Finding the Best Gene Candidate(s) as a Potential Therapeutic Target for N-MYC Overexpressing Neuroendocrine Prostate Cancer (NEPC)

Neuroendocrine prostate cancer (NEPC) is the most aggressive form of prostate tumorigenesis. Recent studies have shown that one of the key genes that regulate the development of NEPC cells is the N-MYC oncogene, along with the loss of tumor suppressors such as TP53 and RB1 (Lee et al., 2016). Resistance to current treatments results in the transformation of prostate cancer (PC) cells into Castration-resistant prostate cancer (CRPC), which at later stages trans-differentiates into neuroendocrine prostate cancer (NEPC). NEPC is resistant to hormonal therapy as cancer cells lack androgen receptors (AR) at this level, which results in rapid death (Huang et al., 2019). Due to the molecular structure of the N-MYC protein, N-MYC cannot be directly targeted as it lacks a binding pocket. Thus, finding a target gene on which N-MYC expression is dependent will result in introducing a novel therapy. My master’s thesis aims to apply the concept of synthetic dosage lethality to identify target genes that become essential when N-MYC is overexpressed. Synthetic dosage lethality (SDL) denotes a genetic interaction whereby underexpression of gene A combined with overexpression of gene B results in the killing of the cell (Megchelenbrink et al., 2015). This approach requires the overexpression of one gene, such as N-MYC, with the loss of function of a second gene to cause lethality in cells. Accordingly, genes that exhibit SDL with N-MYC should result in lethality in N-MYC+ prostate cancer cells. The Vizeacoumar lab performed genome-wide shRNA and CRISPR screening to identify genes that become essential in N-MYC overexpressing cells. My work will specifically focus on validating three candidate genes (WNT1, SOX17, and FOXN1) identified from the genome-wide screen. Moreover, to suggest a more effective strategy to treat NEPC, we applied a combination of gene knockout and drug therapy. Three drugs, Chidamide, Belinostat, and Fludarabine, were tested to check cell viability and find the best drug for treatment.

Name thesis:degree_name

Master of Science (M.Sc.)

Level thesis:degree_level

Masters

Discipline thesis:degree_discipline

Health Sciences

Grantor

University of Saskatchewan

Year dc:date.issued

2023

Author dc:creator

• Sharifi, Mobina

Advisors dc:contributor.advisor

• Vizeacoumar, Franco
• Freywald, Andrew

Committee members dc:contributor.committeemember

• Decoteau, John
• Krishnan, Anand

• Neuroendocrine Prostate Cancer, Synthetic Dosage Lethality

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10388/15010

OAI identifier oai:identifier

oai:harvest.usask.ca:10388/15010