The role of cell cycle regulators in neuroendocrine prostate cancer transdifferentiation and resistance in therapy
Author ORCID Identifier
https://orcid.org/0000-0001-8803-2485
Standing
Graduate (PhD)
Type of Proposal
Oral Presentation
Faculty
Faculty of Science
Faculty Sponsor
Dr. Lisa Porter
Proposal
Prostate adenocarcinoma (AdPC) can transdifferentiate to an aggressive treatment-resistant subtype termed neuroendocrine prostate cancer (NEPC). The majority of NEPC tumors are androgen receptor (AR)-suppressed and they express some of NE markers. Determining how AdPC tumors progress to become resistant to AR-inhibition is a high priority. Our lab has characterized a novel cell cycle regulator, coined Spy1, which is found in many aggressive and stem-like forms of cancer and functions to override senescent barriers in the cell cycle. We have preliminary data to support that elevated Spy1 levels correlate with suppressed AR expression, N-myc elevation, increasing stemness in NE-like and high-grade prostate cancers with a lower survival rate. Also, our in vitro and zebrafish xenograft model indicates a direct correlation between Spy1 overexpression and migration ability of AdPC cell lines. Herein, we hypothesize that Spy1 compensates for AR loss in AdPC and facilitates progression to a proliferative, NE-like and stem-like phenotype. In this work, we evaluate the role of different cell cycle regulators including Spy1 in AdPC progression and address whether this could represent a novel therapeutic direction for NEPC patients. This research could lead to higher success rates of AR-suppressed diagnosis and survival of patients with NEPC.
Grand Challenges
Understanding Borders
The role of cell cycle regulators in neuroendocrine prostate cancer transdifferentiation and resistance in therapy
Prostate adenocarcinoma (AdPC) can transdifferentiate to an aggressive treatment-resistant subtype termed neuroendocrine prostate cancer (NEPC). The majority of NEPC tumors are androgen receptor (AR)-suppressed and they express some of NE markers. Determining how AdPC tumors progress to become resistant to AR-inhibition is a high priority. Our lab has characterized a novel cell cycle regulator, coined Spy1, which is found in many aggressive and stem-like forms of cancer and functions to override senescent barriers in the cell cycle. We have preliminary data to support that elevated Spy1 levels correlate with suppressed AR expression, N-myc elevation, increasing stemness in NE-like and high-grade prostate cancers with a lower survival rate. Also, our in vitro and zebrafish xenograft model indicates a direct correlation between Spy1 overexpression and migration ability of AdPC cell lines. Herein, we hypothesize that Spy1 compensates for AR loss in AdPC and facilitates progression to a proliferative, NE-like and stem-like phenotype. In this work, we evaluate the role of different cell cycle regulators including Spy1 in AdPC progression and address whether this could represent a novel therapeutic direction for NEPC patients. This research could lead to higher success rates of AR-suppressed diagnosis and survival of patients with NEPC.