C H A P T E R

1
Cancer Theranostics: An Introduction
Xiaoyuan Chen and Stephen T.C. Wong†

Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical
Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, U.S.A.
†
Department of Systems Medicine and Bioengineering, Houston Methodist Hospital Research Institute,
Weill Cornell Medical College, Houston, Texas, U.S.A.

O U T L I N E

Cancer Theranostics: A Definition 3 Theranostic Platforms 5

Theranostic Cancer Biomarkers 4 Challenges and Future Perspectives 7
Molecular Imaging in Cancer Theranostics 4 References 7
Imaging-Guided Cancer Therapy 5

CANCER THERANOSTICS: and 21 items for “theragnostics.” In the past two years,
A DEFINITION literature related to theranostics grew exponentially. As
of October 18, 2013, a PubMed search found 587 items
Theranostics is a portmanteau of therapeutics and for “theranostic,” 562 items for “theranostics,” 85 items
diagnostics. It can be diagnosis followed by therapy to for “theragnostic,” and 48 items for “theragnostics.”
stratify patients who will likely respond to a given There are pieces of information related to theranos-
treatment. It can also be therapy followed by diagnosis tics in the literature. A dedicated journal named
to monitor early response to treatment and predict Theranostics (www.thno.org/) was launched to open up a
treatment efficacy. It is also possible that diagnostics forum to exchange clinical and scientific information
and therapeutics are codeveloped. For example, nano- for the diagnostic and therapeutic molecular and nano-
platforms can be designed to codeliver imaging and medicine community and allied professions involved
therapy components; antibodies can be labeled for in the efforts of integrating molecular imaging and
imaging and conjugated with payload as antibody- molecular therapy [1]. As an evolving multidisciplin-
drug conjugate (ADC) for therapy. Cancer theranostics, ary field catering to the unmet needs of the medical
as the name implies, represents a combinatorial diag- world, cancer theranostics include but are not limited
nosis and therapeutic approach to cancer disease and to the following:
aims to reduce delays in treatment and ease patient
care, and appears to be essential for personalized can- • Identification of novel biomarkers to advance
cer treatment. molecular diagnostics of cancer
Note that in some cases theranostics is also spelled • New molecular imaging probes and techniques for
as theragnostics. A keyword search of PubMed on early detection of cancer
January 7, 2011, right before the launch of new SCI jour- • Molecular imaging guided cancer therapy
nal Theranostics, only found 95 items for “theranostic,” • Nanoplatforms incorporating both cancer imaging
63 items for “theranostics,” 29 items for “theragnostic,” and therapeutic components

X. Chen and S. Wong (Eds): Cancer Theranostics.

DOI: http://dx.doi.org/10.1016/B978-0-12-407722-5.00001-3 3 © 2014 Elsevier Inc. All rights reserved.
4 1. CANCER THERANOSTICS: AN INTRODUCTION

THERANOSTIC CANCER BIOMARKERS cells may be meaningful as potential cancer biomarkers

for early detection of cancer and personalized thera-
Sequencing the human genome has the potential to peutic strategies in clinical settings.
transform the treatment of disease and the practice of Metabolomics can be broadly defined as the study of
medicine. One of the most profound changes to medi- all metabolites produced in the body [7]. Cancer meta-
cine is the movement toward predictive, preventive, per- bolome refers to low molecular weight metabolites
sonalized, and participatory (P4) medicine [2]. As (MW ,1500 Da), including peptides, oligonucleotides,
defined by the President’s Council of Advisors on sugars, nucleosides, organic acids, ketones, aldehydes,
Science and Technology (PCAST), personalized medicine amines, amino acids, lipids, steroids, and in some cases
is the tailoring of medical treatments to the individual drugs or xenobiotics, that are germane to cancer and
characteristics of each patient, and the ability to classify their changes relative to normal tissue. In general, met-
individuals into subpopulations based on their suscepti- abolic requirements of cancer cells are quite different
bility to a particular disease or their responses to a spe- from those of most normal differentiated cells. Tumor
cific treatment [3]. Personalized medicine therefore has cells often have a high proliferation rate, thus needing
the potential to optimize targeted delivery and dosing of additional nutrients, and ultimately directing the nutri-
treatments so patients can receive the most benefit with ents into the synthesis of new biomass. With the use of
the least amount of risk, cutting out the difficulties of the metabolomics, various metabolic pathways between
current trial-and-error process many patients endure to cancer and noncancerous tissue can be differentiated.
find the correct drug and dose to treat a condition. Metabolomics is often combined with other omics disci-
Human genome, epigenome, transcriptome, prote- plines for the confirmation of data from one omics by
ome, and metabolome analysis, high-throughput pheno- another. Currently, most of the targeted cancer thera-
typic assays, and powerful computational methods pies are based on genetic, or in some cases proteomic,
allow for delineating relevant biological networks under- analyses of human tumors. The same strategy can be
lying the cellular and molecular origins of cancer [4]. applied to metabolomic analysis, evaluating the
Efforts have been spent to develop simple, noninvasive response of an individual patient to a given drug on the
tests that indicate disease risk, regression, and recur- basis of the patient’s metabolomic status.
rence, and allow early detection to monitor disease pro-
gression and to classify patients so that they can receive
the most appropriate therapy at the right time. MOLECULAR IMAGING IN
Early detection and definitive treatment of cancer CANCER THERANOSTICS
have been shown to decrease death and suffering in
epidemiologic and intervention studies. Application of Although in vitro diagnostic tests (genomic, transcrip-
genomic approaches in many malignancies has pro- tomic, proteomic, and metabolomic) can identify patients
duced thousands of candidate biomarkers for detection who will likely respond to a particular therapy, or fail to
and prognostication, yet very few have become estab- respond to a given drug or treatment regimen, in vivo
lished in clinical practice. Fundamental issues related molecular imaging is a technique that uses sophisticated
to tumor heterogeneity, cancer progression, natural diagnostic imaging equipment and systems to visualize,
history, and biomarker performance have provided characterize, and measure biological processes at the
challenges to biomarker development [5]. Technical molecular and cellular levels in humans and other living
issues in biomarker assay detection limits, specificity, systems [8]. In the clinic, molecular imaging enables phy-
clinical deployment, and regulation have also slowed sicians to peer into the living body to identify diseases,
progress. The recent emergence of biomarkers and monitor their progression, or treat medical conditions at
molecular imaging strategies for treatment selection a molecular level. It is quite different from in vitro diag-
and monitoring demonstrates the promise of cancer nostics, which typically require laboratory analysis of a
biomarkers. Organized efforts by interdisciplinary sample, such as blood or a biopsy, as molecular imaging
teams will spur progress in cancer diagnostics. can study biological processes in their own physiological
Similar to the Human Genome Project, the Human environment instead of by in vitro or ex vivo biopsy/cell
Proteome Project aims to map the entire human protein culture laboratory techniques.
set, with respect to protein abundance, distribution, There are many different modalities that can be
and subcellular localization, as well as protein interac- used for noninvasive molecular imaging, such as
tions with other biomolecules and protein functions at molecular magnetic resonance imaging (mMRI), posi-
specific time points [6]. Specific post-translational mod- tron emission tomography (PET), single-photon emis-
ifications (e.g., phosphorylation) and/or the status (e.g., sion computed tomography (SPECT), ultrasound (US),
nuclear localization) of particular proteins in cancer photoacoustic imaging (PAI), and optical imaging (OI).

I. IN VITRO DIAGNOSTICS
 THERANOSTIC PLATFORMS 5
Each has its different strengths and weaknesses, and energy spectrum to produce a larger and faster
some are more adept at imaging multiple targets than volume of tissue heating
others. • Cryoablation: Localized destruction of tissue
Through the exploration of specific molecular probes (tumors) by freezing
instead of conventional anatomical and functional imag- • Chemo-embolization: Image-guided treatment
ing, cancer molecular imaging allows characterization of delivering cancer treatment (chemotherapy) directly
tumor-related abnormalities and adoption of innovative to the tumor through its blood supply
targeted therapeutics. The advancement of molecular • Selective internal radiation therapy (SIRT):
imaging is expected to be able to diagnose cancer early, Image-guided treatments to target and treat
measure the pharmacokinetics and pharmacodynamics malignant tumors (e.g., liver cancer) that cannot
of newly developed drugs, and to monitor cancer ther- be removed by surgery
apy response, predicting the effectiveness of a given • Dose painting: Nonuniform radiation dose delivery
therapy, preceding the anatomical size change measured within the tumor volume by targeting radioresistant
by conventional diagnostic modalities such as computed areas defined by functional imaging
tomography (CT) and MRI.

IMAGING-GUIDED CANCER THERAPY THERANOSTIC PLATFORMS

There have been many platforms that can combine
Interventional radiology (IR) uses X-rays and other
imaging and therapy for optimizing efficacy and safety
imaging techniques to “see” inside the body while
of therapeutic regimes. Here we will discuss platforms
guiding catheters and other very small instruments
related to light, magnetism, and sound as examples to
through the body to the site of a problem, treating a
illustrate the potential of cancer theranostics.
variety of medical disorders without surgery. In the
The use of light as a remote-activation mechanism
last two decades, interventional radiology has experi-
for drug delivery has received increased attention due
enced unprecedented growth [9]. Advances in imaging
to its advantages in highly specific spatial and tempo-
equipment and tracking technology have facilitated
ral control of compound release. Phototriggered cancer
the development of new effective and efficient diagno-
theranostic constructs may include photodynamic,
sis and treatment options. Minimally invasive inter-
photothermal, or phototriggered chemotherapy [10].
ventions are replacing more costly open surgery, and
Photodynamic therapy (PDT) is a treatment that uses
this trend is seen particularly in the field of oncology.
a photosensitizer (PS), or photosensitizing agent, and a
Advantages of such interventions include shortened
light of appropriate wavelength, which in the presence
patients’ recovery time, improved patient comfort, and
of oxygen, will lead to the generation of cytotoxic species
lowered risk of complications.
and consequently to cell death and tissue destruction.
During minimally invasive procedures, clinicians
Photothermal therapy (PTT) of cancer involves irra-
rely on combined information from different sources to
diation of cancerous tissue with electromagnetic radia-
build up a mental picture for their actions. Typically, a
tion (VIS-NIR light) to cause thermal damage. Unlike
source of static anatomical information obtained before
PDT, where reactive oxygen species (ROS) are gener-
a procedure, such as a CT scan or a magnetic resonance
ated by excitation of a PS, in PTT the laser energy is
(MR) scan, is combined with real-time devices such as
absorbed by the photoabsorbers and is converted to
ultrasound scanner and interventional device tracker.
heat. PTT can cause biological changes ranging from
The central idea around image-guided intervention is
protein structural changes to carbonization of the tis-
how position of the interventional device can be
sue. Similar to PDT, PTT has spatial specificity and
detected in real time and be superimposed on the
minimal invasiveness, which allows only the diseased
patient’s anatomic image and visualized simulta-
tissue to be irradiated while the surrounding benign
neously for guiding the procedures.
tissue is minimally damaged.
An array of localized, minimally invasive proce-
Phototriggered drug release is an intelligent design
dures include:
of drug conjugates that have light responsiveness. It is
• Radio frequency ablation (RFA): Localized expected that light (UV, visible, and NIR) can trigger
destruction of tissue (tumors) by radio frequency the release of a drug molecule at the right dose, proper
waves or heating timing, and the exact location. The controlled release is
• Microwave ablation: A newer ablation technology often controlled by the wavelength, duration, intensity,
that uses electromagnetic waves in the microwave and location of the light.

I. IN VITRO DIAGNOSTICS
6 1. CANCER THERANOSTICS: AN INTRODUCTION

Different microscopic to whole-body optical imag- chemotherapeutics or bioactive molecules (double-

ing techniques based on absorption, scattering, stranded DNA, small interfering RNA, miRNA, and
fluorescence, transmission, and reflection properties of proteins).
tissue constituents are available for various bio- Reported theranostic applications of magnetic nano-
medical applications. Commonly used optical imaging particles include: imaging (serving as contrast agents
modalities include but are not limited to phosphores- for MRI); therapy (chemotherapy via controlled drug
cence, bioluminescence, fluorescence, Raman, and release and hyperthermia via heat generation in an
photoacoustic imaging. Light responsiveness is attrac- alternating magnetic field); and cell separation (cell
tive as a cancer theranostic method for its sensitive labeling/tracking and isolation using magnetic force).
and specific diagnosis, precise external modulation of Ultrasound is an oscillating sound pressure wave
the site, and rate of delivery of heat, photosensitizer, with a frequency greater than the upper limit of the
or drug of interest. human hearing range. Ultrasound contrast agents are
Conventional widefield microscope-based optical mostly gas-filled microbubbles with a high degree of
imaging techniques are unsuitable for imaging thick tis- echogenicity. Contrast-enhanced ultrasound can
sue and often restricted to open surface or exposed enhance the ultrasound backscatter, or reflection of the
areas of the body such as skins and eyes, despite their ultrasound waves, to produce a unique sonogram with
high spatial resolution at the µm range, owing to the increased contrast due to the high echogenicity differ-
limited depth penetration of light into tissues and ence [14]. Contrast-enhanced ultrasound can be used
blurred, out-of-focus background signal [11]. to image blood perfusion, blood flow, and receptor
Endomicroscope imaging techniques are thus devel- density in tumors and organs.
oped to achieve optical sectioning by removal of the High-intensity focused ultrasound (HIFU, or some-
background intensity using the confocal principle to times FUS for focused ultrasound) is a modality of
obtain high-resolution histology-like images from inside therapeutic ultrasound that applies high-intensity
the human body in real time. The design of an endomi- focused ultrasound energy to locally heat and
croscope either includes a miniaturized scanning head destroy diseased or damaged tissue through ablation
at the distal tip of the optical imaging probe or performs [15]. In addition to HIFU, other modalities include
the scanning outside of the patient and uses a fiber bun- ultrasound-assisted drug delivery, ultrasound hemo-
dle to transfer the scan pattern to the tissue [12]. stasis, ultrasound lithotripsy, and ultrasound-assisted
Magnetic resonance imaging (MRI) has a critically thrombolysis.
important role in molecular imaging and clinical diag- If the biophysiology of ultrasound is carefully used
nosis because it is noninvasive and is capable of pro- and the biophysics of ultrasound is under control, it
ducing images with high spatial and temporal can help move drugs into cells by enhancing extrava-
resolution. Approximately 35% of clinical MR scans sation and interstitial transportation, increase the
need contrast agents to improve their sensitivity and permeability of cell membranes, and help drugs and
diagnostic accuracy. For example, superparamagnetic genes escape from the endosome within the
iron oxide (SPIO) nanoparticles are the prevailing T2 cytoplasm.
contrast agents, especially for lesion detection. Ultrasound-responsive nanoparticles are drug-
It is also known that in the presence of time-varying loaded ultrasound contrast agents that contain a small
magnetic field, magnetic nanoparticles can realign amount of gas. Coencapsulation of a pharmaceutical
their magnetic moments to the applied field [13]. As along with a gas renders the particles acoustically
the excitation frequency of the magnetic field active, allowing contraction and expansion in response
increases, magnetic moments of nanoparticles lag the to ultrasound compression and rarefaction [16]. If the
applied field at a given angle. The resulting power dis- oscillating bubble grows to a certain point exceeding
sipation process associated with this misalignment can the strength of the vesicle, it will rupture and release
increase bulk temperature of magnetic nanoparticles its payloads. A number of ultrasound-responsive
and their surroundings. This phenomenon can be used nanoparticles have been developed, with average dia-
as a method of hyperthermia, suitable for cancer treat- meters of 0.8 to 10 µm, including microbubbles,
ment in low-perfusion tissue. In so-called magnetic micelles, liposomes, metallic nanoparticles, polymeric
fluid thermotherapy, magnetic fluids containing mag- nanoparticles, dendrimers, carbon nanotubes, and
netic nanoparticles (e.g., iron oxide) are delivered to quantum dots. Many therapeutic agents such as che-
the cancer and then heated by an external alternating motherapeutics, antiangiogenics, and genes can be
magnetic field, resulting in hyperthermia or thermo- simultaneously delivered by these nanocarriers to
ablation of cancer tissue. tumor sites to enhance therapeutic effectiveness.
Magnetic nanoparticles can also be used for site- Additionally, an agent containing both imaging and
specific magnetic targeting, and as carriers for therapeutic materials can be utilized as a

I. IN VITRO DIAGNOSTICS
 REFERENCES 7
multifunctional platform for cancer theranostics. In • Regulatory hurdles: There is a lack of clear FDA
addition, multiple therapeutic modalities such as a rules to provide adequate oversight of
combination chemotherapy and hyperthermia can be nanotheranostics.
coadministered to take advantage of the synergistic • Nanotoxicity: A variety of nanoparticles have been
effects of combined therapies. shown to induce cytotoxicity, genotoxicity, and
immunotoxicity related to their nanometer size.
The potential benefits and the possible adverse
CHALLENGES AND FUTURE health effects of nanotheranostics need to be
PERSPECTIVES considered.
• Economy: Although the “value” of nanomedicine
Personalized oncology is evidence-based, individu- appears to be growing, there is probably still a
alized medicine that delivers the right care to the right long way to go for emerging blockbuster
cancer patient at the right time and results in measur- nanotheranostic formulas for ultrasensitive marker
able improvements in outcomes and a reduction in detection, in vivo imaging of cancer targets,
healthcare costs. and tumor-specific delivery of therapeutics.
The essence of personalized oncology lies in the smart Nevertheless, coupling therapy with diagnosis
use of theranostic biomarkers. These biomarkers can be together into a single platform now provides
from tissue, serum, urine, or imaging and must be vali- industrial vendors and pharmaceutical companies
dated rigorously. Advances in genome sequencing and more incentive than conventional diagnostic
other omics technologies have progressed at a rapid molecular imaging agents alone to push for clinical
pace and provide large amounts of big data for identifi- trials for higher perceived values of the final
cation of more reliable and novel molecular biomarkers products.
and for delineation of underlying disease pathways and In summary, it is increasingly clear that a better
crosstalks for early prediction, detection, diagnosis, understanding of the underlying mechanisms of can-
prognosis, and monitoring of diseases. Tools for imple- cer, identification of new definitive biomarkers, devel-
menting preemptive medicine based on molecular diag- opment of tools for ultrasensitive and quantitative
nostics and interventions will have the potential to measurement of theranostic biomarkers, ability to visu-
improve cancer prevention. Molecular imaging technolo- alize cancer at its earliest stage with high resolution
gies that truthfully visualize and quantify hallmarks of and in a quantitative manner, prediction of early
cancer are already influencing the early detection and response to cancer therapy preceding anatomical size
management of cancer patients. Combination of in vitro change and metastasis dissemination, and new inter-
molecular diagnostics and whole-body molecular imag- ventional and molecular targeted treatments, especially
ing readouts is expected to grow significantly in the nanotherapeutics, will all be critical for future individ-
future and will be integrated into new cancer therapies ualized cancer treatment. The integration of all these
as an integrated package, which will provide greater effi- together as cancer theranostics is poised to revolution-
ciency, value, and cost savings. ize our future healthcare delivery and promises to sat-
A wide variety of nanoplatforms that are based on isfy the unmet needs in ultimate eradication of cancer.
diverse nanostructures showed great potential as cancer
theranostics. However, although considerable efforts
have been directed to the development of theranostic
nanoplatforms and approaches, theranostic nanoparti- References
cles have yet to be employed in a clinical setting. We [1] Chen XS. Introducing theranostics journal - from the editor-in-
have to bear in mind the following challenges: chief. Theranostics 2011;1:1 2.
[2] Bradley WG, Golding SG, Herold CJ, Hricak H, Krestin GP,
• Scaled up synthesis: Many complicated Lewin JS, et al. Globalization of P4 medicine: predictive, person-
nanoplatforms with composite structures alized, preemptive, and participatory summary of the proceed-
synthesized in one lab can be difficult to reproduce ings of the Eighth International Symposium of the International
Society for Strategic Studies in Radiology, August 27 29, 2009.
in another lab and to manufacture in large-scale Radiology 2011;258(2):571 82.
quantities. Sterility of nanoformulas is another issue. [3] Food and Drug Administration. Building the Infrastructure to Drive
• Rationale for combined imaging and therapy and Support Personalized Medicine. Available from: www.fda.gov/
components within one nanoformula: Imaging and AboutFDA/ReportsManualsForms/Reports/ucm274440.htm
[4] Tian Q, Price ND, Hood L. Systems cancer medicine: towards
therapy have different requirements for tumor
realization of predictive, preventive, personalized and participa-
targeting and pharmacokinetics. Codelivery of tory (P4) medicine. J Intern Med 2012;271(2):111 21.
imaging and therapy may not have significant [5] Brooks JD. Translational genomics: the challenge of developing
synergistic effect for clinical application. cancer biomarkers. Genome Res 2012;22(2):183 7.

I. IN VITRO DIAGNOSTICS
8 1. CANCER THERANOSTICS: AN INTRODUCTION

[6] Honda K, Ono M, Shitashige M, Masuda M, Kamita M, Miura [12] Jabbour JM, Saldua MA, Bixler JN, Maitland KC. Confocal
N, et al. Proteomic approaches to the discovery of cancer bio- endomicroscopy: instrumentation and medical applications.
markers for early detection and personalized medicine. Jpn J Ann Biomed Eng 2012;40(2):378 97.
Clin Oncol 2013;43(2):103 9. [13] Zhao Q, Wang L, Cheng R, Mao L, Arnold RD, Howerth EW,
[7] Aboud OA, Weiss RH. New opportunities from the cancer et al. Magnetic nanoparticle-based hyperthermia for head &
metabolome. Clin Chem 2013;59(1):138 46. neck cancer in mouse models. Theranostics 2012;2:113 21.
[8] Pysz MA, Gambhir SS, Willmann JK. Molecular imaging: current [14] Postema M, Gilja OH. Contrast-enhanced and targeted ultra-
status and emerging strategies. Clin Radiol 2010;65(7):500 16. sound. World J Gastroenterol 2011;17(1):28 41.
[9] Arai Y. Clinical trials of interventional oncology. Int J Clin [15] Malietzis G, Monzon L, Hand J, Wasan H, Leen E, Abel M, et al.
Oncol 2012;17(4):301 5. High-intensity focused ultrasound: advances in technology and
[10] Rai P, Mallidi S, Zheng X, Rahmanzadeh R, Mir Y, Elrington S, experimental trials support enhanced utility of focused ultra-
et al. Development and applications of photo-triggered thera- sound surgery in oncology. Br J Radiol 2013;86(1024):20130044.
nostic agents. Adv Drug Deliv Rev 2010;62(11):1094 124. [16] Sirsi SR, Borden MA. Advances in ultrasound mediated gene
[11] Wilson T. Optical sectioning in fluorescence microscopy. therapy using microbubble contrast agents. Theranostics 2012;
J Microsc 2011;242(2):111 16. 2(12):1208 22.

I. IN VITRO DIAGNOSTICS