Molecular imaging for personalized cancer care
Moritz F. Kircher, Hedvig Hricak*, Steven M. Larson
Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room C-278, NY 10065, USA
A R T I C L E I N F O
Received 31 October 2011
Received in revised form
20 February 2012
Accepted 20 February 2012
Available online 10 March 2012
MR spectroscopic imaging
A B S T R A C T
Molecular imaging is rapidly gaining recognition as a tool with the capacity to improve ev-
ery facet of cancer care. Molecular imaging in oncology can be defined as in vivo character-
ization and measurement of the key biomolecules and molecularly based events that are
fundamental to the malignant state. This article outlines the basic principles of molecular
imaging as applied in oncology with both established and emerging techniques. It provides
examples of the advantages that current molecular imaging techniques offer for improving
clinical cancer care as well as drug development. It also discusses the importance of mo-
lecular imaging for the emerging field of theranostics and offers a vision of how molecular
imaging may one day be integrated with other diagnostic techniques to dramatically in-
crease the efficiency and effectiveness of cancer care.
ª 2012 Federation of European Biochemical Societies.
Published by Elsevier B.V. All rights reserved.
Molecular imaging is rapidly gaining recognition as a tool that
has the capacity to improve every facet of cancer care. The
growing demand among physicians, patients, and society for
personalized care is increasing the importance of molecular
imaging and shaping the development of biomedical imaging
as a whole. Anatomic imaging will continue to play a role in
cancer management, including cancer detection and staging
and assessment of treatment response. Applications of
anatomical imaging are constantly advancing. For example,
in the assessment of tumor response, tumor volumemeasure-
ment on cross-sectional imaging is being developed and may
eventually replace conventional one- or two-dimensional tu-
mor measurement. Over time, biomedical imaging will be-
come more and more multimodal in nature, as different
anatomic and molecular imaging techniques can complement
each other. Already, positron emission tomography (PET),
which is commonly performed with the radiotracer18F-flu-
* Corresponding author. Tel.: þ1 212 639 7284; fax: þ1 212 794 4010.
E-mail address: firstname.lastname@example.org (H. Hricak).
1574-7891/$ e see front matter ª 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
available at www.sciencedirect.com
M O L E C U L A R O N C O L O G Y 6 (2012) 182e195
sectional imaging in the form of PET/computed tomography
(PET/CT). It is inevitable that combined PET/magnetic reso-
nance imaging (MRI)/MR spectroscopic imaging (MRSI), as
well as optical imaging, will also play important roles in onco-
logic imaging in the future. Judging from recent research, it is
likely that refined molecular imaging will provide a personal-
ized molecular fingerprint of individual tumors, as a basis for
novel treatment algorithms. Furthermore, molecular imaging
will facilitate more rapid development of new drugs, including
theranostic drugs (i.e., agents that combine diagnostic and
Molecular imaging in oncology can be defined as in vivo
characterization and measurement of the key biomolecules
and molecularly basedeventsthatarefundamental to thema-
lignant state. This definition is deliberately broad, and incor-
porates both cellular and molecular features of the cancer
phenotype. Specifically, molecular imaging interrogates the
abnormal molecules as well as the aberrant interactions of al-
tered biomolecules that are the basis for neoplasia. In con-
trast, “classical” diagnostic imaging primarily images the
advanced manifestation of cancer.
This article outlinesthe basicprinciplesof molecular imag-
ingas appliedwith bothestablished and emergingtechniques.
It then provides specific examples of the advantages that cur-
rent molecular imaging techniques offer for improving each
step of clinical cancer care as well as drug development. Fi-
nally, it discusses the importance of molecular imaging for
the emerging field of theranostics and offers a vision of how
molecular imaging may one day be integrated with other diag-
nostic techniques to dramatically increase the efficiency and
effectiveness of cancer care.
2.Principles of molecular imaging in oncology
Although molecular imaging has existed for decades, recent,
tion of molecular imaging is interdisciplinary collaboration
across many fields, including radiology, nuclear medicine,
pharmacology, chemistry, molecular and cell biology, physics,
mathematics, and engineering. An array of sophisticated mo-
lecular imaging technologies are now available for use in pre-
clinical and clinical settings (Bradbury and Hricak, 2005;
Grassi et al., 2008; Kircher et al., 2011; Kircher and Willmann,
in press-a, in press-b; Weissleder and Pittet, 2008; Zavaleta
et al., 2011). These include positron emission tomography
(PET), single photon emission computed tomography (SPECT),
in press-b; Weissleder and Pittet, 2008).
Molecular imaging can be achieved using either endoge-
nous information or exogenous probes. MRSI and certain opti-
cal techniques are examples of molecular imaging using
endogenous information. MRSI combines the ability of spec-
troscopy to acquire a large volume of metabolic information,
with the ability of imaging to localize information spatially.
Although phosphorus (31P) and carbon (13C) MRSI are possible,
proton (1H) MRSI is the technique most often used in clinical
settings. On1H MRSI tumor spectra contain resonances from
taurine, total choline (choline, phosphocholine, and glycero-
phosphocholine), total creatine (phosphocreatine and crea-
tine), and lactate (Howe et al., 1993); generally, tumors
exhibit elevated choline and lactate levels (W.N, 1992). Novel
optical imaging techniques such as intrinsic Raman spectros-
copy can also achieve molecular imaging by using endoge-
nous information. Raman spectroscopy is based on detection
of photons that have changed their wavelength after interac-
tion with specific atomic bonds in molecules, and therefore al-
lows elegant characterization of the underlying tissue
composition (Zavaleta et al., 2011). The ability of Raman spec-
troscopy to discriminate malignant from benign tissues has
already been demonstrated in a multitude of both preclinical
and clinical studies (Zavaleta et al., 2011).
Most molecular imaging approaches, however, rely on the
use of exogenous probes to provide imaging signal or contrast.
In some cases, the probe may be a conventional contrast
agent. For example, with contrast-enhanced (DCE)-MRI, im-
ages are acquired sequentially during the passage of an agent
such as gadolinium within a tissue of interest. DCE-MRI is not
an intrinsically molecular method, but rather provides an in-
direct assessment of molecular processes that influence blood
flow and vascularization (for this reason, it is mentioned here
but not described in detail in the section on applications). As
changes in tumor vascularity can often be detected earlier
than changes in tumor size, DCE-MRI has been used to moni-
tor the early effects of, and predict longer-term responses to,
cancer treatments such as anti-angiogenesis drugs, androgen
deprivation therapy for prostate cancer, radiotherapy for rec-
tal and cervical cancers, and chemotherapy for bladder and
breast cancers (Padhani and Leach, 2005).
The majority of molecular imaging probes have a more so-
phisticated design and include both a targeting component
(e.g. an antibody, peptide, or small molecule) and a signaling
component (e.g. a radionuclide for PET or SPECT, a fluoro-
chrome for optical imaging, or a paramagnetic chelate for
MRI (Kircher and Willmann, in press-a, in press-b)). Molecular
imaging probes can be broadly classified into four categories
(Weissleder and Pittet, 2008):
1) Phenotypic probes are used to assess general features of ma-
lignantphysiology,such as metabolicchanges secondary to
oncogenic activation (Plathow and Weber, 2008), angiogen-
esis (Cai and Chen, 2008; Cai et al., 2008), cell proliferation
(Bading and Shields, 2008; Conti et al., 2008), hypoxia
(Blankenberg, 2008a, 2008b; Strauss et al., 2008), and the ex-
pressionof certain receptors or antigens in tumor cells (e.g.,
hormone receptors and peptide receptors) (Mankoff et al.,
2008; Peterson et al., 2008).
An example of phenotypic imaging is PET with the radiola-
beled glucose analogue18F-FDG, a marker for the elevated glu-
cose metabolism that occurs in most cancers. Recently, a new
type of phenotypic molecular imaging technology has
emerged, termed “hyperpolarized MRI”. By creating an artifi-
cial non-equilibrium of spins, hyperpolarized MRI increases
the sensitivity of MRI by a factor of 10,000 or more
(Kurhanewicz et al., 2011). This strong signal enhancement
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