Year: 2020
Type: dissertation
Abstract: Glioblastoma (GBM) accounts for the majority of astrocytic tumours and represents the most common primary brain cancer. Prognosis for patients is dismal even with aggressive treatment. Because of diffused GBM invasion throughout the brain, it is impossible for surgery to completely remove the tumour. Chemotherapeutic adjuvants are used in attempt to eradicate remnant GBM cells. Unfortunately, the standard clinically used drugs have limited therapeutic benefits. Thus, there is need to identify novel drug targets. Although ion channels contribute to a wide array of fundamental cellular functions, the role of ion channels in GBM is ill-defined. A better understanding of ion channels can potentially present new effective ways to treat GBM. In this thesis, I aimed to fill some of these knowledge gaps by investigating two exciting candidates: the transient receptor potential melastatin 7 (TRPM7), and the swelling induced chloride current (ICl,swell), both of which can potentially serve as cellular "sensors" for key GBM characteristics such as hypoxia and cell volume. In my first aim, I validated the involvement of TRPM7 in GBM cellular functions and the underlying signalling by employing a unique experimental approach. That is, I found that pharmacologically potentiating TRPM7 enhanced GBM motility. In my second aim, I evaluated the therapeutic potential of the specific TRPM7 antagonist waixenicin A. By employing both in vitro and in vivo approaches, I provided evidence suggesting that waixenicin A reduced GBM cellular functions. Lastly, in my third aim, I expanded my scope of study in order to gain a broader understanding of ion channels' roles in GBM by examining ICl,swell, a target that may complement TRPM7 in various physicochemical sensory roles. Here, I observed that inhibiting ICl,swell can also suppress GBM cellular functions. Overall, the objective of my thesis is to elucidate the ill-defined roles of TRPM7 and ICl,swell in GBM in order to identify potential targets for pursuit of further drug development.
Source: TSpace (University of Toronto)
Author: Wong, Raymond Yin Cheung
Institution: University of Toronto
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7132954829