Investigating the Role of Novel Transcripts in the MYCN Locus Driving Neuroendocrine Prostate Cancer
Abstract
The mainstay therapy for advanced prostate cancer (PCa) is androgen-targeted therapy, which starves PCa cells of androgens required for the cancer cells to survive and grow. While this therapy is initially effective, some PCa cells change their physical characteristics to adapt to low levels of androgens allowing them to survive and grow in these conditions. One such emergent subtype is referred to as treatment-emergent neuroendocrine prostate cancer (tNEPC) and it occurs in approximately 20% of advanced PCa patients treated with hormonal therapies. Despite the recent development of new drugs that prolong the survival time of patients with advanced PCa, tNEPC is highly aggressive and untreatable, and the 5-year survival rate for these patients is only 12.6%. Recent studies have shown that about 40% of patients with tNEPC have high expression of the MYCN gene. This has also been recorded in other neuronal or neuroendocrine (NE) related cancers and is predictive of poor outcome. N-myc protein, encoded by the MYCN gene, is known for its role in transforming cells into having a more neuronal/NE profile. Therefore, the emergence of N-myc in tNEPC is thought to drive some of the neuroendocrine and therapy resistance features observed in tNEPC. Closer examination of the MYCN gene location has shown us that there are two additional proteins made alongside N-myc that have never been studied or described. We examined the function of these novel proteins in PCa cells and have data to show that it is these two proteins, not N-myc, that upregulate NE markers and promote resistance to the chemotherapies. On the other hand, N-myc downregulated the androgen receptor signaling axis and promoted resistance to androgen targeted therapies, whereas the other two proteins did not. These features, in combination, describe what is observed in patients with tNEPC. Therefore, we hypothesize that the collaboration of all three proteins may better describe tNEPC as it is observed in patients. We now aim to fully characterize these novel proteins and better define how they may contribute to the lethal features observed with tNEPC. We will achieve this with the following aims: (1) we will examine whether these novel proteins promote resistance to therapies when expressed in animal models of advanced PCa; (2) we will determine whether these novel proteins regulate and interact with other genes and proteins that are part of biological pathways relevant to tNEPC; and 3) we will validate our findings in patient datasets of tNEPC by examining for expression of markers regulated by these novel proteins. Together, these aims will address in the short term the function of these novel proteins in tNEPC, with the long- term impact of potentially revealing new targetable options for the development of more effective targeted therapies for patients with lethal tNEPC. Therefore, this project directly addresses the FY21 overarching challenge of defining the biology of lethal prostate cancer to reduce death.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210797
Entities
People
- Nataly Stylianou
Organizations
- Queensland University of Technology
- United States Army