The majority of patients diagnosed with metastatic prostate cancer (PCa) will, over time, relapse and develop lethal, castration-resistant, prostate cancer (CRPC). Long noncoding RNAs or lncRNA, has emerged as a critical regulatory element of many cellular biological processes. Scientists believe that IncRNA may serve as therapeutic targets for combating prostate cancer progression.[1]

Scientists at the University of Virginia in collaboration with a team of researchers at Manchester UK based APIS Assay Technologies have discovered Hormone-Upregulated lncRNA within the lymphocyte-specific protein tyrosine kinase (HULLK) which is detectable in non-invasive prostate cancer patient samples.

According to the researchers, the breakthrough provides a potential new approach to address the unmet medical need of early diagnostics for prostate cancer, while, at the same time, avoiding an invasive cancer tissue sample collection from a biopsy.

Daniel Gioeli, Ph.D., Associate Professor, Microbiology, Immunology, and Cancer Biology at the University of Virginia, has shown that HULLK could be isolated from the urine of prostate cancer patients. As a result, it may provide a major advantage compared to the current invasive sample collection.

Annual Meeting
The data on the detection of HULLK in urine samples from patients with high-grade prostate cancer (PCa) were presented during the 2020 Annual Meeting of the Society for Basic Urologic Research (SBUR), Saturday, November 14, 2020.

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Gioeli and his team noted that HULLK, an unannotated lncRNA within exon six and the 3’UTR of the LCK gene, is dramatically upregulated by androgen in a dose-dependent manner. They also noted that this hormone-induced increase is completely blocked by the anti-androgen enzalutamide (Xtandi®; Astellas/Pfizer), a nonsteroidal antiandrogen or NSAA, which completely blocks this hormone-induced increase.

Another observation was that HULLK transcripts were not only expressed in prostate cancer cell lines but also in prostate cancer patient tissue. Remarkably, there was a significant positive correlation between HULLK expression and high-grade PCa in three independent cohorts from the University of Virginia, the University of Texas Southwestern, and The Cancer Genome Atlas.

“Virtually all patients with metastatic prostate cancer (PCa) will relapse and develop lethal castration-resistant prostate cancer (CRPC),” Gioeli confirmed.

The new data supports the hypothesis on the potential use of HULLK as a biomarker for PCa.

“Our discovery definitely enhances our understanding of lncRNA and prostate cancer biology.  We believe that this and may help in the development of additional biomarkers or more effective therapeutic targets for advanced prostate cancer. However, to succeed, more work, including prospective clinical research, is required to move this discovery into the clinic,” Gioeli noted.

“The latest data, which demonstrates the presence of this biomarker in non-invasive biofluids such as urine, is an exciting step forward,” explained Ian Kavanagh, Chief Operation Officer of APIS Assay Technologies.

“Our intention at APIS Assay Technologies is to implement HULLK into a clinically relevant signature for early detection of patients with metastatic prostate cancer and provide a guide for further treatment,” Kavanagh added.

The overall goal of the collaboration between UVA and APIS is to address the unmet medical need associated with PCa and evaluate the level of HULLK in PCa patients in order to establish the parameters necessary for a clinical trial demonstrating the effectiveness of HULLK as a relevant Biomarker.

“Overall lncRNAs are emerging as critical regulatory elements of many cellular biological processes, that’s why APIS is also working with other lncRNA biomarkers in additional cancer-related indications,” Joachim Schorr, Ph.D., Chief Executive Officer of APIS Assay Technologies.

Non-protein-coding sequences
Despite most cancer studies have been focused on protein-coding genes, the evidence that about 97% of the human genome consists of non-protein-coding sequences led scientists to investigate the untranslated transcripts, called non-coding RNAs (ncRNAs).

The untranslated transcripts, called non-coding RNAs (ncRNAs) can be classified in short (19–31 nucleotides), mid (20–200 nucleotides), and long (> 200 nucleotides) based on their length. long-ncRNAs (lncRNAs), which represent the largest class of non-coding transcripts with about 55,000 genes along the human genome.

lncRNAs may regulate gene expression through their interaction domains for DNA, mRNAs, miRNAs, and proteins. The ncRNAs have cell type, tissue, and cancer specificity, thus RNA profiling has become a means to identify useful biomarkers of tumor development, progression, and metastasis. Although miRNAs represent the most widely investigated ncRNAs, lncRNAs are emerging as cancer key regulators. [2]

LncRNA expression profiles can also identify clinically relevant cancer subtypes that predict tumor behavior and disease prognosis, which defines them as very promising diagnostic and therapeutic biomarkers.

Common disease
With nearly one in every five men diagnosed during their lifetime, prostate cancer (PCa) is a worldwide common disease. The implementation of screening and aggressive treatment has led to improved survival rates, while “overtreatment” and treatment-related side effects can influence the quality of life for survivors and has come under considerable controversy over the last decade.[3]

APIS Assay Technologies and the University of Virginia entered into a Research Agreement in December 2019, after optioning the HULLK technology, which was described in a previous publication from Gioeli´s Group demonstrating the potential role of this biomarker in FFPE samples from PCa patients. [4]

Highlights of Prescribing Information
Enzalutamide (XtandI®; Astellas/Pfizer). [Prescribing Information]

[1] Ta HQ, Whitworth H, Yin Y, Conaway M, Frierson HF Jr, Campbell MJ, Raj GV, Gioeli D. Discovery of a novel long noncoding RNA overlapping the LCK gene that regulates prostate cancer cell growth. Mol Cancer. 2019 Jun 28;18(1):113. doi: 10.1186/s12943-019-1039-6. PMID: 31253147; PMCID: PMC6598369.
[2] Grillone K, Riillo C, Scionti F, Rocca R, Tradigo G, Guzzi PH, Alcaro S, Di Martino MT, Tagliaferri P, Tassone P. Non-coding RNAs in cancer: platforms and strategies for investigating the genomic “dark matter”. J Exp Clin Cancer Res. 2020 Jun 20;39(1):117. doi: 10.1186/s13046-020-01622-x. PMID: 32563270; PMCID: PMC7305591.
[3] Kim EH, Andriole GL. Prostate Cancer Review. Mo Med. 2018 Mar-Apr;115(2):131. PMID: 30228703; PMCID: PMC6139857.
[4] Ta HQ, Whitworth H, Yin Y, Conaway M, Frierson HF Jr, Campbell MJ, Raj GV, Gioeli D. Discovery of a novel long noncoding RNA overlapping the LCK gene that regulates prostate cancer cell growth. Mol Cancer. 2019 Jun 28;18(1):113. doi: 10.1186/s12943-019-1039-6. PMID: 31253147; PMCID: PMC6598369.

Featured image courtesy: © 2020 copyright APIS Assay Technologies.

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