that can be applied to intact disc samples to provide a chemical analysis of metabolites, such as proteoglycans and collagen which can be compared to quantitative biomechanical and biochemical analysis of the same sample, thereby providing a direct correlation of chemical changes associated with disc degeneration and the underlying causes of these changes. Importantly, proton spectroscopy methods for studying these metabolites may potentially be
developed and applied in vivo, and therefore provides a means for in situ disc biochemical characterization that may provide important, but currently unavailable information for the clinical management of low back pain. The goals of this proposal are to: 1) identify chemical changes associated with disc degeneration using ex vivo proton HRMAS spectroscopy; 2) determine whether this methodology complements the MR derived measures of tissue water content, relaxation measures and diffusion; and 3) establish the potential utility of in vivo proton spectroscopic markers of disc degeneration.
Department of Defense - PC030909 “Targeting MRS-defined dominant intraprostatic lesions with inverse-planned high dose rate brachytherapy”
I this grant I (co-investigator) team up with Dr. Pouliot in the UCSF Department of Radiation Oncology in order to use MRI/MRSI in planning High Dose Rate Brachytherapy. It has been shown that combined MRI and MR-spectroscopy can be used to identify the location and extent of cancer within the prostate. Clinical literature suggests that the local control can be improved by delivering more radiation dose to the prostate. Furthermore, there is a growing body of evidence from radiobiology in favor of hypo-fractionation for prostate cancer, making High Dose Rate Brachytherapy with its ability to deliver highly conformal dose distribution in a very small number of fractions, an option of choice for the treatment of prostate cancer. MRI/MRS Functional imaging is starting to be used to target cancer-validated areas in the prostate with external beam radiation therapy or permanent prostate implants. It has never been used for High Dose Rate Brachytherapy and the appropriate level of dose escalation remains unknown. Our hypothesis is that using our multi constraint dose optimization algorithm for HDR we can develop Dominant Intraprostatic Lesions (DIL) specific class solutions to provide dose boosts to DIL of the order of 150% or more of the prescribed dose while better protecting the organs at risk. This is supported by the fact that HDR planning with optimization is highly conformal and that protection to organs at risk for prostate cancer is achieved solely by conformity and not by protraction/fractionation regimen.