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GRPR antagonists for prostate cancer—prospects and caveats

Nature Reviews Urology volume 10, page 424 (2013)Cite this article

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In their Review, Mansi and colleagues provide an excellent overview of the role of the gastrin-releasing peptide receptor (GRPR) in the progression of prostate cancer and other urological cancers, and discuss the potential of GRPR as a therapeutic target (Mansi, R., Fleischmann, A., Mäcke, H. R. & Reubi, J. C. Targeting GRPR in urological cancers—from basic research to clinical application. Nat. Rev. Urol. 10, 235–244; 2013).1 As acknowledged by the authors, the first human trial of a GRPR antagonist was performed at our institution (G. Schwartsmann was the principal investigator).2 Our phase I study enrolled 25 patients with diverse types of advanced solid malignant tumours, six of whom (24%) had prostate cancer and three patients (12%) had kidney cancer. Patients were given either one or two daily subcutaneous injections of the selective GRPR antagonist RC-3095 at doses up to 96 μg/kg. Although no objective tumour responses to the treatment were observed, there were no significant toxic effects related to drug administration, and a phase II study is planned. In our opinion, it is worth pointing out some additional issues not addressed by Mansi et al.1 that might be relevant for the clinical development of GRPR antagonists for prostate cancer.

Regarding the cellular mechanisms involved in GRPR-driven tumour progression, prostate cancer might have a unique response to GRPR activation owing to a close functional interaction between the GRPR and the androgen receptor (AR). GRP—the endogenous GRPR agonist in humans, detected in 50–60% of prostate cancer specimens3—can activate the AR and enhance the proliferation and migration of prostate cancer cells in androgen-depleted conditions. Importantly, androgen-independent growth of prostate cancer cells transfected to overexpress GRP requires GRPR activation and is inhibited by RC-3095.4 These findings strongly indicate that the GRPR can mediate cancer initiation and growth by modulating AR signalling, even in the absence of androgen stimulation. Thus, the GRPR is a particularly promising target for the inhibition of tumour progression in patients with castration-resistant prostate cancer.4,5 Further investigation of the crosstalk between GRPR and AR signalling is crucial for the characterization of therapeutic opportunities to block the GRPR in prostate cancer.

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References

  1. Mansi, R., Fleischmann, A., Mäcke, H. R. & Reubi, J. C. Targeting GRPR in urological cancers—from basic research to clinical application. Nat. Rev. Urol. 10, 235–244 (2013).

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Acknowledgements

The authors are supported by the National Council for Scientific and Technological Development (CNPq; grant numbers 303703/2009-1 and 484185/2012-8 to R. R.); the National Institute for Translational Medicine (INCT-TM); the University Hospital Research Fund (FIPE-HCPA); and the South American Office for Anticancer Drug Development.

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  1. Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Ramiro Barcelos 2350, Porto Alegre RS, 90035-003, Brazil

    Rafael Roesler

  2. Department of Internal Medicine, School of Medicine, Federal University of Rio Grande do Sul, Rua Ramiro Barcelos 2350, Porto Alegre RS, 90035-003, Brazil

    Gilberto Schwartsmann

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Correspondence to Rafael Roesler.

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Roesler, R., Schwartsmann, G. GRPR antagonists for prostate cancer—prospects and caveats. Nat Rev Urol 10, 424 (2013). https://doi.org/10.1038/nrurol.2013.42-c1

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