There are 2 reasons for the slow development of clinically-useful prostate cancer biomarkers, according to Josep Domingo-Domenech, MD, PhD, of the department of pathology, Icahn School of Medicine at Mountain Sinai in New York, New York.
“First and foremost, it has to do with the prolonged natural history of prostate cancer,” he told Cancer Therapy Advisor. “For example, in breast and lung cancers, most of disease relapses and patient deaths occur within the first 5 years after diagnosis, while in prostate cancer patients these sad events happen after 10 to 15 years.”
That means that depending on its intended clinical uses, prospectively assessing a candidate prostate cancer biomarker can require more than a decade.
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Secondly, clinical translation and adoption of biomarkers is most likely when they are “theranostic,” Dr Domingo-Domenech said, meaning the biomarker should have prognostic significance and it should be a therapeutic target.
“A clear example of a biomarker successfully developed into the clinic is HER2, which, besides giving prognostic information, also guides anti-HER2 therapies that improve breast cancer patients’ survival,” Dr Domingo-Domenech said. “Unfortunately, to date for prostate cancer, no biomarker has proven theranostic value.”
Dr Domingo-Domenech and his colleagues believe, however, that they may have found a theranostic biomarker for prostate cancer: the endothelial transcription factor, GATA2.
GATA2 is linked to hematopoiesis and prostate cancer progression and metastasis. GATA is overexpressed in primary prostate tumor samples from patients with relapsed disease and regulates cell adhesion and motility—2 important factors affecting the spread of tumor cells to distant organs.
“GATA2 has theranostic value,” Dr Domingo-Domenech said. “GATA2 is overexpressed in lethal prostate cancer and can be therapeutically targeted. GATA2 is a ‘pioneer’ transcription factor, meaning that it is the first 1 to bind to chromatin and open it for other transcription factors to regulate transcription.”
“GATA2 in prostate cancer acts as a master regulator that controls the transcriptional activity of the androgen receptor, which has a critical role in prostate cancer, and also the expression of other transcription factors implicated in invasion, motility, tumorigenicity, and survival,” he said. GATA2 overexpression also seems to increase prostate tumor resistance to standard therapies.1
GATA affects insulin-like growth factor 2 (IGF2), a ligand for IGF1 receptor and insulin receptor (INSR), as well as other downstream effectors like PAK4, ARRDC3, DPYSL3, FOXM1, and GLNT7. Targeting these effectors “could offer a new therapeutic strategy for treating patients with prostate cancer,” he and his team have argued.2
GATA2 therefore holds potential as a research biomarker for the development of targeted agents, and as a potential clinical assay for identifying patients at greatest risk of disease progression, metastasis, and death.
“Clinically, GATA2 expression can be assessed at the protein or RNA levels on primary prostate cancer tumor samples to identify patients at high risk of relapse,” explained Dr Domingo-Domenech.
Immunostaining and gene expression assays for GATA2 activity in prostate cancer biopsy specimens are reproducible, “easy to interpret,” and readily implemented in clinical use, Dr Domingo-Domenech and colleagues reported. Once validated and tested clinically, GATA2 prognostic and predictive tests could help personalize prostate cancer treatment.
Dr Domingo-Domenech and colleagues are working to validate GATA2’s prognostic and predictive value as a gene-expression (RNA) and proteomic biomarker “in large cohorts of prostate cancer patients,” he said.
They are also exploring ways to detect GATA2 expression in circulating tumor cells and exosomes, with an eye toward developing a GATA2 “liquid biopsy” test. That would allow noninvasive assessments of GATA2 levels in patients with prostate cancer at any stage of disease.
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For now, GATA2 activity can only be inhibited indirectly in the lab, using upstream Notch signaling pathway inhibition, downstream inhibition of its INSR or IGF1R effectors, or by targeting epigenetic (acetylation) modulation of GATA2 activity, Dr Domingo-Domenech.
The GATA2 gene is frequently mutated or amplified in hematologic cancers, but that is not the case in prostate cancer, suggesting that in prostate cancer, expression could be regulated epigenetically. A 2015 study found that GATA2 methylation can distinguish pre-cancerous prostate adenoma and prostate tumor tissue. 3
Validating GATA2 biomarker tests will be an important step toward clinical utility of the test itself, and its use in targeted drug development.
References
- Rodriguez-Bravo V, Carceles-Cordon M, Hoshida Y, Cordon-Cardo C, Galsky MD, Domingo-Domenech J.. The role of GATA2 in lethal prostate cancer aggressiveness. Nat Rev Urol. 2016 Nov 22. doi: 10.1038/nrurol.2016.225 [Epub ahead of print]
- Vidal SJ, Rodriguez-Bravo V, Quinn SA, et al. A targetable GATA2-IGF2 axis confers aggressiveness in lethal prostate cancer. Cancer Cell. 2015;27(2):223-39. doi: 10.1016/j.ccell.2014.11.013
- Dmitriev AA, Rosenberg EE, Krasnov GS, et al. Identification of novel epigenetic markers of prostate cancer by Noti-microarray analysis. Dis Markers. 2015;2015:241301. doi: 10.1155/2015/241301
