Thesis Format
Monograph
Degree
Master of Science
Program
Pathology
Supervisor
Nichols, Anthony
Abstract
Anaplastic Thyroid Cancer (ATC) is rare. Most patients present with extensive disease that is surgically unresectable. Frequently tumours are resistant to chemotherapy and radiation, leaving patients with few treatment options. A subset of ATC patients carry a BRAFV600E mutation and may be offered a first generation BRAF inhibitor (Dabrafenib). However, only some respond, and all will eventually acquire resistance and progress. A novel class of pan-RAF inhibitors has been developed that may benefit patients with BRAF and other currently unactionable mutations. One such inhibitor, Naporafenib, decreased cell viability in BRAFMUT and wild-type ATC cell lines greater than Dabrafenib. Naporafenib also decreased immune checkpoint inhibitor molecule PDL1 expression in ATC cells, indicating potential synergy with immunotherapies. Importantly, Naporafenib decreased MAPK signaling in ATC cells, as demonstrated through immunofluorescence-microscopy and RNA sequencing. RNA sequencing also highlighted potential off-target effects of Naporafenib. Our work demonstrates the activity of these pan-RAFi in ATC models.
Summary for Lay Audience
Anaplastic Thyroid Cancer (ATC) is a rare but lethal disease. Current treatments are only applicable for tumours with a genetic change in a gene called BRAF (BRAF mutations), and only some patients with BRAF mutations will respond. Responders will only do so briefly before the cancer develops resistance and their tumours grow again. Recently a new therapy was developed called pan-RAF inhibitors (pan-RAFi). They may have a deeper and longer lasting response in patients with BRAF mutations and may be used in patients with tumours that have other mutations that are currently ineligible for treatment. We aimed to explore the efficacy of pan-RAFi in ATC cells, as well as the mechanisms by which they work. We showed pan-RAFi are superior to currently used inhibitors at decreasing cancer cell viability. One drug of interest, Naporafenib, impacts the cell’s abilities to form colonies in some cell lines. We observed that Naporafenib decreased signaling of the protein pathway it was intended to target, by both looking at the expression of relevant proteins with a microscope, and by looking at the relevant amount of RNA, a mediator between our genetic information (DNA) and protein. Changes in RNA showed Naporafenib may impact more than one pathway. Naporafenib also decreased the expression of a surface molecule on our cancer cell lines. This molecule is the target of many immunotherapy drugs and suggests they may work in combination with Naporafenib. Our work demonstrates that these pan-RAFi may be a viable alternative for the treatment of ATC patients.
Recommended Citation
Ryan, Sarah EB, "Investigation of Novel Pan-RAF Inhibitors in Anaplastic Thyroid Cancer" (2023). Electronic Thesis and Dissertation Repository. 9760.
https://ir.lib.uwo.ca/etd/9760