Anton G. T. Terwisscha van Scheltinga

Bio: Anton G. T. Terwisscha van Scheltinga is an academic researcher from Leiden University. The author has contributed to research in topics: Drug repositioning & Clear cell renal cell carcinoma. The author has an hindex of 4, co-authored 5 publications receiving 95 citations.

Cationic Liposomes : A Flexible Vaccine Delivery System for Physicochemically Diverse Antigenic Peptides

Abstract: PurposePersonalized peptide-based cancer vaccines will be composed of multiple patient specific synthetic long peptides (SLPs) which may have various physicochemical properties To formulate such SLPs, a flexible vaccine delivery system is required We studied whether cationic liposomes are suitable for this purposeMethodsFifteen SIINFEKL T cell epitope-containing SLPs, widely differing in hydrophobicity and isoelectric point, were separately loaded in cationic liposomes via the dehydration-rehydration method Particle size and polydispersity index (PDI) were measured via dynamic light scattering (DLS), and zeta potential with laser Doppler electrophoresis Peptide loading was fluorescently determined and the immunogenicity of the formulated peptides was assessed in co-cultures of dendritic cells (DCs) and CD8(+) T-cells in vitroResultsAll SLPs were loaded in cationic liposomes by using three different loading method variants, depending on the SLP characteristics The fifteen liposomal formulations had a comparable size (< 200nm), PDI (< 03) and zeta potential (22-30mV) Cationic liposomes efficiently delivered the SLPs to DCs that subsequently activated SIINFEKL-specific CD8(+) T-cells, indicating improved immunological activity of the SLPsConclusionCationic liposomes can accommodate a wide range of different SLPs and are therefore a potential delivery platform for personalized cancer vaccines

Personalised drug repositioning for Clear Cell Renal Cell Carcinoma using gene expression.

Abstract: Reversal of cancer gene expression is predictive of therapeutic potential and can be used to find new indications for existing drugs (drug repositioning). Gene expression reversal potential is currently calculated, in almost all studies, by pre-aggregating all tumour samples into a single group signature or a limited number of molecular subtype signatures. Here, we investigate whether drug repositioning based on individual tumour sample gene expression signatures outperforms the use of tumour group and subtype signatures. The tumour signatures were created using 534 tumour samples and 72 matched normal samples from 530 clear cell renal cell carcinoma (ccRCC) patients. More than 20,000 drug signatures were extracted from the CMAP and LINCS databases. We show that negative enrichment of individual tumour samples correlated (Spearman’s rho = 0.15) much better with the amount of differentially expressed genes in drug signatures than with the tumour group signature (Rho = 0.08) and the 4 tumour subtype signatures (Rho 0.036-0.11). Targeted drugs used against ccRCC, such as sirolimus and temsirolimus, which could not be identified with the pre-aggregated tumour signatures could be recovered using individual sample analysis. Thus, drug repositioning can be personalized by taking into account the gene expression profile of the individual’s tumour sample.

Transcriptome Signature Reversion as a Method to Reposition Drugs Against Cancer for Precision Oncology.

Abstract: Transcriptome signature reversion (TSR) has been hypothesized as a promising method for discovery and use of existing noncancer drugs as potential drugs in the treatment of cancer (i.e., drug repositioning, drug repurposing). The TSR assumes that drugs with the ability to revert the gene expression associated with a diseased state back to its healthy state are potentially therapeutic candidates for that disease. This article reviews methodology of TSR and critically discusses key TSR studies. In addition, potential conceptual and computational improvements of this novel methodology are discussed as well as its current and possible future application in precision oncology trials.

The impact of estimated tumour purity on gene expression-based drug repositioning of Clear Cell Renal Cell Carcinoma samples

Abstract: To find new potentially therapeutic drugs against clear cell Renal Cell Carcinoma (ccRCC), within drugs currently prescribed for other diseases (drug repositioning), we previously searched for drugs which are expected to bring the gene expression of 500 + ccRCC samples from The Cancer Genome Atlas closer to that of healthy kidney tissue samples. An inherent limitation of this bulk RNA-seq data is that tumour samples consist of a varying mixture of cancerous and non-cancerous cells, which influences differential gene expression analyses. Here, we investigate whether the drug repositioning candidates are expected to target the genes dysregulated in ccRCC cells by studying the association with tumour purity. When all ccRCC samples are analysed together, the drug repositioning potential of identified drugs start decreasing above 80% estimated tumour purity. Because ccRCC is a highly vascular tumour, attributed to frequent loss of VHL function and subsequent activation of Hypoxia-Inducible Factor (HIF), we stratified the samples by observed activation of the HIF-pathway. After stratification, the association between estimated tumour purity and drug repositioning potential disappears for HIF-activated samples. This result suggests that the identified drug repositioning candidates specifically target the genes expressed by HIF-activated ccRCC tumour cells, instead of genes expressed by other cell types part of the tumour micro-environment.

Microneedles for transdermal drug delivery: a systematic review.

Abstract: Transdermal route has been explored for various agents due to its advantage of bypassing the first pass effect and sustained release of drug. Due to strong barrier properties of the skin, mainly stratum corneum (SC), the delivery of many therapeutic agents across the skin has become challenging. Few drugs with specific physicochemical properties (molecular weight <500 Da, adequate lipophilicity, and low melting point) can be effectively administered via transdermal route. However, delivery of hydrophilic drugs and macromolecular agents including peptides, DNA and small interfering RNA is challenging. Drug penetration through the SC may involve bypass or reversible disruption of SC layer by various means. Recently, the use of micron-scale needles has been proposed in increasing skin permeability and shown to dramatically increase permeation, especially for macromolecules. Microneedles (MNs) can penetrate through the SC layer of the skin into the viable epidermis, avoiding contact with nerve fibers and blood vessels that reside primarily in the dermal layer. This review summarizes the types of MNs and fabrication techniques of different types of MNs. The safety aspects of the materials used for fabrication have been discussed in detail. Biological applications and relevant phase III clinical trials are also highlighted.