Advances in genomics are enabling integration of various -omics to reveal the complexities underneath carcinogenesis. Multivariate signaling pathways are deregulated and evolve spatially and temporally depending on the tumor microenvironment. This finding shifts the focus of cancer research from “one disease–one target and drug” to “one disease–multiple pathway targets and combinational therapy” and imposes new challenges on the imaging community in terms of imaging targets, scales and information levels. In current clinical settings, most imaging modalities assess cancer risk through alternations in anatomy, function, metabolism, cellularity, or limited molecular events. Few clinical-translatable imaging modalities are capable of detecting aberrations in signaling pathways at the level of tissue biology. An exception to this is hyperpolarized 13 C magnetic resonance spectroscopic imaging (HP 13 C MRI), which is capable of imaging the molecular signatures of special metabolic enzymes using HP 13 C-labeled substrates. HP 13 C MRI can identify multiple metabolites including intermediates and products simultaneously to allow extraction of critical parameters such as flux alterations for multiple metabolic pathways. Meanwhile, recent progress in cancer metabolism research affirms that metabolic alterations are directly controlled by signaling pathways. Thus, in vivo assessment of aberrations occurring in signaling pathways becomes feasible through HP 13 C imaging. This report briefly reviews the connections between signaling pathways and cancer metabolic phenotypes, the current status of HP 13 C MRI in assessing signal pathways, and recent advances in HP 13 C MRI techniques. Integrated with cancer genomics and animal models, HP 13 C MRI may hold high promise in exploring important issues in cancer that are linked to functionality of signaling pathways. Examples include genomic-driven therapy, intratumoral heterogeneity, and drug resistances.
Tumor growth relies on various nutrient metabolic processes such as glycolysis, lipogenesis, and glutaminolysis. Many of the important metabolites are small molecules containing carbon and nitrogen. Molecules with isotopic variants of carbon ( 13 C) and nitrogen ( 15 N) have been useful in gaining insight into the complete metabolic process by magnetic resonance spectroscopy (MRS). But 13 C MRS has rarely been used in vivo in clinical studies until recently, with the emergence of a technique called dissolution dynamic nuclear polarization. This novel hyperpolarization technique can increase 13 C signal-to-noise ratio (SNR) >10,000-fold in liquids . Such an enhancement is sufficient for collection of images with a few acquisitions or even a single scan.
Imaging modality based on this technique, the HP 13 C MRI, is expanding rapidly, primarily driven by interests of cancer metabolism. Using 13 C-labeled molecules of low molecular weight, this technique permits imaging of biochemical reactions in vivo for monitoring cancer and other diseases. Because many 13 C labeled probes have spin-lattice relaxation times (T 1 ) as short as minutes or less, an initial concern was whether this technique could have any impact on the clinical practice. To explore the clinical feasibility of HP 13 C MRI and its potential translational impact for cancer studies, the National Cancer Institute Cancer Imaging Program held a workshop at the 2010 ISMRM in Stockholm, Sweden. A consensus document (white paper) from the workshop was published in the early of 2011 . This white paper focused on the status, challenges and translational barriers to clinical applications for HP 13 C imaging and concluded that there were no significant barriers in translation to clinical utility. Recently a first-in-human study on prostate cancer was completed with HP [1- 13 C]pyruvate in 31 patients at University of California at San Francisco, demonstrating the clinical feasibility of this technology . Another clinic study with HP [1- 13 C]fumarate is under development at Cambridge University. These studies support the idea that HP 13 C MRI can become a new modality for clinical evaluation of metabolic phenotypes of cancer. Nevertheless, in the current era of cancer genomics and with the thought that all kinds of -omics are mutually attached in some as yet to be determined way, a specific question must be asked. Can HP 13 C MRI help us understand the fundamentals of cancer beyond the metabolism?
The progress in cancer genomics achieved in past decade is reshaping our strategies in evaluation and treatment of cancer. Genetic mutations, genetic instability, and microenvironment cause cancer to evolve in a complex way. Among the many suspected mutated genes found, a small group of genes have been identified that comprise a dozen essential signaling pathways to drive tumorigenesis . With these discoveries, present research paradigms are shifting from “one disease–one target and drug” to “one disease–multiple pathway targets and combinational therapies . This suggests a transition from the traditional genetic medicine, which is based on understanding the impact of single genes on disease, to a genomics-based medicine, which considers the impact of the entire genome along with environmental factors on diseases and health. This conceptual transition imposes new challenges on the imaging community where the interest is shifting to advance quantitative imaging technology to study signaling pathways in clinic setting. Recent advances in our understanding of cancer metabolism provide substantial evidence that cancer metabolism is directly linked to many signaling pathways . With these connections between cancer genomics and cancer metabolism, and with the promise and potential of HP 13 C MRI in studies of cancer metabolism, we are posed to explore the possibility of using HP 13 C MRI to assess signaling pathways in vivo, especially those critical pathways associated with tumor growth.
This report provides a brief summary of the current understanding of signaling pathways and their relationships to cancer metabolism. The unique features of HP 13 C MRI in differentiation of metabolic pathways and a summary of current applications in assessing signaling pathways and new utilities generated by the advanced imaging techniques are also presented. While HP 13 C MRI shows potential to explore various aspects of cancer metabolism, only those issues associated with manipulations and differentiations of signaling pathways will be discussed here. Because appropriate animal models offer unique systems for studying the signaling pathways, a summary of available animal models is presented. Methods of producing HP molecules with various mechanistic mechanisms are not included in this paper. Extensive reviews on this topic can be found elsewhere .
Signaling Pathways: Where are the Targets?
Comprehensive genomic sequencing efforts in the past decade have led to the completion of mutated gene maps, known as genomics landscapes, for common human cancers . In general, these landscapes contain a few high percentage mutated genes appearing as “mountains” and a much larger number of infrequently mutated genes (<5%) appearing as “hills.” About 140 of the frequently mutated genes are identified to function as “driver” of tumorigenesis, called “driver genes.” Among these driver genes, there are 64 tumor oncogenes, the genes that have high potential to cause cancer, and there are 74 tumor suppressor genes, the genes that can cause a loss of function and lead to cancer. These driver genes can be grouped into 12 signaling pathways in cell fate, cell survival, and genome maintenance, which represent three core cellular processes in tumorigenesis. Normally, oncogenes are directly targetable (i.e., it is known that 31 of the 64 oncogenes have enzymatic activities that can be targeted by drugs). Compared to the oncogenes, the tumor suppressor genes are not targetable. However, the inactivation caused by the mutation of tumor suppressor gene may activate some growth signaling at downstream that is targetable by small molecules. Therefore, multiple targeting of downstream nodes of the same signaling pathway becomes an important strategy to apply in the presence of mutated tumor suppressor genes. For typical solid tumors with 30 to 70 mutated genes, 2 to 8 of them are driver genes. Most solid tumors are dominated by the mutated tumor suppressor genes, and a few of them can contain more than one mutated oncogene. In these cases, pathway targeting or multisite simultaneous targeting become important approaches .
Metabolic Phenotypes: What are Their Linkages to Signaling Pathways?
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Metabolic Imaging: Why HP 13 C MRI?
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HP 13 C MRI in Assessing Signaling Pathways: What Have Been Done?
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HP 13 C MRI Techniques: What’s New?
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Assessing Signaling Pathways: What’s Next?
Potential opportunities
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Animal models
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Genomics-Driven Approach
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Conclusions
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Acknowledgment
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