Research Highlights
Ongoing imaging advances continue to improve patient outcome across all cancer types, enabling clinicians to detect cancer at earlier stages when there is the greatest chance for cure , to guide treatment delivery with unprecedented precision and to monitor treatment efficacy over time. Here is an overview of key discoveries by members of the Cancer Imaging Research Program:
- PET Reporter gene technology for use in multiple applications was developed and validated by Dr. Gambhir . The use of the mutant Herpes-Simplex Virus Type 1 thymidine kinase (HSV1-sr39tk) and fluorinated acycloguanosine PET reporter probes (e.g., fluorinated penciclovir, FHBG) were validated in his laboratories ( Nat Rev Cancer 2:683, 2002). Several strategies for indirect monitoring of gene therapy using bi-directional strategies, internal ribosomal entry site (IRES) based strategies, two-step transcriptional amplification (TSTA) strategies for use with weak tissue-specific promoters, and co-administration of two vectors, were also developed in his laboratory ( Genes Dev 17:545, 2003). Some of these approaches have now entered clinical trials for gene therapy and cell trafficking imaging in cancer patients (in collaboration with UCLA and City of Hope ; Dr. Gambhir has an IND on FHBG). They are expected to impact human gene therapy monitoring by utilizing PET for imaging location (s), magnitude, and time-variation of gene expression in patients ( Gastroenterology 128:1787, 2005) . Multiple fusion reporter technologies to marry the best of optical and PET imaging, and fundamental assays for imaging intracellular events such as imaging protein-protein interactions and Bioluminescence resonance energy transfer (BRET) in living subjects were also developed in the laboratory ( Proc Natl Acad Sci USA 99:15608, 2002; Faseb J 19:2017, 2005). These assays are already in use by drug companies to study drugs targeted against signal transduction.
- The development and validation of bioluminescence reporter gene based in vivo with firefly and other luciferases, were pioneered by Dr. Contag and colleagues at Stanford. These have subsequently been applied to numerous areas including tumor growth models, metastatic models, immune cell trafficking ( Mol Ther 12:42 , 2005) , transgenic models, and non-invasive monitoring of anti-cancer therapies. Bioluminescence based assays are now one of the most commonly employed molecular imaging strategies throughout the world due to their low cost, simplicity, and generalizability. The effects of this work on pre-clinical cancer models are quite diverse and have clinical impact due to drug testing in mouse models. A number of IND applications have been submitted to the FDA using images obtained by BLI as supporting data.
- Development of novel 3D visualization methods for CT colonography ( J Comput Assist Tomogr 24:179, 2000) ; Assessment of radiologist reader accuracy using various 2D and 3D imaging modes ( Radiology 212:203, 1999) ; Development of algorithms for computer aided detection of polyps ( IEEE Trans Med Imaging 23:661, 2004) ; Methods for registering supine and prone CT datasets ( Med Phys 31:2912, 2004) ; and Assessment of the effects of CAD on reader interpretations ( J Comput Assist Tomogr 28:318, 2004) , are contributions made by Dr. Beaulieu and his group.
- The development of 99m Tc-Annexin to image apoptosis in small animals and more recently in patients, was pioneered by Dr. Blankenberg and colleagues . This is an excellent example of an imaging probe that was validated all the way from molecular target to clinical imaging. This strategy is now being used by many centers in Europe and the USA and is the focus of a multi-center trial for monitoring cancer therapy. Its applications for monitoring anti-cancer therapy as well as cardiovascular applications is only the beginning of what may be a very generalizable strategy with excellent potential for routine human use ( Curr Pharm Des 10:1457, 2004; IEEE Eng Med Biol Mag 23:51, 2004; J Nucl Med 45:1373, 2004).
- The development of a number of novel probes, for the study of protease function, have been accomplished by Dr. Bogyo and colleagues over the past few years. In particular, they have developed probes for papain family cysteine proteases, the proteasome, caspases and legumain ( Nature Chem. Biol 1:33, 2005) as well as novel fluorescent imaging probes ( Nature Chem. Biol 1:203, 2005) and have used these reagents to define the function of proteases in disease conditions ranging from cancer to malaria (Cancer Cell 5:443, 2004).
- Temperature imaging methods, that are robust to tissue motion, used to monitor thermal therapy in liver and prostate cancer have been developed by Dr. Butts and her research group ( Magn Reson Med 51:1223, 2004). They have also developed i) a method to quantitate and map temperature isotherms in prostate tissue and cancer undergoing cryoablation ( Acad Rad 12:1080, 2005) and ii) x-ray compatible MR RF receive coils for use with the integrated X-ray and MR system ( Magn Reson Med 53:1049, 2005). Also developed are methods to modify device artifacts so that the visualization of devices can be modified as needed by the interventionalist ( JMRI 9:586, 1999), and ways to prolong the period of contrast enhancement of breast cancer for MR-guided biopsy ( Proc of the ISMRM, 2005).
- An RGD peptide tracer for visualization and quantification of tumor integrin expression level in vivo ( Mol Imaging 3:96, 2004; J Nucl Med. In-press; Cancer Res ; 64:8009, 2004), has been developed by Dr. Chen and colleagues at Stanford. This probe with excellent tumor targeting efficacy and favorable pharmacokinetics is being translated into clinical trials to validate its safety, tumor detectability, and ability to document tumor integrin levels in cancer patients. Also developed are a series of radiometal labeled RGD peptides, which demonstrate high integrin affinity and specificity and sustain prolonged retention in integrin expressing tumor xenograft models ( J Nucl Med. 46:in press, 2005) . These compounds hold great potential for both peptide receptor radionuclide imaging and therapy.
- Dr. Dai is one of the world's leaders in carbon nanotube synthesis, characterization and device applications. He has pioneered patterned synthesis of nanotubes to obtain controllable nanotube architectures. He was the first to demonstrate nanotube sensors, and his nanotube FETs with high-k gate insulators represent the most advanced nanotube transistors to date ( Nature Mat. 1:241, 2002). His group's original effort on nanotube sensors ( Science 287:622, 2000) represents the beginning of current worldwide nanosensor research. His nanotube sensors exhibit demonstrated sensitivity down to 100 ppt ( Nano Lett. 3:347, 2003), and he published one of the first papers on real-time protein sensing with high sensitivity and selectivity ( PNAS 100:4984, 2003).
- The first report of use of rapid spiral imaging, for breast cancer, was by Dr. Daniel in 1998. His significant improvements include the development of 3D spiral imaging and pharmacokinetic modeling and display. These techniques are now used on ~1200 clinical breast MRIs every year at Stanford. In the field of prostate cancer cryoablation, Dr. Daniel and Dr. Butts patented a method for MRI-based thermal mapping of frozen tissues, and have demonstrated in-vivo application of the work using novel 1/2 pulse excitation methods in vivo. In addition, MR imaging with diffusion-weighted scanning has been developed and correlated to the extent of injury induced during cryoablation ( JMRI 17:131, 2003).
- Pioneering work that defined the normal and pathological anatomy of the thorax using cross sectional imaging modalities was initiated and performed by Dr. Glazer in the early eighties, as this field was emerging and becoming established. His work in the imaging and staging of lung cancer received international recognition and was adopted in the 1980's in routine clinical practice ( Chest 96:44S, 1989; Lung Cancer, AJR 142:1101, 1984; Contemp Issues Comput Tomogr 4:37, 1984; AJR 144:261, 1985; AJR 147:469, 1986; Radiology 168:429, 1988). As magnetic resonance imaging diffused into medicine, Dr. Glazer focused his research on the non-invasive tissue characterization of lesions using MRI techniques ( Gastrointest Radiol. 11:263, 1986; Radiology 155:417, 1985; Radiology 158:73, 1986; Radiology 169:409, 1988). This work resulted in MR classifications being developed to distinguish benign from cancerous tumors in the liver and adrenal glands. On the basis of this work Dr. Glazer was elected to the Society for Body Computed Tomography in 1984, at a time when there were only twenty members in the world. Dr. Glazer's research efforts in the early days of CT and MRI have had lasting impact on the success and efficacy of noninvasive imaging in the clinic.
- Novel methods of rapid dynamic imaging of physiological function, have been developed by Dr. Glover . The spiral-in/out technique ( Magn. Reson. Med. 46:515, 2001) was pioneered at Stanford and is in use by dozens of investigators on campus and extramurally. These 2D and 3D methods have found widespread application in brain imaging as well as for imaging of breast cancer ( J. Magn Reson Imaging 11:351, 2000) .
- A virtual mouse model, anatomically constructed from the segmentation of a real mouse's CT images, that can be used to convert serial ex vivo activity concentrations into exact organ doses ( J.Nuc.Med 46(supplement 2):194P, 2005) has been developed by Dr. Goris . Dr. Goris has conducted multiple clinical studies on radioimmunotherapy ( Radiotherapy and Oncology 24:169, 1992; Antibody Immunoconfigurates and Radiopharmaceuticals 6:197, 1993; Radiation Research 135:24, 1993; Progress in Clinical and Biological Research 363:531, 1991; Clinical Cancer Research 10:7792, 2004; J Clin Oncol . 23:712, 2005).
- Development of breast cancer MRI-guided needle localization ( J Am Coll Surg 200:527, 2005; Am J Surg 190:633, 2005) and core biopsy methods for MRI-detected findings evaluation of needle core biopsy methods ( Acad Radiol 4:508, 1997; Hwang et al., ISMRM Meeting, Tokyo, Japan, 2004 ) and their clinical relevance ( Lin et al., ISMRM Meeting, Orlando, FL, 2005 ), evaluation of CAD programs and their clinical significance in breast cancer detection ( Radiology 236:451, 2005; Radiology 230:811, 2004), evaluation of mammographic findings correlated to pathology ( Radiology 219:192, 2001) and evaluation of ultrasound findings with correlation to pathology ( Radiology 213:579, 1999; AJR 169:703, 1997) are all accomplishments of Dr. Ikeda's team. Dr. Ikeda chaired the American College of Radiology (ACR) committee responsible for development and publication of the ACR MRI BI-RADS lexicon for contrast-enhanced MRI findings in breast disease (ACR BI-RADS MRI TM , American College of Radiology, Reston , VA , 2003). These research efforts demonstrate the ability of Dr. Ikeda's group to correlate and describe breast cancer imaging findings as related to pathology, and to implement and evaluate new technologies to biopsy image-detected breast findings using various imaging and biopsy techniques. Their research also demonstrates the group's unique ability to collaborate with basic scientists to produce new, clinically relevant imaging and biopsy methods coupled with the ability of the physician scientists to test and implement the new optimized methods in everyday clinical use in patients, subsequently evaluating outcomes to judge the clinical relevance of the new methods.
- The invention of the capacitive micromachined ultrasonic transducer (cMUT) that is becoming the transducer of choice in many ultrasound medical imaging applications, is the most significant development of Dr. Khuri-Yakub's group ( http://piezo.stanford.edu ) ( IEEE Transactions on UFFC 52:37, 2005 ; IEEE Transactions on UFFC 52:51, 2005; IEEE Transactions on UFFC 52:326, 2005; IEEE Transactions on UFFC , Letters 52:578, 2005; IEEE Transactions on UFFC In Press).
- The construction of both fluorescence and reflection microscopes is in progress by Dr. Kino and colleagues. Breadboard models have been demonstrated with a penetration depth into tissue of as much as 1mm. The first miniature device will be a handheld one for imaging skin followed by an endoscope to be used in vivo for observing dysplasia in the esophagus and cancerous polyps in the colon ( Nano Letters 4:957, 2004; Optics Letters 28:1915, 2003; Optics Letters 28:414, 2003; Gastrointestinal Endoscopy 57:suppl.1:AB76, 2003).
- Seminal contributions to mid-course adaptive designs and interim analysis of clinical trials, by Dr. Lai, have been awarded the Abraham Wald Prize (August 2005) in Sequential Analysis ( Biometrics 57:1039, 2001).
- The building of imaging tools (instrumentation and software) and setting up of acquisition parameters that push the limits of cancer sensitivity, has been achieved by Dr. Levin and colleagues at Stanford. They have built a high sensitivity handheld clinical gamma ray camera and are currently packaging it for use in the clinic. The initial plans for this camera are to use it to assist cancer diagnosis and staging ( Physica Medica Submitted, 2004). They are also building high resolution, high sensitivity clinical and pre-clinical PET systems for imaging cancer ( Physica Medica Submitted, 2005).
- New and novel ways of assessing CNS diseases, primarily in the use of diffusion and perfusion MR that has revolutionized neuroimaging, have been developed by Dr. Moseley over the last 15 years. This work has focused on three-dimensional pictures (tensor) of water diffusion in brain, spine, and peripheral nerve. The analysis of this tensor yields unique information on white matter maturation in neonates, de-myelination of white matter diseases such as MS, tumors, and infarction, and offers a non-invasive measure of white matter connectivity ( NMR Biomed 15:553, 2002; Brain Cogn 50:396, 2002; AJNR 24:5, 2003).
- Several approaches, directly applicable to the detection of cancer, have been innovated by Dr. Napel's group. Among them are highly accurate methods for registration of multiple modalities, particularly suited for correction of distortions in magnetic resonance images ( Magnetic Resonance in Medicine 31:40, 1994), novel methods for visualization ( J Comput Assist Tomogr 24:179, 2000) and segmentation ( Med Phys 30:2572, 2003) of large quantities of cross-sectional imaging data, and several highly accurate methods for computer-aided detection of colon and lung cancer from cross-sectional images ( IEEE Transactions on Medical Imaging 23:661, 2004).
- High-resolution magnetic resonance imaging methods for elucidating regions of subtle tumor invasions have been developed by Dr. Nishimura . This holds great significance, as other medical imaging methods do not offer the proper combination of imaging performance and contrast to achieve such visualization ( J Magn Reson Imaging 21:590, 2005; Magn Reson Med 53:1468, 2005; IEEE Trans Med Imaging 24:799, 2005).
- Dr. Pauly and the Magnetic Resonance Systems Research Laboratory have made major contributions in rapid MR Imaging, real-time interactive MRI ( Magn. Reson. Med. 38:355, 1997) , Magnetic Resonance Spectroscopic Imaging (MRSI) ( Magn Reson Med . 53:1033, 2005) , image reconstruction algorithms ( IEEE Trans Med Imaging . 24:799, 2005 ), and RF pulse design for MRI ( IEEE Trans. Med. Imag , 10:53, 1991) and MRSI ( Magn. Reson. Med. 29:776, 1993 ) .
- A number of new MR techniques, including cardiac cine imaging ( Magnetic Resonance Annual 1988 Raven Press: 299-333, 1988), phase contrast velocity imaging ( Mag Res Quarterly 7:229, 1991), rapid imaging methods ( Magn Reson Med 50:892, 2003) and chemical shift separated imaging ( Mag Res Med 55:35, 2004), have been developed by Dr. Pelc and his group. Previous accomplishments in CT include the development of high-resolution fan-beam reconstruction methods (65th RSNA, 1979), fully 3D filtered back-projection (also relevant in PET) ( J. Comput. Assist. Tomog. 3:385, 1979), methods with reduced sensitivity to motion artifacts (U.S. Patent 4,580,219, 1986), and fundamental work in new CT system concepts ( Med Phys 31:2623, 2004). Dr. Pelc and his group have also pioneered technology for hybrid imaging platforms ( JMRI 13:294, 2000).
- Computer simulation models that yield predictions on the impact of new image-based cancer screening technologies on long-term patient outcomes and health care costs, have been produced in Dr. Plevritis' research program. These computer models have been applied to evaluate the impact of screening for breast cancer with mammography in the US population trends from 1975 to 2001 ( NEJM In press, 2005); currently, they are being applied in combination with clinical trial data to evaluate the effectiveness and cost-effectiveness of screening for breast cancer with magnetic resonance imaging (MRI) in women who carry BRCA 1/2 mutations ( Cancer 100:3, 2004), and to evaluate the cost-effectiveness of screening with computerized tomography (CT) in current and former smokers.
- An imaging technique for viewing fusion PET/CT in three-dimensional volumes, has been developed by Dr. Quon, Sam Gambhir and colleagues in the Molecular Imaging Program and 3D laboratory at Stanford. This allows for the simultaneous visualization of the functional data from PET and the anatomical data from CT in “fly-through” formats such as virtual colonoscopy and bronchoscopy. The pilot study shows that this new viewing format greatly aids in pre-surgical and pre-procedural planning when resecting or sampling tumor masses ( Journal of Nuclear Medicine 46:108p{abstr313;suppl}, 2005).
- A series of fluorogenic substrates that are able to detect gene expression at different physiological settings from single cells to whole living animals, have been developed by Dr. Rao and his colleagues ( J. Am. Chem. Soc. 125:11146, 2003; J. Am. Chem. Soc. 127:4158, 2005). They have also developed and demonstrated a ribozyme-based approach to target and image endogenous mRNAs in single living cells ( Proc. Natl. Acad. Sci. USA 100:14892, 2003; J. Am. Chem. Soc. 126:7158, 2004). This strategy holds potential for imaging tumor-specific oncogene expression in living subjects.
- Lung cancer is the leading cause of cancer-related deaths in the US . Both primary and metastatic lung cancer most commonly manifest as pulmonary nodules, which are readily visualized radiographically. CT scanning is currently the most sensitive non-invasive means available for detecting pulmonary nodules, but has suffered from limited sensitivity and high interobserver variability, particularly of smaller nodules. The recent development of multi-detector-row CT (MDCT) allows imaging of the lungs with unprecedented three-dimensional spatial resolution, up to 10 times greater than single-row CT systems within a single less than 10 second breathhold. For radiologists to harness the higher spatial resolution of MDCT data to improve lung nodule detection, they must overcome two key challenges: (1) time efficient interpretation of the 300-600 images that result from high-resolution MDCT scans of the lungs and (2) improve nodule detection sensitivity without losing specificity when examining 1-mm thick CT sections, where lung nodule and blood vessel discrimination is more difficult due to the greater similarity of their appearance when compared to thick-section acquisitions. The research focus of Dr. Rubin and colleagues is to improve the detection of lung cancer with CT using computer algorithms for automated detection (CAD) of lung nodules and to understand how the availability of CAD results affects radiologists' accuracy and efficiency when interpreting lung CT scans. The overall goal is to maximize the detection of early lung cancer from CT scans, while minimizing false positive detections that might lead to unnecessary medical procedures. This work is supported by a grant from the NCI, 1R01 CA109089 ( IEEE Trans Med Imaging 23:661, 2004; Radiology 234:274, 2005).
- Magnetic nanoparticles are being developed to assist in locating and imaging cancer cells. Dr. Sinclair's research group has carried out synthesis of such particles that include the incorporation of heavy elements (e.g., Au in Fe). In order to passivate their surfaces, methods of encapsulating them with carbon (graphite) overcoats have also been established. These particles are characterized using high resolution electron microscopy to determine their structure and the degree of carbon encapsulation, and their MRI contrast enhancement compares favorably with more traditional agents ( Proc. Microscopy and Microanalysis, In Press).
- Microoptics and photonic crystals that enable miniaturization of devices for creation, manipulation, and measurement of optical fields, has been developed by Dr. Solgaard and his collaborators. These devices have been combined and integrated to create a variety of biological instruments including spectrometers (Proc 13th Internat Conf on Solid-State Sensors, Actuators and Microsystems (Transducers '05), Seoul, Korea, June 5-9, 2005, pp. 1250-1254) and cell sorters (pp. 441-444). Prof. Solgaard and his students have invented a near-field probe, based on Atomic Force Microscopy, for quantitative measurement of elastic properties with molecular-scale spatial resolution ( Sensors and Actuators: A Physical 114:183, 2004; Phys. Rev. B 69:article 165416, 2004).
- Ultrasonic applicator technology that has been tested extensively in a canine model and found capable of rapid and accurate ablation of selected regions of prostatic tissue, have been developed by Dr. Sommer and colleagues. These results have been described in several recent publications ( Int J Hyperthermia 20:739 , 2004; Med Phys 32:733, 2005; Phys Med Biol 49:189, 2004; Med Phys 32:1555, 2005) and the work was given the award for best paper at the European Society of Uroradiology in 2002.
- Highly efficient volumetric proton magnetic resonance spectroscopic imaging techniques have been developed by Dr. Spielman and collaborators. These techniques have significantly enhanced the ability of MRS for detecting mulitfocal lesions, developing treatment plans, and evaluating therapies ( Phys Med Biol. 47:3567, 2002; Magn Reson Med. 51:458, 2004; and Magn Reson Med. 53:1177, 2005).
- Dr. Wang is among the pioneers in the use of magnetic nanoparticles for bio-detection and Microarray-based DNA profiling ( Journal of Forensic Sciences 50:1109, 2005). As the lead architect of MagArray™ biochips, he has authored or co-authored six patent applications on these subjects, all of which are being licensed for biomedical applications. He has also authored or co-authored a series of papers on magnetic nanotags and their biological applications, one of which ( J. Am. Chem. Soc. 126:273, 2004) has been placed at #1 on the “Hot Ten” list (Chemistry) compiled by Science Index/Science Watch. A book chapter (with G. Li) entitled “Spin Valve Biosensors with Magnetic Nanoparticle Tags” is to appear In Biomedical Applications of Nanotechnology, edited by V. Labhasetwar and D.L. Leslie-Pelecky, Wiley, 2005. In addition, he has co-invented room temperature spin filters (with M. Chapline) for spintronics and low resistance magnetic integrated inductors for system-in-package and system-on-chip (with A.M. Crawford, D.W. Lee and L. Li).
- Professor Wender (Bergstrom Professor in the Department of Chemistry; Professor of Molecular Pharmacology by courtesy) heads a multidisciplinary effort with an emphasis on the design, synthesis, assay and advancement of new therapies and new drug/probe delivery systems. Studies on bryostatin analogues, laulimalide analogs, apoptolidin, kinase activators and inhibitors, and novel drug delivery and imaging systems, are recent programs of interest. Bryostatin is in human clinical trials. Its range of activities is unique and includes restoration of apoptotic function, synergy with other oncolytics, enhancement of the immune system, reversal of multidrug resistance and, remarkably, the ability to facilitate learning and enhance memory retention in animal models of Alzheimer's disease. His group has designed agents that are more available and potent than bryostatin itself ( Chemistry & Biology 11:1261, 2004) . These studies involve computer modeling of ligands and receptors, synthesis, cellular assays especially real time translocation studies of GFP fusion proteins, protein profiling to establish systems biology, and in vivo studies. These agents are under preclinical evaluation. Laulimalide is a new microtubule-targeting agent that is effective against taxol resistant cancers. His group has designed, synthesized, and evaluated new analogs and has uncovered new activities of these analogs ( Proc. Natl. Acad. Sci. USA 101:8803, 2004) . Like the bryostatin program, these studies rely heavily on modeling and synthesis and are followed by comprehensive evaluations of leads in cells with an eye toward therapeutic applications. Apoptolidin is one of the most selective agents (top 0.1% of 37,000 compounds) to be screened by the National Cancer Institute. It is virtually inactive against normal glial cells but effects apoptosis in oncogene transformed cell lines. The Wender group has isolated new and more potent apoptolidins from natural sources, established features of their structure that contribute to activity, and uncovered aspects of their mode of action ( Organic Lett. 7:3025, 2005) . Investigations on the origins of selective activity are key to 21st century approaches to cancer therapies. A grand challenge in science is to develop strategies for breaching biological barriers. This is central to the advancement of imaging technologies, to new diagnostics and to new therapies. Dr. Wender's group has reported on the design, synthesis, and evaluation of molecular transporters, agents which when attached to a molecule will enable or enhance its uptake into cells and across barriers such as the plasma membrane and skin ( Nature Medicine 6:1253, 2000) . Drug conjugates of these transporters have been advanced to phase II human trials. These transporters have figured in the launch of two companies and are being used widely in academia and industry to address bioavailability challenges.
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