Synopsis

Multiparametric imaging enables biologic assessments of cancer because of its multidimensional nature. Multiparametric imaging enables more accurate detection, localization, characterization & response assessments. §Imaging biomarkers development frameworks are accelerating the adoption of quantitative imaging in drug development and for high precision medicine

Introduction

• Precision medicine requires detailed knowledge of changing tumor biology - biopsies (targeted/liquid) are limited for serial & heterogeneous assessments
• Functional & molecular imaging (FMI) enable noninvasive, quantitative measurements of tumor biology in-situ of the full disease burden in serial assays
• FMI methods allow imaging of therapy targets, drug PK & PD, providing markers of therapy efficacy - complementary to tissue based biomarkers

Observing tumor proliferation and cell death with diffusion MRI

• Evaluates microscopic motion of water in tissues (nm-µm scale)
• Reflects tissue architectural properties including vessels/ducts, extracellular space tortuosity & intracellular complexity

Perfusion, cellular arrangements, cell size distributions & cellular density, extracellular space viscosity, glandular structures, integrity of membranes, nuclear-cytoplasmic ratio & the unique interconnected “social” properties of intracellular water

• ADC (x10-3 mm2/s; µm2/s): net impeded water diffusivity of tissues

Programmed tumor cell death (PCD) mechanism affects ADC values

Necroptosis: “homicide”

– Large numbers of cells destroyed including stroma destruction

– Cell & nuclear lysis (membrane disruption)

– Inflammation & edema ® Marked increases in free water pool & higher ADC ↑↑*

Apoptosis: “suicide”

– Fewer cells without adjacent cell/stroma damage

– Organelles & proteins in apoptotic bodies are intact; lipid droplets present

– No inflammation

--> ADC change depends on balance between apoptosis, autophagy & tumor repopulation (modest ADC ↑)

Angiogenesis

• Angiogenesis critical for tumour growth and driven by hypoxia (pO2<10mmHg)
• Tumor vessels are disorganised, irregular and tortuous
• Structural abnormalities of tumor vessels forms the basis for differential contrast enhancement
• Development of anti-vascular drugs has made imaging of angiogenesis important in assessing therapeutic efficacy
• Traditional anatomic imaging are insensitive to detect early changes in tumor vasculature as antiangiogenic therapies are cytostatic

Dynamic contrast enhancement

Continuously monitoring after bolus IV contrast medium over a short period of time (2-7 minutes)

– Low molecular weight contrast media (<1 kDa) with no access to the intracellular space

– 2 distinct enhancement patterns observed (+ve or –ve): dynamic susceptibility ( T2*W DSC) and dynamic contrast enhancement (T1W DCE)

Evaluation methods

• Qualitative - curve shape of signal enhancement data
• Physiological indices - from contrast medium concentration changes using pharmacokinetic modeling

– DCE-MRI - extended Toft’s, St Lawrence & Lee, Shutter speed

• Model-free indices that describe one or more parts of enhancement curves

– Wash-in, wash-out gradients, max amplitude, time to peak etc

– Area under signal intensity or [Gd] curve (IAUGC)

– Hepatic perfusion index (HPI = arterial flow/total flow) for liver tumors with dual blood supply

Common quantitative kinetic parameters from T1W DCE-MRI

• Transfer constant (Ktrans; wash-in rate; min-1) – contrast flow from blood to the interstitial space; represents both blood flow and permeability surface area
• Extracellular leakage space (ve; %) – space between cells
• Rate constant (kep; wash-out rate; min-1) – backflow of contrast from extravascular extracellular space into the intravascular compartment
• Fractional blood volume (vp; %)
• Initial area under Gd curve (IAUGC60; mmol.s) – amount of contrast reaching a tissue and being retained for 60 seconds
• Enhancing pixels (%) – proportion of vascularised pixels

Common metabolic events in cancer

Increased anaerobic glycolysis even in conditions of high oxygen tension (Warburg phenomenon)

Increased pentose phosphate pathway for nucleotide synthesis (RNA/DNA)

Increased serine biosynthesis: one-carbon metabolism for amino acid & folate metabolism

Shutdown of aerobic metabolism (↑ aerobic glycolysis) results in increased glutamine metabolism to replenish the TCA cycle, for fatty acid biosynthesis & amino acid metabolism

MR spectroscopy allows limited evaluations of human tumor metabolism

Appearance or relative elevations of metabolites

• Lactate, Lipids, Choline

Reduction of metabolites that should be present → neoplastic replacement

• N-acetyl aspartate (neuronal marker)
• Citrate & polyamines (prostate glandular markers)

Concentration of metabolites are not measured, so ratios are used instead

• Choline:NAA ratio Choline+creatinine:Citrate ratio

Choline signal: conveys information on cell membrane synthesis (Kennedy pathway) and degradation

Free lipids: depicts necrosis & apoptosis in tumors

Lactate signal: reflects level of anaerobic metabolism (glucose → pyruvate → lactate)

Key challenges

1. Integration of multiple individual tests all of which can be done at a single patient visit at patient/region/lesion level (new bioinformatics challenge)
2. Understanding the biology behind the image (gene expression profiles, proteomics, serum & urinary biomarkers) & therapeutic efficacy biomarkers
3. Dealing with heterogeneity that exists within lesions, between lesions (in the same patient) between patients, and over time (in response to therapy)
4. Developing roadmaps for imaging BM qualification fit for drug development and personalized medicine

Conclusions

Multiparametric imaging enables biologic assessments of cancer because of its multidimensional nature

Multiparametric imaging enables more accurate detection, localization, characterization & response assessments

High precision medicine (right drug for the right patient, at the right time, for the right duration) requires appropriately validated imaging biomarkers (with tissue BMs)

Imaging biomarkers development frameworks are accelerating the adoption of quantitative imaging in drug development and for high precision medicine

Acknowledgements

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