F-18 Fluoromisonidazole for Imaging Tumor Hypoxia: Imaging the Microenvironment for Personalized Cancer Therapy☆
Introduction
Several novel targeted anticancer agents and modalities have been introduced for personalized cancer therapy, providing new opportunities for molecular imaging in localizing and characterizing targets. Molecular imaging has the potential to be an in vivo “biopsy” as it has the ability to noninvasively image the targets in primary and metastatic lesions in a snap-shot fashion.1 Intratumoral heterogeneity remains one of the major challenges facing personalized cancer therapy both in the identification of targets and instituting therapy against them. However, the ultimate goal of personalized therapy remains to achieve cure by blocking the multiple pathways of cancer development and proliferation.2 Hypoxia, one of the major microenvironmental factors, was described by Thomlinson and Gray in 1955 and still remains a stubborn and intriguing problem in cancer management.3 The dawn of molecular imaging coupled with the availability of an expanding array of molecular probes is augmenting the role of molecular medicine in the treatment of cancer.4 This is complemented by technological advances in radiation delivery such as intensity-modulated radiotherapy (IMRT) and the availability of novel therapeutic agents,5 making personalized cancer therapy a real possibility.6, 7, 8, 9, 10
Development of hypoxia in the tumor microenvironment is a dynamic process that is primarily dictated by abnormal vasculature and results in changes in metabolism and cellular proliferation. A clear understanding of the role of these processes and the interactions between them is important when considering personalized cancer therapy.4 Typically, focal areas of hypoxia develop in many solid tumors (generally in the center of the tumor) as they grow and because of direct consequences of unregulated cellular growth that results in a greater demand of oxygen (as well as other nutrients) for energy metabolism. Hypoxia response is one of the many derepression “atavistic” traits exhibited by multicellular organisms in an attempt to express primitive unicellular characteristics as a means of “cellular survivalism.”11 Cancer cells revert back to primitive protozoanlike functions that exist quiescently in any normal cell but can be derepressed by carcinogenic transformation. The ability to survive the lack of oxygen or hypoxia is one such trait, and hypoxia response itself is a characteristic prephotosynthesis biological trait when there was lack of molecular oxygen in the atmosphere; this response trait is evolutionarily highly conserved in nature, as exemplified by the stabilization mechanism of hypoxia-inducible factor (HIF)1α under hypoxic conditions.
Section snippets
Hypoxia-Induced Changes in Tumor Behavior
A number of hypoxia-related genes have been found to be responsible for the genomic changes, and associated downstream transcription factors have been identified,12, 13 for example, expression of endothelial cytokines such as vascular endothelial growth factor (VEGF) and signaling molecules such as IL-1, tumor necrosis factor (TNF) alpha, and transforming growth factor (TGF) beta, and selection of cells with mutated p53 expression14 and increased glucose transporter activity.15 The paradoxical
Hypoxia-Inducible Factor
The seminal mechanism for cellular oxygen sensing and response appears to be mediated by a heme-protein that uses O2 as a substrate to catalyze hydroxylation of proline in a segment of HIF1α,19, 20, 21 leading to its degradation. In the absence of O2, it survives and becomes an important transcription factor, regulating proteins that promote survival of There are hypoxia-directed therapies including reagents against HIF1α itself.18, 22, 23, 24
Tumor Hypoxia and Clinical Outcome
Negative influence of hypoxia on response to radiation therapy (XRT) has long been recognized by radiobiologists with the understanding that oxygen is necessary for “fixing,” in the sense of making permanent, the radiation-induced products in tissues.25 Clinical and laboratory experience indicate that it can take three times as much photon radiation dose to cause the same cytotoxic effect in hypoxic cells as in normoxic cells.26 Boost radiation to a hypoxic subvolume (HV) could be effectively
Hypoxia as a Prognostic Marker
Fluoromisonidazole (FMISO) uptake in a solid tumor reflects the degree of hypoxia and hence the changes affecting the biology of cancer. Noninvasively identifying tumors with significant hypoxia in the tumor microenvironment along with other molecular markers of tumor biology, aggressiveness, and treatment resistance, for example, glucose metabolism and cellular proliferation, will help us in selecting the appropriate therapy early in the process as a personalized approach.17, 56, 57, 58
PET has
Methods for Evaluating Hypoxia
Currently available assays for tumor hypoxia can be largely categorized as in vivo (invasive and noninvasive) or ex vivo (invasive biopsy).8, 59 To be clinically useful, an assay must distinguish normoxic regions from the ones that are hypoxic at a level relevant to cancer—oxygen partial pressure (PO2) in the 5 mm Hg range. Beginning with clinical evaluation and polarographic electrode measurements, several methods of evaluation have been attempted but they all have been shown to have weaknesses
Heterogeneity Issues
Spatial heterogeneity in the distribution of hypoxia requires an assay that provides locoregional evaluation of the tumor in its entirety. Hypoxia that is heterogeneously distributed should benefit from a differential delivery of radiation dose to a subvolume by dose painting based on semiquantitative measures of hypoxia and radiosensitivity maps.39, 62, 63 Imaging, in general and PET in particular, has all of these advantages to overcome these limitations and to be effectively used in the
FMISO History
Hypoxia imaging was developed in our laboratory as an outgrowth of the development of radiosensitizers, which were pioneered in the 1970s to improve response of tumors to XRT.64 Radiation oncologists were searching for a compound that was not consumed like O2 and could therefore diffuse farther than O2 and radiosensitize the poorly perfused hypoxic cells.65, 66 This oxygen mimetic might reach tissue regions where PO2 was insufficient to elicit the maximal cytotoxic effect of ionizing radiation.
The Hypoxia-Glucose Metabolism Connection
Increased glucose metabolism in cancer because of aerobic glucolysis, the “Warburg effect,” is ubiquitous and has a major role in clinical oncologic imaging using F-18 FDG-PET tracer. Anerobic glycolysis can also occur and so FDG has also been suggested as an indirect marker for hypoxia.87 Because glucose metabolism is increased in cancer cells even in the presence of oxygen, FDG should not be as accurate as FMISO in reflecting the degree of tumor hypoxia. As FMISO and FDG look at two
Robust Quantification for Clinical Use
Although the tumor-to-background ratio image does not show high contrast, this does not compromise image interpretation. Hypoxia images can be interpreted in several ways, both qualitatively or quantitatively. Qualitative interpretations have been used with a scoring system to grade the uptake in a tumor compared with adjacent normal tissue.41 After extensive validation studies, we have preferred a simple but accurate quantitation method using a venous blood sample drawn during the imaging
Clinical Applications of FMISO
After extensive preclinical and clinical trials, FMISO has remained as the most highly investigated and used PET tracer for the evaluation of tumor hypoxia. Pretherapy hypoxia and FMISO uptake in predicting prognosis has been confirmed in several human studies—glioblastoma multiforme, head and neck cancer,53, 56, 58, 101, 102 lung cancer,103, 104 breast cancer,105 pancreatic cancer,9 gynecologic cancers—cervical cancer,106 and sarcoma,107 as demonstrated in the following images (Figure 4,
Summary
Our ability to use molecular imaging to characterize therapeutic targets and apply this information for therapeutic interventions is growing rapidly.40, 42, 94, 108, 109 Evaluation of hypoxia and its biological ramifications to effectively plan appropriate therapy that can overcome the cure-limiting effects of hypoxia provides an objective means for treatment selection and planning. FMISO-PET imaging of tumor hypoxia continues to be the lead radiopharmaceutical for the evaluation,
Acknowledgments
We thank Ms Lanell Peterson for her help in preparing this manuscript and numerous colleagues who have been active in developing hypoxia imaging.
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This study was supported in part by NIH, USA P01 CA042045 and S10 RR17229.