IMAGING inONCOLOGY

Biomedical EngineeringP Verdonck

D De NaeyerS Staelens

Gastro-oncologyM Peeters

N Van DammeV Casneuf

RadiologyP Smeets

RadiotherapyT Boterberg

Nuclear MedicineC Van De Wiele

Surgical OncologyW CeelenI Debergh

Imaging of Angiogenesis

• Direct: In Vivo Microscopy; molecular probes• Indirect

– Blood volume– Vessel surface area– Vessel permeability– Vessel ‘normalization’

Neoplastic vessels are morphologically and functionally deficient

• Highly irregular and tortuous • Dependent on cell survival factors (VEGF) • Hyperpermeable

– deficient pericyte coverage– absence of a basement membrane– deficient intercellular junctions– presence of cellular lacunae– vascular mimicry

• Resulting in abnormal microenvironment: hypoxia, low pH, interstitial hypertension

Corrosion casting – SEM; Konerding et al. BJC2001

Hyperpermeability of tumor vessels is important

• Results in increased interstitial fluid pressure

• Enhances macromolecular leakage

• Permeability change is a surrogate marker of angiogenesis

The concept of vessel normalisation by anti-angiogenic therapy

• Return to ‘normal’ phenotype by vascular pruning

• Results in more efficient drug delivery by lowering IFP and restoring microvessel function paradoxical synergism of anti-angiogenesis agents and cytostatic drugs

• Results in more efficient RT by enhanced oxygenation

Willett et al. NATURE MEDICINE VOLUME 10 | NUMBER 2 | FEBRUARY 2004

Bevacizumab normalises rectal cancer microvessels

Known Effects of Radiotherapy on tumor vessels

• Induces endothelial cell apoptosis• Induces EC ‘senescent’ phenotype• Stimulates production of endothelin• Effects on vascular permeability dependent

on dose, fractionation, tissue type• Direct or bystander effect?

Garcia-Barros et al. Tumor Response to Radiotherapy (15 Gy)Regulated by Endothelial Cell Apoptosis. Science 2003

Apoptosis resistant

TUNEL

How does anti-angiogenic therapy increase radiotherapy efficacy?

1. Inhibits protective VEGF signaling from tumor EC2. Enhances oxygenation 3. Reduces number of circulating EC and progenitor cells

Phase I trials combining neoadjuvant CRT with anti-angiogenic therapy in rectal cancer

• Czito IJROBP 2007– 11 patients, 50.4 Gy, capecitabine,oxaliplatin, and bevacizumab– Acceptable toxicity– 18% pCR; 27% microscopic disease

• Willett JCO 2005– 5 patients, 50.4 Gy, 5-FU, bevacizumab 10 mg/kg– 2 complete responses seen in patients with DLT

Functional imaging using Dynamic Contrast Enhanced MRI

• Inject contrast agent bolus• Acquire a series of MR images over time with

sufficient temporal resolution• Measure signal intensity changes as a

consequence of leakage of CA from the vascular compartment into the interstitial space

DCE-MRI Data Analysis

• Description of enhancement curve

• Semi-quantitative approach: AUC, TTP, maximal enhancement

• Pharmacokinetic compartmental models

• Statistical models

Enhancement curve evaluation in DCE-MRI

Farmacokinetic models in DCE-MRI

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Physiological significance of calculated endothelial transfer constant

• Small MW contrast agent: flow >> permeability

• Large MW contrast agent (preclinical): permeability >> flow

Oncology Imaging Research @ UZ Gent

• Preclinical– DCE-MRI

• Rat colorectal cancer model• Mouse pancreas cancer model

– Molecular MRI– Sequence optimisation; simulation; modelling– In vivo flurescence microscopy

• Hamster melanoma and pancreas cancer model• Human CRC model in athymic mouse

• Clinical– DCE-MRI in metastatic CRC treated with folfox-bevacizumab– USPIO in advanced solid tumors

In collaboration with researchdept. of Guerbet SA

Effects of RT on neovascular permeability measured with DCE-MRI using P792

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Before RT After RT

Ceelen et al. Int J Radiat Oncol Biol Phys 2006

rhEPO prevents radiotherapy-induced reduction in neovascular permeability

Ceelen et al. Br J Cancer 2007

Arg-Gly-Asp (RGD) peptide

Beta 3 integrin

Molecular imaging by targeting αvβ3 integrin

Pre 20 min Post

Molecular imaging in HT29 tumors using a αvβ3 integrin targeted MR probe

Debergh I, Van Damme N, Smeets P, Peeters M, Pattyn P, Ceelen W. Molecular imaging of tumor associated angiogenesis using P1227, a novel MRI contrast agent targeting avb3 integrin. Br J Surg 2008;95 Suppl 6: 13.

Dorsal Skin Window Chamber model

Collaboration with the biomedical engineering department

• Modelling of the AIF in DCE-MRI (PhD student)– D De Naeyer et al. Modelling the arterial input function for P792 in dynamic contrast enhanced magnetic resonance imaging: concepts and

validation. Submitted, MRM

• Modelling interstitial fluid pressure and drug transport with computational fluid dynamics software (Fluent) based on DCE-MRI data (thesis student)

• Hyperpolarized gas MRI; 19F MRI (hypoxia imaging)• Small animal nuclear imaging

CFD model of a solid tumor. Zhao et al. Microvascular Research 73 (2007) 224–236

• Micro SPECT (spatial resolution 0.35 mm)• Micro CT (spatial resolution <15 µm), GE• Small animal PET• Dedicated radiopharmacy unit (Prof Devos)

Small animal nuclear imaging: installed hardware

DCE-MRI in patients with metastatic CRC using MS-325

Large liver metastasis

Aims of the project• Study interaction of RT with anti-angiogenic

therapy• Verify phenomenon of ‘vascular normalization’

and its importance for therapy planning• Validate functional and molecular imaging as a

tool to monitor therapy response• Validate CFD modelling of vascular normalization

and drug transport

Methods• Athymic mouse model; human CRC cell line• AZD2171 (Cediranib, 6 mg/kg), RT, or both• Measurements and imaging

– Non invasive: DCE-MRI; P1227– Semi-invasive: IVM– Invasive: pO2, IFP

• Modelling of IFP and drug transport using Fluent• Possibility to study nuclear molecular probes in parallel

AZD 2171

Wedge et al. Cancer Res 2005

Contact

WP Ceelen, MD, PhDGhent University Hospital

Wim.ceelen@ugent.be

M Peeters, MD, PhDMarc.peeters@ugent.be