Molecular Imaging of Cancer

_____ people will develop cancer during their lifetime

Molecular Imaging

Non-invasive assessment of the dynamics of a given biological process at the cellular and molecular level in the physiological intact organism over time

imaging biomarkers

Molecular imaging uses ________ rather than pictures of the presence/absence of the disease

characteristic that can be objectively measured from imaging data as an indicator of normal processes or response to therapeutic intervention

An imaging biomarker is defined as a…

difference between the cancer and surrounding normal tissue

A general principle of molecular imaging of cancer is cancer can be imaged if there is…

exploits structural or functional differences to provide a “contrast” between normal and diseased tissue

A general principle of molecular imaging of cancer is each modality…

transmission of a signal through the body or emission of a signal from the body

A general principle of molecular imaging of cancer is that imaging requires…

structural, functional, and molecular information

A general principle for molecular imaging of cancer is that imaging will provide some combination of…

molecular imaging techniques, specific tracers, cancer-specific biomarkers

Molecular phenotypes of cancer can be determined by molecular pathology with _________ using _________ for visualisation and characterisation of _________.

Pharmacodynamics

Study of how drugs affect the body through biochemical, physiological, and molecular effects of drugs and their mechanisms of action

Pharmacokinetics

Study of how the body interacts with drugs through processes of absorption, distribution, metabolism, and excretion

structure (anatomy), function (biological process), qualitative visual (pharmacodynamic), semi-quantitative (pharmacokinetic)

Different imaging methodologies can be based on imaging either _______ or ______. This can give _________ and _______ information in vivo.

structural information, computerised tomography (CT)

Structural imaging provides ______. ________ is an example of a structural imaging method.

mechanism of action, target receptor binding equilibrium process

Pharmacodynamic functional imaging provides information on _________, e.g. ________.

processes happening in living organisms, liberation/absorption/distribution/metabolism/elimination (LADME)

Pharmacokinetic functional imaging provides information on _________ using the principles of __________.

laboratory-to-humans research, i.e. moving discoveries and knowledge into initial clinical testing

T1 translational research involves…

all phases of clinical trials

Clinical research includes…

evidence-to-practice research, i.e. implementing best practices in prevention and treatment to the community

T2 translational research involves…

disease biomarker identification and validation > molecular probe development > preclinical biomarker imaging > clinical translation

The imaging biomarker research path is:

anatomical, emitting high frequency sound waves (>20,000 Hz) from a transducer that is reflected back from the internal organ under examination

Ultrasound is a ______ imaging methodology that works by…

sound speed, image algorithm used, backscattering, and attenuation of sound

Imaging contrast in ultrasound depends on…

widely available/safe/low cost, presence of bone and air artefacts causing poor sound wave transmission

The pros of ultrasound imaging is that is it ______________, while challenges include ___________.

depth of penetration

A limitation of ultrasound imaging is…

contrast agents, tumour blood flow and perfusion during tumour angiogenesis, Targeted microbubbles, lack of tumour specificity

Ultrasound can get some functional imaging information through ________, mostly involving _________. _________ were recently developed to enhance imaging contrast, however a challenge is ________.

measuring tumour size and volume quantification, blood flow evaluation, targeted injections and biopsies, contrast agents determination of real-time tumour perfusion, cardiovascular blood flow

Applications of ultrasound imaging:

using low energy X-rays to determine structures based on differences in X-ray absorption

The “plain” X-ray works by…

density and elemental composition of the absorbing material, high atomic mass number dependency

X-ray absorption is determined by __________. There is a _______ for low energy X-ray absorption by the photoelectric effect.

Bremsstrahlung principle, electrons are accelerated in a vacuum tube and allowed to interact with a metal like tungsten, deflected by the metal nuclei and the kinetic energy is converted to X-ray radiation

X-rays are produced by utilising the ________. In this process, ____________. The electrons slow when they are _____________.

high resolution and high contrast

Modern X-ray technology provides _______ images.

internal structure of an object can be reconstructed from multiple projections of the object

The principle behind CT is that….

X-ray tube circling the patient, X-ray beams that pass through the patient and is absorbed by a ring of detectors, absorption characteristics of the tissue it passes through

X-ray CT (CAT) scans use a _________ that produces ___________. The intensity of the X-ray beam that reaches the detectors is dependent on __________.

one continuous volume of data for the entire region scanned

Unlike the separate data sets produces for each individual slice in standard CT, spiral CT produces…

speed of image acquisition and removal of motion artefacts

Advantages of spiral CT compared to standard CT include…

high resolution images, non-invasive, plain X-ray has low radiation dose, inexpensive and available, whole body imaging possible, high resolution microCT animal imaging instrumentation available

Strengths of X-ray imaging include:

can not differentiate isodense soft tissue lesions from surrounding tissues, CT has high radiation dose, can not differentiate between surgical site disruption of tissue and residual or recurrent tumour, measures tissue structure but not activity or function

Weaknesses of X-ray imaging include:

hydrogen-1 and phosphorus-31 and sodium-23 and carbon-13 and fluorine-19, hydrogen-1, high isotopic abundance and high tissue concentration

_____________ are nuclei that have been imaged in vivo using MRI. ____ is by far the most important being in ___________________.

nuclei that have a magnetic moment, aligning them in a strong stable magnetic field, exciting them to a high energy state with pulses of radiofrequency radiation, return to ground state and emit radiofrequency radiation

MRIs can observe energy emissions from __________ which are induced to emit energy by __________ and then ________. They then ________.

T1 signal, one slower emission due to growth of longitudinal magnetic vector, t2 signal, one faster emission due to loss of transverse magnetic vector from spinning nuclei

Two distinct emissions from excited spinning nuclei in MRI occur: _____ (which is __________) and _____ (which is __________).

spin-lattice relaxation, spin-spin relaxation

The MRI T1 signal is also called ________, while the T2 signal is also called ______.

stable high magnetic fields produced with superconducting magnets, physics of magnetic field generation, 11 tesla

MRI requires ___________. The ____________ may limit fields for human scanners (at present there are clinical machines up to ______).

structural, tissue differences related to physical and chemical environment

Basic MRI is a _______ imaging technique relying on ________.

changes in blood flow characteristics (rate, volume, oxygenation), rapid sequential imaging

Functional MRI (fMRI) is a modern enhancement of MRI technology whereby ___________ are determined by _______. This is mostly used in neurological studies.

specific output signals of nuclei, endogenous biomolecules or the distribution of tracer drugs incorporating these nuclei

The ability of MRI to be tuned to _________ has allowed the use of techniques to determine tissue function based on _________.

Magnetic resonance spectroscopy, unique fingerprint associated with tissue volume

_____________ (MRS) allows cellular biomolecules to be observed as a _________. This is a new and rapidly developing molecular imaging technique.

high resolution images, non-invasive, no ionising radiation, whole body imaging possible, can be used in some circumstances for functional and molecular imaging, animal imaging instruments at high field are available

Strengths of MRI imaging include:

expensive instruments and waiting times, imaging can be stressful for some patients, can not differentiate between surgical site disruption of tissue and residual or recurrent tumour, measures tissue structure in standard application but not activity or function

Weaknesses of MRI imaging include:

detection of light emission through laser technology using a sensitive photon imaging device in a dark box, bioluminescent visible light

The principle of optical imaging is ____________. This measures _________.

visible or near infra-red light, in vivo pre-clinical research, GFP, fluorophores

Optical imaging subtype fluorescence imaging (FLI) detects __________ and is an emerging method in ________. Fluorescence proteins such as _______ and _______ can be used.

luciferase-expressing breast cancer cells in mice, therapeutic effects

An example of FLI in in vivo pre-clinical research is ___________ to analyse _______.

very limited, absorption and scatter of light causing diffuse signals, Degree of scatter, depth and travel distance of the emitted signal, small objects like nude mice

Applications of FLI in humans are ______ because of _________. ________ depends on _________, therefore best signals are from ________.

internally deposited gamma-emitting radioactive drugs

SPECT and PET imaging use _________.

single photon emitters such as iodine-123 incorporated into radiopharmaceuticals with particular biological distribution characteristics, planar, 3 dimensional, single photon emission computerised tomography (SPECT)

Conventional nuclear medicine uses _________. Both ______ and _____ imaging with _________ are possible.

Positron emission tomography, positron emitters such as carbon-11 or oxygen-15 incorporated into radiopharmaceuticals, positron annihilation

________ (PET) uses _________ and the features of _________ to produce an image.

expensive camera systems, more or less activity in the tumour relative to surrounding tissue

Both SPECT and PET use _______ to record imaging data and contrast requires _________.

radiotracer is prepared, administered, and allowed to distribute and localise radioactivity > radionuclide decays with the production of penetrating gamma rays that exit the body > patient is imaged using multiple views with a gamma camera > radionuclide disappears from body by biological elimination or physical decay

SPECT steps:

can detect lesions before they are visible by X-ray or MRI, whole body imaging possible with capability to detect metastatic disease, mature technology available in most major centres, tracers well developed and available, minimally invasive, animal imaging systems available

Strengths of SPECT imaging include:

relatively poor resolution compared to MRI and CT, some complexity in preparing radiopharmacueticals, ionising radiation injected, medical personnel receive radiation doses, relatively expensive camera systems, no universal agent for all tumours, not generally quantitative

Weaknesses of SPECT include:

compact particle accelerator used in nuclear medicine to produce short-lived radionuclides, hot cells, radioactive containment chambers

A PET cyclotron is a _________. Products can be stored in ______, which are _______.

reduced cost, many animal models for human disease, and PET allows the same animal to be studied repeatedly

Some researchers use small animal PET because of…

target specificity, high membrane permeability to reach target, rapid blood clearance, no or slow peripheral metabolism, low non-specific binding to increase target-to-nontarget ratio > 1, small number of transport and biochemical reaction steps to allow kinetic modelling

Molecular probes for imaging (i.e. radiotracers) must meet selection criteria:

Michaelis-Menten, competing with endogenous substrates for the same enzyme binding site

Probes based on enzyme-mediated transformations use the ______ equation and work by…

phosphorylation through hexokinase, phosphorylation through thymidine kinase, and phosphorylation through choline kinase

Examples of probes targeting tumour enzymes include:

rate of enzyme-catalysed reactions (V) as a function of substrate concentration ([S]), V = (Vmax*[S]) / (Km + [S]) where Vmax is the maximum velocity reached when the enzyme is fully saturated with substrate and Km is the Michaelis constant

The Michaelis-Menten equation models _________. The formula is…

low Vmax and high Km, compete unfavourably with the endogenous substrate thus there is reduction of metabolic trapping and low signal, high Vmax and low Km, suitable enzyme kinetics and high rate of metabolic trapping thus good signal

Probes based on enzyme-mediated transformation must have favourable kinetic characteristics. In case 1, the probe has ___________ thus will _________. In case 2, the probe has _________ thus has __________.

[fluorine-18]FDG

An example of a probe based on enzyme-mediated transformations is…

receptor systems or neurotransmitter presynaptic reuptake or enzymes, high specific activity

Probes based on stoichiometric binding interactions, for example based on _______________, must have ___________.

FDOPA (amino acid), [carbon-11]DTBZ (tetrabenazine derivative), and [carbon-11]WIN (cocaine-derivative)

Example of a probe based on stoichiometric binding interactions are…

high glucose metabolism, enhanced glycolysis in tumour cells, glucose, GLUT1, phosphorylated by hexokinase and cannot undergo further glycolysis, accumulates in the cell due to low membrane permeability (intracellular trapping)

[¹⁸F]FDG is used to image _______, such as ________. It mimics ______ and is therefore transported into the cell by _______. It is then ________, therefore it ________.

FES, PET tracer, estrogen sensitive breast cancer

16α-[¹⁸F]Fluoro-17β-estradiol (____) is a ______ used for imaging ______.

3-O-Methyl-[¹⁸F]FDOPA, cross the BBB

________ is a PET tracer that can ______, therefore it can be used to image brain tumours.

[¹⁸F]DOPA, image dopaminergic neurons that decarboxylate Dopa to dopamine

_______ is a PET tracer used to __________, primarily for diagnosing Parkinson’s disease.

[¹⁸F]Fluoride, fluoride is incorporated into the bone matrix by associating with positively charged calcium

______ is a PET tracer that is used to image bone cancers because ________.

[¹¹C]Choline, localises to increased phospholipid synthesis in tumour cells

_______ is a PET tracer that is primarily used to detect prostate cancer because it _______.

almost all tumours are imaged with FDG, quantitative imaging possible, relatively non-invasive, functional and molecular imaging can be performed, animal imaging is well developed at high resolution

Strengths of PET imaging include:

low spatial resolution, requires local isotope production with a cyclotron, complex radiopharmaceutical preparation, very expensive infrastructure, not readily available at major centres, injected radionuclide gives radiation doses to patients and staff

Weaknesses of PET imaging include: