To generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims... Show moreTo generate a successful novel therapy, a deep understanding of oncogenesis in combination with mechanistic understanding of anti-cancer compounds are needed. The work described in this thesis aims to contribute to the knowledge on SUMO regulated oncogenesis, understanding the consequences of abolishment of SUMO signaling and exploiting the potential of SUMO E1 inhibitors. To this end, we describe SUMO as a potential biomarker for cancer aggressiveness and increase our understanding on SUMO’s role in cell cycle progression. We exploited the potential of SUMO E1 inhibition by combining with hypomethylating compound 5-Aza-2’ deoxycytidine, leading to increased cytostatic efficacy. Furthermore, we repurposed the SUMO E1 inhibitor TAK981 and hypomethylating drug 5-Aza-2’ deoxycytidine to improve engineered TCR (eTCR) T cell therapy and broaden our understanding of its immunomodulatory potential. Show less
One of the most effective anticancer therapy still remains chemotherapy, however, both used as single agent as in combinational regimens, chemotherapy still encounters the problem of therapeutic... Show moreOne of the most effective anticancer therapy still remains chemotherapy, however, both used as single agent as in combinational regimens, chemotherapy still encounters the problem of therapeutic resistance. Limitations of chemotherapy have led to the exploration of alternative anti-cancer approaches in order to improve efficacy, such as chemoprevention. Chemopreventive agents interfere with rate limiting steps in tumor progression, such as for example the establishment of a functional tumor vasculature. Currently, there is a large and unfolding picture of rate-limiting steps during tumor progression which can provide us with numerous potential therapeutic targets, where it is becoming increasingly clear both the tumor itself as its microenvironment contribute in these steps. Current research focuses on exploring chemopreventive approaches as part of combination strategies. One of the most investigated approaches in these combinational strategies is targeting the tumor with chemotherapy together with chemopreventive agents. This thesis explores the use of chemopreventive approaches as monotherapy and in combinational approaches with chemotherapy and explores and discusses their effects on both the tumor as the tumor__s microenvironment. It shows that these combinational approaches hold great promise, if taking both the tumor as the tumor__s microenvironment into account as therapeutic targets. Show less
