towards improved death receptor targeted therapy for ... - TI Pharma

Introduction
AAG, that targets Hsp90. Hsp90 is a potential target that plays an important role in the
tumorigenesis of NSCLC [18]. Of note, it interacts and stabilizes several key signaling
proteins/ kinases, like Akt, ErbB2, c‐Met, and Raf‐1. Chapter 6 describes the synergistic
effect of TRAIL with the novel chemotherapeutic TFT, a thymidylate synthase (TS) inhibitor
that interferes with thymidylate production and in its triphosphate form can be
incorporated into the DNA causing DNA damage. Underlying mechanisms of synergy were
examined by studying the cell‐cycle kinases, the intrinsic and extrinsic apoptotic pathways
and TRAIL‐R1 and TRAIL‐R2 expression levels after TFT exposure. TFT is degraded by
thymidine phosphorylase (TP), leading to strong decreases in the bioavailability of TFT. TP
is often overexpressed in human cancers and was also found to play a role in the
stimulation of angiogenesis, resulting in blood vessel formation sustaining tumor
progression. The exact molecular mechanism of how TP stimulates angiogenesis is not
fully clear. It is hypothesized that thymidine‐derived sugars might play a role in this
process. TP catalyzes the conversion of thymidine (TdR to thymine and deoxyribose‐1‐
phosphate (dR‐1‐P), which can be converted to dR‐5‐P, glyceraldehydes‐3‐phosphate
(G3P) or deoxyribose (dR). We characterized the thymidine‐derived sugars that are
related with the angiogenesis induction by TP, which is described in Chapter 7.
Furthermore, subcellular localization of thymidine‐derived sugars and whether they are
secreted by the cancer cells were determined. Finally, a summary of the work presented
in this thesis is provided and discussed in Chapter 8, including a view on the future
perspectives of TRAIL therapy. A summary in Dutch concludes this thesis and can be found
in Chapter 9.
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