Targeted therapy in oncology: mechanisms and toxicity

This thesis focuses on targeted anticancer agents. An important class of these agents are the tyrosine kinase inhibitors (TKIs). One of the first steps in TKI treatment development is defining whether a specific type of cancer, for example the sarcomas in chapter 3 of this thesis, express the receptors that are targeted. Once a TKI is developed, phase I studies are conducted to characterize the safety and side effects of the drug when administered to patients. When relevant side effects emerge, studies investigating the underlying mechanisms leading to these side effects are called for. Also pharmacogenetic studies can be performed to investigate whether certain heritable genetic variations influence efficacy or safety of the drug. After the phase I studies have proven the drug to be safe, the drug can be further developed. This includes the investigation of the TKI when combined with other anticancer agents. Items of all the described steps in TKI development are described in this thesis.Financial support for printing this thesis by SKOL (Stichting Klinische Oncologie Leiden), AZL Onderzoeks- en Ontwikkelingskrediet Apotheek, Abbott, Amgen, Astra Zeneca, Bayer Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Janssen-Cilag, Merck, Merck Sharp & Dohme, Nerviano MS, Novartis, Pfizer, Sanofi-Aventis, and Wyeth is gratefully acknowledgedUBL - phd migration 201

Influence of pharmacogenetic variability on the pharmacokinetics and toxicity of the aurora kinase inhibitor danusertib

Objectives Danusertib is a serine/threonine kinase inhibitor of multiple kinases, including aurora-A, B, and C. This explorative study aims to identify possible relationships between single nucleotide polymorphisms in genes coding for drug metabolizing enzymes and transporter proteins and clearance of danusertib, to clarify the interpatient variability in exposure. In addition, this study explores the relationship between target receptor polymorphisms and toxicity of danusertib. Methods For associations with clearance, 48 cancer patients treated in a phase I study were analyzed for ABCB1, ABCG2 and FMO3 polymorphisms. Association analyses between neutropenia and drug target receptors, including KDR, RET, FLT3, FLT4, AURKB and AURKA, were performed in 30 patients treated at recommended phase II dose-levels in three danusertib phase I or phase II trials. Results No relationships between danusertib clearance and drug metabolizing enzymes and transporter protein polymorphisms were found. Only, for the one patient with FMO3 18281AA polymorphism, a significantly higher clearance was noticed, compared to patients carrying at least 1 wild type allele. No effect of target receptor genotypes or haplotypes on neutropenia was observed. Conclusions As we did not find any major correlations between pharmacogenetic variability in the studied enzymes and transporters and pharmacokinetics nor toxicity, it is unlikely that danusertib is highly susceptible for pharmacogenetic variation. Therefore, no dosing alterations of danusertib are expected in the future, based on the polymorphisms studied. However, the relationship between FMO3 polymorphisms and clearance of danusertib warrants further research, as we could study only a small group of patients

Tomographic approach to resolving the distribution of LISA Galactic binaries

The space based gravitational wave detector LISA is expected to observe a large population of Galactic white dwarf binaries whose collective signal is likely to dominate instrumental noise at observational frequencies in the range 10^{-4} to 10^{-3} Hz. The motion of LISA modulates the signal of each binary in both frequency and amplitude, the exact modulation depending on the source direction and frequency. Starting with the observed response of one LISA interferometer and assuming only doppler modulation due to the orbital motion of LISA, we show how the distribution of the entire binary population in frequency and sky position can be reconstructed using a tomographic approach. The method is linear and the reconstruction of a delta function distribution, corresponding to an isolated binary, yields a point spread function (psf). An arbitrary distribution and its reconstruction are related via smoothing with this psf. Exploratory results are reported demonstrating the recovery of binary sources, in the presence of white Gaussian noise.Comment: 13 Pages and 9 figures high resolution figures can be obtains from http://www.phys.utb.edu/~rajesh/lisa_tomography.pd

Accurate X-ray position and multiwavelength observations of the isolated neutron star RBS 1774

We report on X-ray, optical, infrared and radio observations of the X-ray dim isolated neutron star (XDINS) 1RXS J214303.7+065419 (also known as RBS 1774). The X-ray observation was performed with the High Resolution Camera on board of the Chandra X-ray Observatory, allowing us to derive the most accurate position for this source (alpha = 21h43m3.38s, delta= +6deg54'17".53; 90% uncertainty of 0."6). Furthermore, we confirmed with a higher spatial accuracy the point-like nature of this X-ray source. Optical and infrared observations were taken in B, V, r', i', J, H and Ks filters using the Keck, VLT, Blanco and Magellan telescopes, while radio observations were obtained from the ATNF Parkes single dish at 2.9GHz and 708MHz. No plausible optical and/or infrared counterpart for RBS 1774 was detected within the refined sub-arsecond Chandra X-ray error circle. Present upper limits to the optical and infrared magnitudes are r'>25.7 and J>22.6 (5 sigma confidence level). Radio observations did not show evidence for radio pulsations down to a luminosity at 1.4 GHz of L < 0.02 mJy kpc^2, the deepest limit up to date for any XDINS, and lower than what expected for the majority of radio pulsars. We can hence conclude that, if RBS 1774 is active as radio pulsar, its non detection is more probably due to a geometrical bias rather than to a luminosity bias. Furthermore, no convincing evidence for RRAT-like radio bursts have been found. Our results on RBS 1774 are discussed and compared with the known properties of other thermally emitting neutron stars and of the radio pulsar population.Comment: 8 pages, 9 figures, accepted for publication on MNRA

Imatinib, sunitinib and pazopanib:From flat-fixed dosing towards a pharmacokinetically guided personalized dose

Tyrosine kinase inhibitors (TKIs) are anti-cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral TKIs have been introduced in the treatment of solid tumours, all administered in a fixed dose, although large interpatient pharmacokinetic (PK) variability is described. For imatinib, sunitinib and pazopanib exposure-treatment outcome (efficacy and toxicity) relationships have been established and therapeutic windows have been defined, therefore dose optimization based on the measured blood concentration, called therapeutic drug monitoring (TDM), can be valuable in increasing efficacy and reducing the toxicity of these drugs. In this review, an overview of the current knowledge on TDM guided individualized dosing of imatinib, sunitinib and pazopanib for the treatment of solid tumours is presented. We summarize preclinical and clinical data that have defined thresholds for efficacy and toxicity. Furthermore, PK models and factors that influence the PK of these drugs which partly explain the interpatient PK variability are summarized. Finally, pharmacological interventions that have been performed to optimize plasma concentrations are described. Based on current literature, we advise which methods should be used to optimize exposure to imatinib, sunitinib and pazopanib

PSR J1723-2837: An Eclipsing Binary Radio Millisecond Pulsar

We present a study of PSR J1723-2837, an eclipsing, 1.86 ms millisecond binary radio pulsar discovered in the Parkes Multibeam survey. Radio timing indicates that the pulsar has a circular orbit with a 15 hr orbital period, a low-mass companion, and a measurable orbital period derivative. The eclipse fraction of ~15% during the pulsar's orbit is twice the Roche lobe size inferred for the companion. The timing behavior is significantly affected by unmodeled systematics of astrophysical origin, and higher-order orbital period derivatives are needed in the timing solution to account for these variations. We have identified the pulsar's (non-degenerate) companion using archival ultraviolet, optical, and infrared survey data and new optical photometry. Doppler shifts from optical spectroscopy confirm the star's association with the pulsar and indicate a pulsar-to-companion mass ratio of 3.3 +/- 0.5, corresponding to a companion mass range of 0.4 to 0.7 Msun and an orbital inclination angle range of between 30 and 41 degrees, assuming a pulsar mass range of 1.4-2.0 Msun. Spectroscopy indicates a spectral type of G for the companion and an inferred Roche-lobe-filling distance that is consistent with the distance estimated from radio dispersion. The features of PSR J1723-2837 indicate that it is likely a "redback" system. Unlike the five other Galactic redbacks discovered to date, PSR J1723-2837 has not been detected as a gamma-ray source with Fermi. This may be due to an intrinsic spin-down luminosity that is much smaller than the measured value if the unmeasured contribution from proper motion is large.Comment: 11 pages, including 8 figures and 5 tables. Accepted by the Astrophysical Journa

A spiral structure in the disk of EX Draconis on the rise to outburst maximum

We report on the R-band eclipse mapping analysis of high-speed photometry of the dwarf nova EX Dra on the rise to the maximum of the November 1995 outburst. The eclipse map shows a one-armed spiral structure of ~180 degrees in azimuth, extending in radius from R ~0.2 to 0.43 R_{L1} (where R_{L1} is the distance from the disk center to the inner Lagrangian point), that contributes about 22 per cent of the total flux of the eclipse map. The spiral structure is stationary in a reference frame co-rotating with the binary and is stable for a timescale of at least 5 binary orbits. The comparison of the eclipse maps on the rise and in quiescence suggests that the outbursts of EX Dra may be driven by episodes of enhanced mass-transfer from the secondary star. Possible explanations for the nature of the spiral structure are discussed.Comment: To appear in the Astrophysical Journal Letters; 8 pages, 2 figures; coded with AAS latex styl

Doppler tomography as a tool for detecting exoplanet atmospheres

High-resolution Doppler spectroscopy is a powerful tool for identifying molecular species in the atmospheres of both transiting and non-transiting exoplanets. Currently, such data is analysed using cross-correlation techniques to detect the Doppler shifting signal from the orbiting planet. In this paper we demonstrate that, compared to cross-correlation methods currently used, the technique of Doppler tomography has improved sensitivity in detecting the subtle signatures expected from exoplanet atmospheres. This is partly due to the use of a regularizing statistic, which acts to suppress noise, coupled to the fact that all the data is fit simultaneously. In addition, we show that the technique can also effectively suppress contanimating spectral features that may arise due to overlapping lines, repeating line patterns, or the use of incorrect linelists. These issues can confuse conventional cross-correlation approaches, primarily due to aliasing issues inherent in such techniques, whereas Doppler tomography is less susceptible to such effects. In particular, Doppler tomography shows exceptional promise for simultaneously detecting multiple line species (e.g. isotopologues), even when there are high contrasts between such species – and far outperforms current CCF analyses in this respect. Finally, we demonstrate that Doppler tomography is capable of recovering molecular signals from exoplanets using real data, by confirming the strong detection of CO in the atmosphere of τ Boo b. We recover a signal with a planetary radial velocity semi-amplitude Kp = 109.6 ± 2.2 km s−1, in excellent agreement with the previously reported value of 110.0 ± 3.2 km s−1

RXTE Observations of 1A 1744-361: Correlated Spectral and Timing Behavior

We analyze Rossi X-ray Timing Explorer (RXTE) Proportional Counter Array (PCA) data of the transient low mass X-ray binary (LMXB) system 1A 1744-361. We explore the X-ray intensity and spectral evolution of the source, perform timing analysis, and find that 1A 1744-361 shows `atoll' behavior during the outbursts. The color-color diagram indicates that this LMXB was observed in a low intensity spectrally hard (low-hard) state and in a high intensity `banana' state. The low-hard state shows a horizontal pattern in the color-color diagram, and the previously reported `dipper QPO' appears only during this state. We also perform energy spectral analyses, and report the first detection of broad iron emission line and iron absorption edge from 1A 1744-361.Comment: 20 pages, 4 tables, 4 figures, accepted for publication in Ap

A Spatially Resolved `Inside-out' Outburst of IP Pegasi

We present a comprehensive photometric dataset taken over the entire outburst of the eclipsing dwarf nova IP Peg in September/October 1997. Analysis of the lightcurves taken over the long rise to the peak-of-outburst shows conclusively that the outburst started near the centre of the disc and moved outwards. This is the first dataset that spatially resolves such an outburst. The dataset is consistent with the idea that long rise times are indicative of such `inside-out' outbursts. We show how the thickness and the radius of the disc, along with the mass transfer rate change over the whole outburst. In addition, we show evidence of the secondary and the irradiation thereof. We discuss the possibility of spiral shocks in the disc; however we find no conclusive evidence of their existence in this dataset.Comment: 8 pages, 8 figures, to be appear in MNRA