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研究摘要
Project 1. Targeting HIF-1 complex in NEPC
Aim 1. To characterize hypoxia and LncHIFCAR as progression factors for NEPC
1a. Hypoxia as a master inducer of NED/NEPC progression
1b. LncHIFCAR as a key regulator of hypoxia-induced NED/NEPC progression
Aim 2. To characterize LncHIFCAR as a biomarker and potential therapeutic target for NEPC
2a. Examination of LncHIFCAR levels in the tissue and blood samples of NEPC as potential markers
2b. Evaluation of LncHIFCAR as therapy target for NEPC
Project 2: Targeting ZBTB46/LIF in NEPC
Summary of pervious results
- LIF promotes a malignant phenotype in prostate cancer
- LIF induces prostate cancer resistance to AR-targeted therapeutics
- LIF and ZBTB46 expressions are correlated with NEPC progression
Aim1: To determine the roles of ZBTB46 in regulation LIF of prostate cancer
- To clarify LIF associates with ZBTB46 expression and contributes to CRPC-NE progression
- To determine whether LIF-induced NE differentiation is ZBTB46-dependent
- To study whether ZBTB46 binds directly to the LIF regulatory sequence and enhances its transcription
Aim2: To characterize the potential to develop new diagnostic options for prostate cancer patients
- To study weather LIF titers in serum as a diagnostic and prognostic biomarker for prostate cancer
Project 3 Targeting L1CAM
Previous progress:
Hypoxia and arbiraterone can induce L1CAM expression in NEPC-like cells (PC3, CWR22r-v1)
L1CAM promotes the resistance of AR-targeted therapy (CWR22r-v1)
L1CAM mediates the CSC property of de novo NEPC cells (PC3)
Current proposal:
Aim 1: To evaluate the clinically relevant of L1CAM as a diagnostic and/or predictive marker for NEPC.
Aim 2 to investigate the feasibility of nuclear L1CAM as a drugable target for NEPC-associated mCRPC
Project 4: Targeting ADAM9/sADAM9 in NEPC/mCRPC
Progress
ADAM9 shedding L1CAM different from previous report of ADAM10 shedding site.
Increased ADAM9 can be detected in the early stage of androgen independent progression
Stromal released sADAM9 play important role to induce prostate cancer cell migration
Aim 1: Characterize the role of ADAM9 and sADAM9 in NEPC progression.
Aim 2: Evaluate other factors in t-NEPC progression.
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