Each year nearly 200,000 men are diagnosed with prostate cancer. Although the prostate antigen specific (PSA) blood test has improved detection, it fails to indicate whether the cancer is aggressive or slow-growing. The current approach of “active surveillance” means that many patients spend years undergoing repeat blood tests and invasive biopsies to monitor the cancer’s growth. Any changes in PSA results or biopsy samples may signal a need to alter treatment.
“There are a lot of questions in prostate cancer like, ‘Do you treat or not?’” says John Kurhanewicz, director of the Prostate Imaging Group and Biomedical NMR Lab, Department of Radiology and Biomedical Imaging, University of California San Francisco (UCSF), who has tracked a cohort of men under active surveillance for the last decade. “Current [imaging] techniques fall short.”
Unsatisfied with the lack of diagnostic precision in prostate cancer, Kurhanewicz and colleague Daniel Vigneron, associate director of the Surbeck Imaging Laboratory at UCSF, in collaboration with GE Healthcare, have applied a new method that can assess tumor aggressiveness rapidly and noninvasively. This technique, hyperpolarized carbon-13 magnetic resonance imaging, measures metabolic activity (the chemical reactions that sustain the tumor) within a tumor and homes in on specific chemical products produced by aggressive tumors.
Identifying Aggressive Prostate Tumors
Aggressive tumors are known to produce high levels of lactate. In a proof-of-concept study in mice with prostate tumors, the UCSF researchers tracked the tumor’s uptake of hyperpolarized pyruvate (a compound known to convert to lactate) and the tumor’s subsequent lactate production. Results showed that less aggressive tumors contained lower levels of lactate and more aggressive tumors had higher levels of lactate.
The researchers plan to begin a patient trial during the first half of 2010. The trial will examine dose safety of the imaging agent and how well carbon-13 MRI can characterize human prostate tumors. “This trial is critical because it takes metabolic probes that are inherently insensitive and makes them highly sensitive,” explains Kurhanewicz. “It will give us a tool that gives a more direct assessment of disease in the clinic.” Not only will diagnosis and treatment be more accurate, but the time it takes to perform a prostate staging exam is likely to decrease. Kurhanewicz suggests that the imaging technique could reduce the current 1-hour prostate tumor staging exam to 30 minutes, lower the exam’s cost, and be less stressful for the patient.
Imaging Metabolic Activity
For their studies, the UCSF team images lactate generation with pyruvate and another byproduct, alanine. In a perfect world, the researchers would inject pyruvate, flip a switch, and see the chemical reactions as they occur. But reality makes imaging more challenging.
Magnetic resonance imaging of compounds other than water is limited by poor signal quality and lack of sensitivity. To overcome this hurdle, the team hyperpolarizes the pyruvate in a separate polarizer instrument located in a sterile room next to the main MRI scanner. First, carbon-13-enriched pyruvate is placed in a solution that remains semi-frozen at supercool temperatures. Next, the solution is cooled to -272°C. A strong magnetic field and microwaves applied to the solution cause the atoms to align in an ordered array. The super-cooled polarizing process generates an MR signal that is a 50,000-fold improvement over conventional MR signals.
After hyperpolarization, the solution is warmed to room temperature and whisked to the main MR scanner and injected into the subject. In the prostate studies, the carbon-13-enriched pyruvate was injected into a catheter in the jugular vein of each mouse. Although the polarizing effects begin to decrease with time, enough polarization remains to provide a strong signal during imaging studies.
The one drawback to the super-cooled approach: the signal lasts just one minute from the time of injection. “We can’t study long-term metabolism,” says Vigneron. “It forces us to focus on fast processes.” The rapid signal loss also means imaging times are much shorter than conventional MR imaging times.
To detect the signals from the highly aligned carbon atoms, the researchers developed new MR coils for the imaging system. Vigneron notes that current clinical systems could be retrofitted or easily adapted to accommodate carbon-13 imaging.
Moving Beyond Cancer
Although hyperpolarized compounds will play a key role in imaging metabolic activity associated with cancer, they will likely make diagnosis of other diseases more precise as well. These compounds are attractive because they do not alter cardiac function and the doses needed to image are similar to current MR contrast agents and less than CT contrast doses. “If we can pave the way with one hyperpolarized agent in man, then more will follow,” says Kurhanewicz.
The UCSF group is investigating a number of different compounds, including fructose to study sugar metabolism, bicarbonate to examine abnormal pH levels that are often associated with cancer and inflammation, and alanine to assess liver function. Kurhanewicz envisions a single system that can co-polarize multiple probes and, when coupled with MRI, provide an image for each probe’s path. Because each probe gives off a signal at a different frequency, a composite image could be created to monitor multiple reactions.
In preclinical research, the hyperpolarized agents could increase understanding of how drugs interact with specific networks of molecules to alter cell function. “MRI alone is not good at targeting specific pathways,” says Kurhanewicz. Because hyperpolarized agents greatly increase the sensitivity of MR spectroscopy, “they may allow us to track targeted agents to see if they are hitting the pathways they should.”
“The future of medicine is in the molecular signatures of disease,” says Rahim Rizi, an associate professor of radiology at the University of Pennsylvania and a leading researcher in hyperpolarized MRI. “Carbon-13 imaging will lead to the right path. For now, it’s the best game in town.”
This work is supported in part by the National Institute of Biomedical Imaging and Bioengineering.
Albers MJ, Bok R, Chen AP, Cunningham CH, Zierhut ML, Zhang VY, Kohler SJ, Tropp J, Hurd RE, Yen YF, Nelson SJ, Vigneron DB, Kurhanewicz J. Hyperpolarized 13C lactate, pyruvate, and alanine: Noninvasive biomarkers for prostate cancer detection and grading. Cancer Res. 2008 Oct 15;68(20):8607-15.
Chen AP, Albers MJ, Cunningham CH, Kohler SJ, Yen YF, Hurd RE, Tropp J, Bok R, Pauly JM, Nelson SJ, Kurhanewicz J, Vigneron DB. Hyperpolarized C-13 spectroscopic imaging of the TRAMP Mouse at 3T-initial experience. Magn Reson Med. 2007 Dec;58(6):1099-106.
Hu S, Chen AP, Zierhut ML, Bok R, Yen YF, Schroeder MA, Hurd RE, Nelson SJ, Kurhanewicz J, Vigneron DB. In vivo carbon-13 dynamic MRS and MRSI of normal and fasted rat liver with hyperpolarized 13C-pyruvate. Mol Imaging Biol. 2009 Nov-Dec;11(6):399-407.
Nelson SJ, Vigneron D, Kurhanewicz J, Chen A, Bok R, Hurd R. DNP-hyperpolarized 13C magnetic resonance metabolic imaging for cancer applications. AppI Magn Reson. 2008;34:533-44.