Therapeutic potential of combining PARP inhibitors and immune checkpoint inhibitors in cancer treatment

Bergen, Stella van (2021) Therapeutic potential of combining PARP inhibitors and immune checkpoint inhibitors in cancer treatment. Master's Thesis / Essay, Biomedical Sciences.

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Abstract

Breast cancer (BC) is a common cancer in women. Both environmental and genetic factors contribute to the development. Environmental factors that have been shown to increase the risk include increased age, obesity and alcohol use. Genes responsible for hereditary BC are BRCA1/2. These genes are active during the cell cycle and important for DNA damage repair. There are various ways to treat BC, however, they lack specificity. The BRCA proteins activate DNA repair pathways when DNA damage is induced. Mutation of these genes causes failure of DNA repair mechanisms. Recently, researchers have been focussing the use of PARP inhibitors (PARPi) to treat BRCA1/2 pathogenic BC. PARP is also involved in DNA damage repair. PARP1 functions through the cGAS/STING pathway and mediates transcription of proinflammatory proteins. Treatment of BRCA-deficient BC with PARPi creates synthetic lethality and has shown promising results in clinical studies. However, resistance is still prevalent. Various resistance pathways have been hypothesised; reactivation of the BRCA1/2 gene, restoration of stable replication forks and reduction of PARP trapping. A recent discovery is the combination of PARPi with immune checkpoint inhibitors (ICI). PARPi upregulates PD-L1, however, the constant PD-1/PD-L1 activation results in exhausted T-cells. Inhibiting PD-L1 restores T-cells. Combining PARPi and an ICI could therefore promote anti-tumour immune response and provide a promising new therapy to treat cancer.

Item Type:	Thesis (Master's Thesis / Essay)
Supervisor name:	Vugt, M.A.T.M. van
Degree programme:	Biomedical Sciences
Thesis type:	Master's Thesis / Essay
Language:	English
Date Deposited:	09 Jul 2021 14:02
Last Modified:	09 Jul 2021 14:02
URI:	https://fse.studenttheses.ub.rug.nl/id/eprint/25117

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