Towards novel cancer (immuno)therapy using TRAIL and Galectin-9

Valerie Rose Wiersma

Towards novel cancer (immuno)therapy using TRAIL and Galectin-9

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TRAIL is een eiwitmolecuul dat in geringe hoeveelheden voorkomt op bepaalde immuuncellen en dat door deze cellen wordt gebruikt om kankercellen te doden. Tijdens het onderzoek van Valerie R. Wiersma is onderzocht of het mogelijk is om extra TRAIL moleculen op immuuncellen ‘te plakken’ om op deze wijze hun antikankeractiviteit te vergroten. Hiertoe zijn nieuwe zogenaamde TRAIL fusie-eiwitten ontwikkeld waarbij TRAIL gekoppeld werd aan een antilichaamfragment dat specifiek aan immuuncellen bindt. Bij de keuze voor het antilichaamfragment is een doelwit geselecteerd op immuuncellen dat ook kan worden gebruikt om deze cellen te activeren. Twee vliegen in één klap dus; extra TRAIL afleveren op immuuncellen en wel op zo’n manier dat het deze immuuncellen ook nog eens extra activeert. Het onderzoek laat inderdaad zien dat met behulp van deze aanpak de antikankeractiviteit van verschillende immuuncellen aanzienlijk kan worden vergroot. Mogelijk kan deze strategie in de toekomst worden ingezet voor de immunologische behandeling van kanker.

Daarnaast is onderzoek gedaan naar de therapeutische mogelijkheden van galectine-9. Galectine-9 is een lichaamseigen eiwit met vele functies. Wiersma ontdekte dat galectine-9 ook in staat is om kankercellen te doden. Galectine-9 veroorzaakt celdood in kankercellen door een proces dat ’autofagie’ wordt genoemd selectief te remmen. Bepaalde kankercellen gebruiken ‘autofagie’ om te kunnen overleven tijdens chemotherapie. Deze resultaten suggereren dus dat Galectine-9 in de toekomst mogelijk kan worden ingezet om therapieresistente kankercellen te behandelen.

Vervolgonderzoek is nodig om te onderzoeken of en hoe TRAIL fusie-eiwitten en galectine-9 kunnen worden doorontwikkeld voor toepassing bij de behandeling van kanker.

Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	Helfrich, Wijnand, Supervisor Bremer, Edwin, Co-supervisor
Datum van toekenning	10-mei-2017
Plaats van publicatie	[Groningen]
Uitgever	Rijksuniversiteit Groningen
Gedrukte ISBN's	978-90-367-9768-9
Elektronische ISBN's	978-90-367-9767-2
Status	Published - 2017

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title = "Towards novel cancer (immuno)therapy using TRAIL and Galectin-9",

abstract = "In oncology new therapeutic strategies are needed to increase efficacy and reduce side effects. For her thesis, Valerie R. Wiersma studied the anticancer activity of the human proteins TRAIL and galectin-9. TRAIL is a protein that immune cells (e.g. T-cells) use to prevent and fight cancer by selectively inducing programmed cell death (apoptosis) in malignant cells. Unfortunately, cancer cells develop various ways to resist or counteract the anticancer activity of immune cells. Therefore, new recombinant fusion proteins were designed to act as drugs that promote and/or reactivate anticancer immune responses. For this purpose, TRAIL was genetically fused to an antibody fragment with immune-activating properties. In this way, various types of immune effector cells could be activated and simultaneously armed with TRAIL, which significantly enhanced their anticancer activity. It is well-known that cancer cells develop resistance to commonly used anticancer drugs as a result of mutations in cell death signaling pathways or in metabolic processes that promote cancer cell survival. Wiersma uncovered that galectin-9 can be used to induce cell death in cancer cells. The mode-of-action of galectin-9 involved the selective inhibition of autophagy, a catabolic process that cancer cells misuse to gain resistance towards conventional anticancer drugs. This discovery suggests that galectin-9 may be of use to overcome therapy resistance in cancer cells. Further research is ongoing to evaluate the suitability of TRAIL fusion proteins and galectin-9 for future clinical use in cancer patients.",

author = "Wiersma, {Valerie Rose}",

year = "2017",

language = "English",

isbn = "978-90-367-9768-9",

publisher = "Rijksuniversiteit Groningen",

school = "University of Groningen",

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TY - BOOK

T1 - Towards novel cancer (immuno)therapy using TRAIL and Galectin-9

AU - Wiersma, Valerie Rose

PY - 2017

Y1 - 2017

N2 - In oncology new therapeutic strategies are needed to increase efficacy and reduce side effects. For her thesis, Valerie R. Wiersma studied the anticancer activity of the human proteins TRAIL and galectin-9. TRAIL is a protein that immune cells (e.g. T-cells) use to prevent and fight cancer by selectively inducing programmed cell death (apoptosis) in malignant cells. Unfortunately, cancer cells develop various ways to resist or counteract the anticancer activity of immune cells. Therefore, new recombinant fusion proteins were designed to act as drugs that promote and/or reactivate anticancer immune responses. For this purpose, TRAIL was genetically fused to an antibody fragment with immune-activating properties. In this way, various types of immune effector cells could be activated and simultaneously armed with TRAIL, which significantly enhanced their anticancer activity. It is well-known that cancer cells develop resistance to commonly used anticancer drugs as a result of mutations in cell death signaling pathways or in metabolic processes that promote cancer cell survival. Wiersma uncovered that galectin-9 can be used to induce cell death in cancer cells. The mode-of-action of galectin-9 involved the selective inhibition of autophagy, a catabolic process that cancer cells misuse to gain resistance towards conventional anticancer drugs. This discovery suggests that galectin-9 may be of use to overcome therapy resistance in cancer cells. Further research is ongoing to evaluate the suitability of TRAIL fusion proteins and galectin-9 for future clinical use in cancer patients.

AB - In oncology new therapeutic strategies are needed to increase efficacy and reduce side effects. For her thesis, Valerie R. Wiersma studied the anticancer activity of the human proteins TRAIL and galectin-9. TRAIL is a protein that immune cells (e.g. T-cells) use to prevent and fight cancer by selectively inducing programmed cell death (apoptosis) in malignant cells. Unfortunately, cancer cells develop various ways to resist or counteract the anticancer activity of immune cells. Therefore, new recombinant fusion proteins were designed to act as drugs that promote and/or reactivate anticancer immune responses. For this purpose, TRAIL was genetically fused to an antibody fragment with immune-activating properties. In this way, various types of immune effector cells could be activated and simultaneously armed with TRAIL, which significantly enhanced their anticancer activity. It is well-known that cancer cells develop resistance to commonly used anticancer drugs as a result of mutations in cell death signaling pathways or in metabolic processes that promote cancer cell survival. Wiersma uncovered that galectin-9 can be used to induce cell death in cancer cells. The mode-of-action of galectin-9 involved the selective inhibition of autophagy, a catabolic process that cancer cells misuse to gain resistance towards conventional anticancer drugs. This discovery suggests that galectin-9 may be of use to overcome therapy resistance in cancer cells. Further research is ongoing to evaluate the suitability of TRAIL fusion proteins and galectin-9 for future clinical use in cancer patients.

M3 - Thesis fully internal (DIV)

SN - 978-90-367-9768-9

PB - Rijksuniversiteit Groningen

CY - [Groningen]

ER -

Towards novel cancer (immuno)therapy using TRAIL and Galectin-9

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