April 2016 – Page 29 – 1stOncology™: Cancer Intelligence Service

[(18)F]tetrafluoroborate as a PET tracer for the sodium/iodide symporter: the importance of specific activity.

[(18)F]BF4 (-), the first (18)F-labelled PET imaging agent for the sodium/iodide symporter (NIS), was produced by isotopic exchange yielding a product with limited specific activity (SA, ca. 1 GBq/μmol) posing a risk of sub-optimal target-to-background ratios (TBR) in PET images due to saturation of NIS in vivo. We sought to quantify this risk and to develop a method of production of [(18)F]BF4 (-) with higher SA.
A new radiosynthesis of [(18)F]BF4 (-) was developed, involving reaction of [(18)F]F(-) with boron trifluoride diethyl etherate under anhydrous conditions, guided by (11)B and (19)F NMR studies of equilibria involving BF4 (-) and BF3. The SA of the product was determined by ion chromatography. The IC50 of [(19)F]BF4 (-) as an inhibitor of [(18)F]BF4 (-) uptake was determined in vitro using HCT116-C19 human colon cancer cells expressing the human form of NIS (hNIS). The influence of [(19)F]BF4 (-) dose on biodistribution in vivo was evaluated in normal mice by nanoPET imaging and ex vivo tissue counting.
An IC50 of 4.8 μΜ was found in vitro indicating a significant risk of in vivo NIS saturation at SA achieved by the isotopic exchange labelling method. In vivo thyroid and salivary gland uptake decreased significantly with [(19)F]BF4 (-) doses above ca. 10 μg/kg. The new radiosynthesis gave high radiochemical purity (&gt;99 %) and moderate yield (15 %) and improved SA (&gt;5 GBq/μmol) from a starting activity of only 1.5 GBq.
[(18)F]BF4 (-) produced at previously reported levels of SA (1 GBq/μmol) can lead to reduced uptake in NIS-expressing tissues in mice. This is much less likely in humans. The synthetic approach described provides an alternative for production of [(18)F]BF4 (-) at higher SA with sufficient yield and without need for unusually high starting activity of [(18)F]fluoride, removing the risk of NIS saturation in vivo even in mice.
ISRCTN75827286 .

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Serum Natriuretic Peptides as Differential Biomarkers Allowing for the Distinction between Physiologic and Pathologic Left Ventricular Hypertrophy.

Given the proven utility of natriuretic peptides as serum biomarkers of cardiovascular maladaptation and dysfunction in humans and the high cross-species sequence conservation of atrial natriuretic peptides, natriuretic peptides have the potential to serve as translational biomarkers for the identification of cardiotoxic compounds during multiple phases of drug development. This work evaluated and compared the response of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide (NT-proBNP) in rats during exercise-induced and drug-induced increases in cardiac mass after chronic swimming or daily oral dosing with a peroxisome proliferator-activated receptor γ agonist. Male Sprague-Dawley rats aged 8 to 10 weeks were assigned to control, active control, swimming, or drug-induced cardiac hypertrophy groups. While the relative heart weights from both the swimming and drug-induced cardiac hypertrophy groups were increased 15% after 28 days of dosing, the serum NT-proANP and NT-proBNP values were only increased in association with cardiac hypertrophy caused by compound administration. Serum natriuretic peptide concentrations did not change in response to adaptive physiologic cardiac hypertrophy induced by a 28-day swimming protocol. These data support the use of natriuretic peptides as fluid biomarkers for the distinction between physiological and drug-induced cardiac hypertrophy.
© The Author(s) 2016.

EGFR inhibitors Identified as a Potential Treatment for Chordoma in a Focused Compound Screen.

Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on 3 well-characterised chordoma cell lines. 154 compounds were selected from the single concentration screen (1 μM) based on their growth inhibitory effect. Their half-maximal effective concentration (EC50 ) values were determined in chordoma cells and normal fibroblasts. Twenty-seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of 7 chordoma cell lines, 4/7 of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho-EGFR and its downstream-pathways in a dose-dependent manner. Analysis of substituent patterns suggested that EGFR-inhibitors with small aniline substituents in the 4- position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in 2 xenograft mouse models (U-CH1 xenograft and a patient-derived xenograft SF8894). One of the resistant cell lines (U-CH2) was shown to express high levels of phospho-MET, a known bypass signalling pathway to EGFR. Neither amplification (EGFR, ERBB2, MET), nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p-) EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo.
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The Novel Oral Syk Inhibitor, Bl1002494, Protects Mice From Arterial Thrombosis and Thromboinflammatory Brain Infarction.

Ischemic stroke, which is mainly caused by thromboembolic occlusion of brain arteries, is the second leading cause of death and disability worldwide with limited treatment options. The platelet collagen receptor glycoprotein VI is a key player in arterial thrombosis and a critical determinant of stroke outcome, making its signaling pathway an attractive target for pharmacological intervention. The spleen tyrosine kinase (Syk) is an essential signaling mediator downstream of not only GPVI but also other platelet and immune cell receptors. We sought to assess whether Syk might be an effective antithrombotic target.
We demonstrate that mice lacking Syk in platelets specifically are protected from arterial thrombus formation and ischemic stroke but display unaltered hemostasis. Furthermore, we show that mice treated with the novel, selective, and orally bioavailable Syk inhibitor BI1002494 were protected in a model of arterial thrombosis and had smaller infarct sizes and a significantly better neurological outcome 24 hours after transient middle cerebral artery occlusion, also when BI1002494 was administered therapeutically, that is, after ischemia.
These results provide direct evidence that pharmacological Syk inhibition might provide a safe therapeutic strategy to prevent arterial thrombosis and to limit infarct progression in acute stroke.
© 2016 American Heart Association, Inc.

Stepwise group sparse regression (SGSR): gene-set-based pharmacogenomic predictive models with stepwise selection of functional priors.

Complex mechanisms involving genomic aberrations in numerous proteins and pathways are believed to be a key cause of many diseases such as cancer. With recent advances in genomics, elucidating the molecular basis of cancer at a patient level is now feasible, and has led to personalized treatment strategies whereby a patient is treated according to his or her genomic profile. However, there is growing recognition that existing treatment modalities are overly simplistic, and do not fully account for the deep genomic complexity associated with sensitivity or resistance to cancer therapies. To overcome these limitations, large-scale pharmacogenomic screens of cancer cell lines–in conjunction with modern statistical learning approaches–have been used to explore the genetic underpinnings of drug response. While these analyses have demonstrated the ability to infer genetic predictors of compound sensitivity, to date most modeling approaches have been data-driven, i.e. they do not explicitly incorporate domain-specific knowledge (priors) in the process of learning a model. While a purely data-driven approach offers an unbiased perspective of the data–and may yield unexpected or novel insights–this strategy introduces challenges for both model interpretability and accuracy. In this study, we propose a novel prior-incorporated sparse regression model in which the choice of informative predictor sets is carried out by knowledge-driven priors (gene sets) in a stepwise fashion. Under regularization in a linear regression model, our algorithm is able to incorporate prior biological knowledge across the predictive variables thereby improving the interpretability of the final model with no loss–and often an improvement–in predictive performance. We evaluate the performance of our algorithm compared to well-known regularization methods such as LASSO, Ridge and Elastic net regression in the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (Sanger) pharmacogenomics datasets, demonstrating that incorporation of the biological priors selected by our model confers improved predictability and interpretability, despite much fewer predictors, over existing state-of-the-art methods.

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Month: April 2016

[(18)F]tetrafluoroborate as a PET tracer for the sodium/iodide symporter: the importance of specific activity.

Serum Natriuretic Peptides as Differential Biomarkers Allowing for the Distinction between Physiologic and Pathologic Left Ventricular Hypertrophy.

EGFR inhibitors Identified as a Potential Treatment for Chordoma in a Focused Compound Screen.

The Novel Oral Syk Inhibitor, Bl1002494, Protects Mice From Arterial Thrombosis and Thromboinflammatory Brain Infarction.

Stepwise group sparse regression (SGSR): gene-set-based pharmacogenomic predictive models with stepwise selection of functional priors.