Molecular imaging in oncology drug development.

Tremendous breakthroughs are being made in cancer drug discovery and development. However, such breakthroughs come at a high financial cost. At a time when there is increasing pressure on drug pricing, in part because of increased life expectancy, it is more important than ever to drive new therapeutics towards patients as efficiently as possible. In this review we discuss the applications of molecular imaging in oncology drug development, with a focus on its ability to enable better early decision making, to increase efficiency and thereby to lower costs.

Near-Infrared-Emitting BODIPY-trisDOTA(111) In as a Monomolecular Multifunctional Imaging Probe: From Synthesis to In Vivo Investigations.

A new generation of monomolecular imaging probes (MOMIP) based on a distyryl-BODIPY (BODIPY=boron-dipyrromethene) coupled with three DOTA macrocycles has been prepared (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). The MOMIP presents good fluorescence properties and is very stable in serum. The bimodal probe was conjugated to trastuzumab, and an optical in vivo study showed high accumulation of the imaging agent at the tumor site. (111) In radiometallation of the bioconjugate was performed in high radiochemical yield, highlighting the potential of this new BODIPY-chelators derivative as a bimodal imaging probe.

Dose-Finding Quantitative 18F-FDG PET Imaging Study with the Oral Pan-AKT Inhibitor GSK2141795 in Patients with Gynecologic Malignancies.

UNLABELLED: AKT (a serine/threonine-specific protein kinase) regulates many cellular processes contributing to cytotoxic drug resistance. This study's primary objective examined the relationship between GSK2141795, an oral, pan-AKT inhibitor, and (18)F-FDG PET markers of glucose metabolism in tumor tissue to determine whether (18)F-FDG PET could be used to guide personalized dosing of GSK2141795. Biomarker analysis of biopsies was also undertaken. METHODS: Twelve patients were enrolled in 3 cohorts; all underwent dynamic (18)F-FDG PET scans and serial pharmacokinetic sampling at baseline, week 2, and week 4 with tumor biopsies before treatment and at week 4. Response was evaluated by RECIST v1.1 and Gynecologic Cancer Intergroup criteria. Biopsy samples were analyzed for mutations and protein expression. RESULTS: GSK2141795 did not significantly influence blood glucose levels. No dose-response relationship was observed between GSK2141795 pharmacokinetics and (18)F-FDG PET pharmacodynamic measures; however, an exposure-response relationship was seen between maximum drug concentrations and maximal decrease in (18)F-FDG uptake in the best-responding tumor. This relationship also held for pharmacokinetic parameters of exposure and 1,5-anhydroglucitol (a systemic measure of glucose metabolism). Phospho-AKT upregulation at week 4 in biopsies confirmed AKT inhibition by GSK2141795. Single-agent activity was observed with a clinical benefit rate of 27% (3/11) and 30% (3/10) CA125 response in the study's platinum-resistant ovarian patients. AKT pathway activation by PIK3CA/PIK3R1 mutation did not correlate with clinical activity, whereas RAS/RAF pathway mutations did segregate with resistance to AKT inhibition. CONCLUSION: GSK2141795 demonstrated an exposure-response relationship with decreased (18)F-FDG uptake and is active and tolerable. This study's design integrating (18)F-FDG PET, pharmacokinetics, and biomarker analyses demonstrates the potential for clinical development for personalized treatment.

Molecular imaging of tumor-associated angiogenesis using a novel magnetic resonance imaging contrast agent targeting αvß 3 integrin.

BACKGROUND: The recent introduction of biological anticancer therapy has renewed the interest in functional imaging of tumor-associated angiogenesis (TAA) as a tool to monitor early therapy response. The present study evaluated imaging of TAA using P1227, a novel, small molecular magnetic resonance imaging (MRI) probe targeting αvß3 integrin. METHODS: HT29 human colorectal cancers were grown in athymic mice. Dynamic MRI was performed using a three-dimensional VIBE sequence up to 110 min after injection of P1227 or gadolinium-tetraazacyclododecane tetraacetic acid (Gd-DOTA). Specificity was assessed by using P1227 1 h after intravenous administration of the αvß3 inhibitor cilengitide. Regions of interest were drawn encompassing the tumor rim and normal muscle. Imaging data were compared with microvessel density and αvß3 expression. RESULTS: Using P1227, specific enhancement of the angiogenic tumor rim, but not of normal muscle, was observed, whereas Gd-DOTA enhanced tumor and normal muscle. After administering cilengitide, enhancement with P1227, but not with DOTA, was significantly suppressed during the first 20 min. When using P1227, a significant correlation was observed between normalized enhancement of the tumor rim and immunohistochemical αvß3 integrin expression. CONCLUSIONS: Molecular MRI using a small monogadolinated tracer targeting αvß3 integrin and moderate magnetic field strength holds promise in assessing colorectal TAA.

Improved evaluation of myocardial perfusion and viability with the magnetic resonance blood pool contrast agent p792 in a nonreperfused porcine infarction model.

OBJECTIVES: To investigate whether a magnetic resonance (MR) blood pool contrast agent enables both evaluation of myocardial perfusion and viability in nonreperfused infarction in pigs. MATERIALS AND METHODS: An optimized MR protocol using the blood pool contrast agent P792 (0.026 mmol/kg, twice the clinical dose, Guerbet, France) was investigated to evaluate nonreperfused myocardial infarction in an animal model. P792 was compared with the extracellular contrast agent Gd-DOTA (0.1 mmol/kg). The MRI findings were compared with histomorphometry performed with microspheres to evaluate perfusion and triphenyltetrazolium chloride (TTC) to evaluate viability. Contrast-enhanced MR imaging of the heart was performed on a 1.5-Tesla scanner 2 days after instrumentation in 6 minipigs. A saturation recovery steady-state free precession sequence was used for perfusion imaging and an inversion recovery fast low-angle shot sequence for evaluation of myocardial viability. RESULTS: P792 tended to depict areas of reduced perfusion more accurately than Gd-DOTA (17.2% +/- 11.1% versus 13.7% +/- 8.0%) in comparison to the gold standard of histomorphometry with microspheres (18.2% +/- 9.8%). Moreover, P792, but not Gd-DOTA, depicted ischemic areas for 30 minutes after intravenous injection. The change in myocardial signal intensity during first pass was not significantly different after P792 compared with Gd-DOTA (140.3% +/- 64.4% versus 123.3% +/- 22.5%, P = 0.56). P792 was highly accurate in depicting infarcted areas (11.1% +/- 7.1%) compared with Gd-DOTA (12.1% +/- 8.2%, r = 0.98, P < 0.001) and histomorphometry with TTC (12.2% +/- 8.0%, r = 0.99, P < 0.001). CONCLUSIONS: Unlike Gd-DOTA, the blood pool contrast agent P792 allows evaluation of myocardial perfusion for a period of 30 minutes and shows good agreement with histomorphometry. P792 must be examined in further studies to evaluate its potential in evaluating early myocardial lesions and reperfusion. In addition, P792 also allows for evaluation of myocardial viability.

In vivo quantification of regional myocardial blood flow: validity of the fast-exchange approximation for intravascular T1 contrast agent and long inversion time.

In the present study we investigated the effects of water exchange between intra- and extravascular compartments on absolute quantification of regional myocardial blood flow (rMBF) using a saturation-recovery sequence with a rather long inversion time (TI, 176 ms) and a T1-shortening intravascular contrast agent (CMD-A2-Gd-DOTA). Data were acquired in normal and ischemically injured pigs, with radiolabeled microsphere flow measurements used as the gold standard. Five water exchange rates (fast, 6 Hz, 3 Hz, 1 Hz, and no exchange) were tested. The results demonstrate that the fast-exchange approximation may be appropriate for rMBF quantification using the described experimental setting. Relaxation rate change (DeltaR1) analysis improved the accuracy of the analysis of rMBF compared to the MR signal. In conclusion, the current protocol could provide sufficient accuracy for estimating rMBF assuming fast exchange and a linear relationship between signal and tissue concentration when quantification of precontrast T1 is not an option.

Importance of parametric mapping and deconvolution in analyzing magnetic resonance myocardial perfusion images.

AIM: : We sought to improve the clinical interpretation of first-pass myocardial magnetic resonance perfusion. Parametric analyses of the myocardial distribution of the contrast agent have been proposed. The objective of the present study was to compare the effectiveness of visual analysis and of a parametric approach in an animal model under acquisition conditions as close as possible to clinical reality. METHOD: : Experiments were conducted in vivo with various kinds of pharmacological stimulation in normal pigs and in pigs with stenosis of the left circumflex coronary artery. First-pass MR images and parametric maps were first assessed by medical experts. MR parameters, the myocardial signal intensity variation DeltaSI, ascending up-slope, and rMBF (blood flow calculated by fast discrete ARMA deconvolution) were then compared with blood flow measurements using radioactive microspheres. RESULTS AND CONCLUSIONS: : Interobserver agreement was 57% and 81% and accuracy 53% and 81%, for visual and for parametric map analysis, respectively. For deconvolution parameters, a linear relationship y = 371 + 1.27x, r = 0.78 was obtained between rMBF calculated by ARMA and the radioactive microsphere blood flow. Moreover, the fast and robust parametric mapping of rMBF by the discrete ARMA method allows MR evaluation of myocardial perfusion independently of hemodynamic conditions.

Intensity non-uniformity correction in MRI: existing methods and their validation.

Magnetic resonance imaging is a popular and powerful non-invasive imaging technique. Automated analysis has become mandatory to efficiently cope with the large amount of data generated using this modality. However, several artifacts, such as intensity non-uniformity, can degrade the quality of acquired data. Intensity non-uniformity consists in anatomically irrelevant intensity variation throughout data. It can be induced by the choice of the radio-frequency coil, the acquisition pulse sequence and by the nature and geometry of the sample itself. Numerous methods have been proposed to correct this artifact. In this paper, we propose an overview of existing methods. We first sort them according to their location in the acquisition/processing pipeline. Sorting is then refined based on the assumptions those methods rely on. Next, we present the validation protocols used to evaluate these different correction schemes both from a qualitative and a quantitative point of view. Finally, availability and usability of the presented methods is discussed.