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  • Hyperpolarized Spectroscopy is a Promising Tool in Cancer Therapy

    April 01, 2014

    MR-compatible metabolic probes are showing progress in diagnosing cancer patients.

    Although radiation therapy is a mainstay for treating many types of cancer, the therapy often doesn’t achieve the success rate that patients and physicians are continually working toward.

    In prostate cancer for example, even with modern conformal radiation therapy—a 3D technique in which beams of radiation are shaped to match the tumor—treatment fails in approximately 45 percent of patients with locally confined disease, according to a June 2013 study in the Journal of Nuclear Medicine (JNM).

    A major challenge in cancer biology is monitoring and understanding cancer metabolism in vivo.

    Increasingly, redox (reduction and oxidation) mechanisms are considered critical to cancer progression, according to researcher David Wilson, M.D., Ph.D., a chemist by training and an assistant professor at the University of California, San Francisco (UCSF). “More studies suggest that reactive oxygen species (ROS), small-molecule antioxidants such as glutathione (GSH), and redox enzymes are highly relevant in cancer aggressiveness and resistance to conventional treatments (radiation and chemotherapy),” Dr. Wilson said.

    To that end, Dr. Wilson is developing MR-compatible molecular imaging techniques that allow assessment of real-time metabolism in vivo, which could greatly enhance the specificity of cancer diagnosis and determine treatment response.

    Dr. Wilson launched his research through a 2010 Toshiba America Medical Systems/RSNA Research Seed Grant for the project, “New 13C Hexose Probes for the Metabolic Characterization of Tumors in Vivo Using Hyperpolarized 13C Spectroscopy,” and is continuing his research through other projects that grew from his RSNA study, including a project his group recently published in JNM. (See sidebar).

    The broad goal of Dr. Wilson’s RSNA project was to identify aggressive phenotypes, or “bad actors,” and predict/monitor response to therapy. “The methods we have developed have the potential to address these processes noninvasively, allowing treatment to be tailored to individual patient phenotypes,” Dr. Wilson said.

    PET Complements Hyperpolarized 13C Spectroscopy

    Hyperpolarization, a relatively new method of dramatically increasing the MR signal for non-1H nuclei, is used to study metabolism in real time using enriched endogenous 13C molecules. Metabolic imaging using hyperpolarized 13C spectroscopy is similar in many aspects to PET using 18F fluorodeoxyglucose (FDG) and the two are potentially complementary, Dr. Wilson said.

    “But 13C offers significant advantages including lack of ionizing radiation, a shorter scan time and compatibility with proton MR with superior soft tissue contrast,” Dr. Wilson said. “The ability to detect the metabolic products of injected 13C substrates is expected to greatly enhance the specificity of cancer diagnosis and assessment of treatment response.”

    In his RSNA research, Dr. Wilson developed the labeled sugars [2-13C] D-fructose and [1-13C] dehydroascorbate as molecular probes for imaging using hyperpolarized 13C spectroscopy and compared these agents to [2-18F] D-deoxyglucose (FDG) currently used in clinical PET scanning.

    “Simply stated, our general approach is to identify a biochemical problem of interest and design 13C, 18F and 11C probes to address it,” he said.

    Dr. Wilson’s lab is looking at probes that are chemically and mechanistically similar, with hyperpolarized 13C and PET methods reinforcing each other. “For example, we compared 13C ascorbates (vitamin C and dehydroascorbate) and 18F ascorbates as cancer-imaging agents,” he said. “Results of hyperpolarized 13C studies in animals have been very useful in the design of the related PET tracers. In many cases, PET tracers may reach the clinic faster than their hyperpolarized counterparts.”

    The RSNA project represents significant progress toward the use of MR-compatible metabolic probes in diagnosing patients, Dr. Wilson said. “Like FDG, the proposed 13C agents are expected to have enhanced uptake in cancer cells, allowing construction of metabolic maps of the human body,” he said. “However, the principal advantage over FDG is the ability to detect real-time metabolism of injected hyperpolarized 13C agents. This feature both potentially enhances the specificity of cancer diagnosis and allows assessment of subtle changes in metabolism that occur in response to treatment.”

    Technique Could Move to Clinical Practice

    Dr. Wilson’s project was completed under the supervision of John Kurhanewicz, Ph.D., a professor of radiology, urology and pharmaceutical chemistry at UCSF, which has a very large hyperpolarized 13C spectroscopic imaging research program.

    Along with expanding the arsenal of 13C agents for hyperpolarized MR studies, the RSNA project also promoted collaborative research with the UCSF Department of Nuclear Medicine and contributed much-needed research comparing hyperpolarized 13C spectroscopy as a complement to PET, Dr. Kurhanewicz said.

    “The preliminary studies conducted by Dr. Wilson are some of the first comparisons of hyperpolarized 13C MR probes to PET,” Dr. Kurhanewicz said. “These studies are essential given the mechanistic similarities between the two approaches.”

    In the long term, Dr. Wilson would like to see the hyperpolarized 13C MR technology move into routine clinical use, which he said is likely. “Given the recent successful clinical trial of the 13C pyruvate imaging probe at UCSF, the potential for clinical translation is very high,” Dr. Wilson said.

    The importance of the RSNA grant to his career and future research can’t be overstated, Dr. Wilson said. “This grant provided key preliminary data for two ROI submissions and was partially responsible for two publications, one in PNAS (Proceedings of the National Academy of Sciences) and one in JNM,” Dr. Wilson said. “In the current NIH funding climate, grants like the R&E grant are exceedingly important for early-stage investigators.” 

    R&E Foundation logoGrants in Action

    Name:
    David Wilson, M.D., Ph.D.

    Grant Received:
    2010 Toshiba America Medical Systems/RSNA Research Seed Grant

    Study:
    “New 13C Hexose Probes for the Metabolic Characterization of Tumors in Vivo Using Hyperpolarized 13C Spectroscopy.”

    Career Impact:
    “The writing of the grant itself had a significant impact, as it forced us to make our ideas more coherent and develop a better grasp of the hyperpolarized 13C and PET literature. This grant also funded key studies that allowed us to gather the preliminary data needed for our R01 application.”

    Clinical Implication:
    “Prostate cancer appears to undergo redox adaptation, whereby they accumulate antioxidants that allow them to detoxify more ROS. This adaptation makes them more difficult to treat. Hyperpolarized MR and PET methods that target redox will help to identify ‘bad actors’ and determine the dosages and types of therapy needed.”

    Web Extras
    Spurred by his RSNA-funded grant, David Wilson, M.D., Ph.D., continued his research as a contributing author to the following studies:

    • “Hyperpolarized [1-13C]Dehydroascorbate MR Spectroscopy in a Murine Model of Prostate Cancer: Comparison with 18F-FDG PET,” June 2013, Journal of Nuclear Medicine; access the study at JNM.snmjournals.org/content/54/6/922.abstract.
    • “Hyperpolarized 13C Dehydroascorbate as an Endogenous Redox Sensor for In Vivo Metabolic Imaging,” November 2011, PNAS; access the abstract at PNAS.org/content/108/46/18606.abstract.
     
    David Wilson, M.D., Ph.D.
    Wilson
    Preliminary study comparing hyperpolarized [1-13C] dehydroascorbate (DHA) MRI
    Researcher David Wilson, M.D., Ph.D., said his recent RSNA project represents significant progress toward the use of MR-compatible metabolic probes in diagnosing cancer patients. Left: Preliminary study comparing hyperpolarized [1-13C] dehydroascorbate (DHA) MRI and FDG-PET in a large transgenic adenocarcinoma of the mouse prostate (TRAMP) tumor. Significant reduction of hyperpolarized [1-13C] DHA to hyperpolarized [1-13C] VitC was observed in tumor voxels, with corresponding accumulation of 18F FDG.
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