PSA splice variant in prostate cancer diagnosis and pathogenesis

Overview

Current clinical prostate cancer screening is heavily reliant on measuring serum prostate specific antigen (PSA) levels. However, two-thirds of these men will not have cancer on biopsy and conversely, other prostate diseases. As a result, for ~75% of patients the large number of indolent tumours diagnosed has led to significant overtreatment creating an urgent need for appropriate prognostic assays that can distinguish indolent, slow growing tumours from the more aggressive and lethal phenotypes. PSA/KLK3 is a member of the tissue-kallikrein family. Recently, we identified a truncated splice variant isoform of PSA (261 aminoacids (aa)), PSA-RP2 (180 aa) to affect the growth and migratory ability of prostate cancer cells. Interestingly, PSA-RP2 was observed to localise in the nucleus of prostate cancer cells unlike PSA protein that is secreted outside the cell. However, the functional role of catalytically inactive PSA-RP2 in prostate cancer pathogenesis and the underlying molecular mechanisms remains elusive. Our expression analysis revealed the higher expression of PSA-RP2 in prostate tumour compared to the benign tissues showing that PSA-RP2 may be more clinically valuable as a diagnostic and prognostic biomarker for prostate cancer.

This project aims to comprehensively the role of this novel KLK3/PSA splice variant in prostate cancer by:

Aim 1. Elucidate the functional role of PSA-RP2 on prostate cancer progression in in vitro and in vivo models

Aim 2. Decipher the mechanistics of action of PSA-RP2

Aim 3. Develop an immunoassay to accurately detect PSA-RP2 isoform and evaluate the diagnostic and prognostic potential.

This project employs a range of cell biology in vitro assays, 3D organoid models and preclinical in vivo models to assess the role of PSA-RP2 in prostate cancer initiation and metastasis. Global expression analysis and high-throughput mass-spectrometry proteome analysis may be undertaken to understand the mechanisms underlying the function effects utilising the overexpression and knockdown models. Aim 3 involves develops a new immunoassay using our custom synthesised anti-PSARP2 antibody and evaluate its diagnostic and prognostic potential by testing in clinical prostate cancer samples resourced through Australian Prostate Cancer BioResource.

Approaches/skills and techniques:

• Cell culture
• Preclinical in vivo models
• Organoid assays
• Omics analysis
• ELISA
• Histology

Outcomes:

Identifying the functional role of PSA-RP2 in prostate cancer aetiology and development. Identify a  novel biomarker for prostate cancer diagnosis and prognosis.

Required skills and experience:

Candidates with skills in cell biology will be advantageous.

Clinical significance/commercial impact:

Developing a rapid PSA-RP2 specific immunoassay will help to substantially address the inaccuracy of the current state of prostate cancer diagnosis, identify men who are at risk of developing aggressive disease in future and lead to better clinical management in men who need not have to undergo any interventions including painful biopsies, surgery and treatment. Accurate diagnosis will thus reduce substantial costs and improve patient survival and lifestyle to a considerable extent.

Keywords

• cancer diagnosis
• metastasis
• biomarker
• prostate cancer

Contact

Contact Dr Sri Srinivasan for more information.