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Induction of the antigen presentation machinery using novel small molecules Ellis, Samantha

Abstract

The immune system is crucial in the prevention and eradication of cancer. However, cancer genomes mutate more frequently than healthy cells and a commonly acquired phenotype is reduced expression of the antigen presentation machinery (APM) that is required for immunosurveillance. This phenotype can allow cancer cells to become invisible to the immune system and metastasize with limited inhibition. Since this phenomenon is seen across a wide variety of cancers discovering methods to reverse this immune evasion could lead to the development of widely applicable therapeutics. A compound, S-(+)-curcuphenol was previously identified as a novel candidate for restoring expression of the APM, however, its synthesis is greatly hindered due to chirality. Therefore, I investigated the ability of curcuphenol analogues to induce expression of the major histocompatibility complex I (MHC-I) in a murine metastatic lung carcinoma cell line in vitro. Two derivatives of curcuphenol, P02-113 and P03-97-1, showed improved outcomes in vitro and I further evaluated them in vivo, as anti-cancer therapeutics. Both compounds reduced tumour burden and increased immune cell infiltration into tumours. To explore a potential mechanism of P02-113 and P03-97-1, I evaluated them for histone deacetylase (HDAC) inhibition based on structural similarity to established HDAC inhibitors. Upon examination I observed a completely novel effect of enhanced class I/II HDAC activity. Furthermore to identify if this effect was direct and to uncover which HDAC enzymes were being affected, I evaluated individual HDAC enzymes. I discovered that HDAC8 was inhibited by both P02-113 and P03-97-1, however, the activities of HDAC 5 and 10 were enhanced upon treatment. While the field of cancer immunotherapy has grown, few therapeutics have been identified to target loss of immunogenicity through the up-regulation of the APM. In this thesis two analogues of curcuphenol P02-113 and P03-97-1 have been identified that up- regulate the APM in vitro and reduce tumour burden in vivo. With these effects P02-113 and P03-97-1 hold great potential as future therapeutics for cancers exhibiting an immunodeficient phenotype through loss of the APM. As well these compounds present ii the first class II HDAC enhancers, as they increase the enzymatic activity of HDAC 5 and 10.

Item Metadata

Title
Induction of the antigen presentation machinery using novel small molecules
Creator
Ellis, Samantha
Publisher
University of British Columbia
Date Issued
2017
Description
The immune system is crucial in the prevention and eradication of cancer. However, cancer genomes mutate more frequently than healthy cells and a commonly acquired phenotype is reduced expression of the antigen presentation machinery (APM) that is required for immunosurveillance. This phenotype can allow cancer cells to become invisible to the immune system and metastasize with limited inhibition. Since this phenomenon is seen across a wide variety of cancers discovering methods to reverse this immune evasion could lead to the development of widely applicable therapeutics. A compound, S-(+)-curcuphenol was previously identified as a novel candidate for restoring expression of the APM, however, its synthesis is greatly hindered due to chirality. Therefore, I investigated the ability of curcuphenol analogues to induce expression of the major histocompatibility complex I (MHC-I) in a murine metastatic lung carcinoma cell line in vitro. Two derivatives of curcuphenol, P02-113 and P03-97-1, showed improved outcomes in vitro and I further evaluated them in vivo, as anti-cancer therapeutics. Both compounds reduced tumour burden and increased immune cell infiltration into tumours. To explore a potential mechanism of P02-113 and P03-97-1, I evaluated them for histone deacetylase (HDAC) inhibition based on structural similarity to established HDAC inhibitors. Upon examination I observed a completely novel effect of enhanced class I/II HDAC activity. Furthermore to identify if this effect was direct and to uncover which HDAC enzymes were being affected, I evaluated individual HDAC enzymes. I discovered that HDAC8 was inhibited by both P02-113 and P03-97-1, however, the activities of HDAC 5 and 10 were enhanced upon treatment. While the field of cancer immunotherapy has grown, few therapeutics have been identified to target loss of immunogenicity through the up-regulation of the APM. In this thesis two analogues of curcuphenol P02-113 and P03-97-1 have been identified that up- regulate the APM in vitro and reduce tumour burden in vivo. With these effects P02-113 and P03-97-1 hold great potential as future therapeutics for cancers exhibiting an immunodeficient phenotype through loss of the APM. As well these compounds present ii the first class II HDAC enhancers, as they increase the enzymatic activity of HDAC 5 and 10.
Genre
Thesis/Dissertation
Type
Text
Language
eng
Date Available
2018-01-31
Provider
Vancouver : University of British Columbia Library
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
DOI
10.14288/1.0342282
URI
http://hdl.handle.net/2429/60473
Degree
Master of Science - MSc
Program
Medical Genetics
Affiliation
Medicine, Faculty of; Medical Genetics, Department of
Degree Grantor
University of British Columbia
Graduation Date
2017-05
Campus
UBCV
Scholarly Level
Graduate
Rights URI
http://creativecommons.org/licenses/by-nc-nd/4.0/
Aggregated Source Repository
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Attribution-NonCommercial-NoDerivatives 4.0 International