Discovery of Novel Targets in Pancreatic Cancer by Investigating Aberrant Signalling Pathways
Prof Geoffrey Candy
Project ended 30 June 2022
Prof Geoffrey Candy
Title of the project
Discovery of novel targets in pancreatic cancer by investigating aberrant signalling pathways.
Project Description
Pancreatic cancer (PDAC) is a devastating and aggressive cancer with a poor prognosis despite several treatment strategies. Hence the discovery of potential new therapeutic targets is essential to improve outcomes. Dysregulation of several key pathways occurs during PDAC. The previous study in our laboratory has identified several of these pathways (Nweke et al, submitted for publication). This approach identified alterations in pathways including IGF/MAPK, Ras, EGFR, integrin, PDGF, CCKR, and VEGF. These pathways have been identified to be involved in cellular proliferation, invasion, and migration. The current study uniquely utilizes a pathway-based approach to identify potential therapeutic targets and intends to investigate the functions of these targets. The study aims to identify (novel) gene targets in dysregulated pathways implicated in the progression of PDAC. Tissue samples would be collected from consenting patients at the Hepatobiliary Units at the Chris Hani Baragwanath and Charlotte Maxeke Hospitals Johannesburg.
Total RNA would be extracted and a nCounter PanCancer pathway panel used for gene expression analysis. This will help identify target genes that may be involved in PDAC initiation and progression. Real-time PCR would be used for the validation of identified gene targets. Gene targets would also be knocked down in cell lines and cell viability assays performed using flow cytometry. The study would identify (novel) gene targets in various dysregulated pathways that could be used for future effective therapies.
How the project was of value in the struggle against cancer
Pancreatic cancer is an aggressive and lethal disease. Unfortunately, its incidence and associated mortality are projected to rise despite new therapeutic options. Patients of African ancestry have the poorest prognosis with this cancer, yet are the least studied group. In this study, we have provided relevant molecular data to elucidate the mechanisms of the progression of the disease in a cohort of South African patients. Importantly, we have observed the potential role of the complement pathway in the progression of this disease. This has potential therapeutic implications as the pathway can be targeted to improve the management and treatment of the disease.
The future plans for this research project
We hope to further elucidate the molecular mechanisms associated with the functions of the complement pathway in pancreatic cancer. In particular, further study is required to elucidate the mechanisms linked to the inhibition of the immune function by the pathway. We have shown that reducing key targets of this pathway, increases the cell proliferation capacity of the cancer cells. Our future work will focus on overexpressing this pathway in the cells and observing its effect. We would simultaneously investigate mechanisms that reduce the expression of this pathway in PDAC.
Publications
- Role of different immune cells and metabolic pathways in modulating the immune response in pancreatic cancer
- SWATH-MS-based proteomic profiling of pancreatic ductal adenocarcinoma tumours reveals the interplay between the extracellular matrix and related intracellular pathways
- Targeting Growth Factor Signaling Pathways in Pancreatic Cancer: Towards Inhibiting Chemoresistance
