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Exploring New and Emerging Mechanisms to Target Difficult to Treat Cancers

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posted on 04.12.2020, 10:46 by Catherine Richards

Gastro-oesophageal cancers are associated with poor survival in patients, due to their aggressive nature, late-stage diagnosis, and a lack of specific targeted therapies. The development of new therapeutics will prove crucial to improve mortality rates. This thesis discusses two novel potential approaches which merit further investigation towards this goal.


Firstly, natural compounds have previously found several uses as chemotherapeutic agents. We found a diterpenoid compound in the same class as Taxol, Crassin, to have significant anti-cancer effects in both gastro-oesophageal cell lines and triple negative breast cancer cell lines. Specifically, Crassin reduced cell viability in a manner dependent on reactive oxygen species, and demonstrated bioefficacy in an in ovo/semi-in vivo model. Interestingly, Crassin did not activate any known cell death mechanisms but rather induced cell stasis through cell-cycle shifts from G1 to G2/M. Since research is highlighting cytostatic inducers as powerful agents in combatting cancer growth, particularly when combined with cytostatic compounds, we suggest that Crassin is a candidate for consideration as a “one-two punch” agent.


Secondly, we examined other potential therapeutic targets in gastro-oesophageal cancers. Previous work in our lab has shown that overexpression of the adhesion molecule Junctional Adhesion Molecule-A (JAM-A) drives proliferation and tumorigenic behaviour in breast cancer. We hypothesised that the overexpression of JAM-A in gastro-oesophageal cancers may play a similar role in driving cancer progression. Furthermore, our group has highlighted a regulatory role of JAM-A for receptor tyrosine kinases (RTKs), including HER and Eph family members. Since gastro-oesophageal cancers are also known to overexpress HER2, we also hypothesised that JAM-A may play an important role driving HER2 overexpression and downstream cell survival. Gastro-oesophageal cell lines demonstrated varied responses to JAM-A loss, but no universal effects on cell viability, colony-forming potential or tumour development and invasion in an in ovo/semi-in vivo model. We could find no apparent mechanism of regulation between JAM-A and three RTKs examined, though some correlations between JAM-A and HER2 and JAM-A and EphB4 expression were discovered in gastro-oesophageal cancer full-face sections. We suggest this is representative of aggressive tumour phenotypes. Excitingly, in JAM-A reduced cells, we identified a ‘primed for apoptosis’ phenotype which increased the efficacy of HER2 targeting therapies in vitro. Hence, we propose JAM-A targeting in this setting, in combination with pro-apoptotic chemotherapies merit future investigation as a “one-two punch” mechanism for treating gastro-oesophageal cancers.


In summary, we have examined potential mechanisms for targeting gastro-oesophageal cancers and have also highlighted a complex role for the adhesion protein JAM-A in that setting. Given the accessibility of JAM-A at the surface of cells, we suggest that targeting JAM-A in this setting could prove beneficial in priming cells for other drugs.

Funding

Science Foundation Ireland

History

First Supervisor

Dr Ann Hopkins

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2019.

Published Citation

Richards C. Exploring New and Emerging Mechanisms to Target Difficult to Treat Cancers [PhD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2019.

Degree Name

Doctor of Philosophy (PhD)

Date of award

30/11/2019

Programme

  • Doctor of Philosophy (PhD)

Exports