Targeting Prolactin Receptor (PRLR) Signaling in PRLR-Positive Breast and Prostate Cancer

In this issue, Agarwal et al. report negative results from a phase I trial of LFA102, a humanized monoclonal antibody (mAb) that binds to and inhibits prolactin receptor (PRLR) signaling, in patients with PRLR-positive metastatic breast cancer or metastatic castration-resistant prostate cancer (mCRPC) [1]. Althoughno anticancer activitywas noted in the study, questions remain regarding the role of PRLR signaling in these and other cancers and whether further efforts to develop PRLR blockers arewarranted. It should be noted that hormonalmanipulation of the hypophyseal-pituitary axis has benefitedpatients through theuseofgonadotropin-releasing hormoneagonists inprostateandbreastcancerandsomatostatin analogs in neuroendocrine tumors [2]. Therefore, it may be possible to exploit the biology of these and other hypophysealpituitary hormones for the benefit of other cancer patients. The authors are to be commended for publishing results of this carefully conducted study in the Clinical Trial Results section of The Oncologist (Panel 1). Although “negative” in terms of antitumor activity, the study provides useful pharmacokinetic and pharmacodynamic information. A rise in serum prolactin levels followed drug administration, possibly an indication of the effective blockade of the receptor by LFA102. However, a temporal delay was noted between pharmacokinetic parameters and pharmacodynamic response, possibly because of the time required for LFA102 to spread to peripheral tissues and inhibit peripheral PRLR, resulting in an elevation in serum prolactin levels as a compensatory feedback mechanism. The lack of response could have many explanations: a failure to maintain inhibition of the pathway throughout the treatment interval, an ineffective degree of inhibition of the receptor, or a failure to translate receptor inhibition into biologically important effects on tumor growth.The study in question did not biopsy tumor during the trial, so we have no information on these issues. Nor was there a selection strategy for tumors highly expressing the receptor, an approach that might have led to a more positive outcome. Returning to the rationale for further workon inhibitors of the prolactin receptor, there is an obvious need to augment current hormonal therapies of breast and prostate cancers [3]. Antiestrogens and antiandrogens play key roles in the therapy of hormone-sensitive breast and prostate cancer, respectively, butmetastatic tumors inevitably develop resistance to current endocrine-based therapies. Expression of prolactin in both breast and prostate tissue has been well-documented, and tumor production of prolactin has been implicated in the growthofbreastandprostatecancerviaautocrineorparacrine pathways [4, 5]. Wen et al. noted that G129R, an antagonist peptide of prolactin (PRL), blocked the tumoral PRL/PRLR axis, resulting in inhibition of tumor growth in orthotopicmodels of human ovarian cancer [6]. Prolonged treatment with G129R caused redundant autolysosomes in cancer spheroids, resulting in type II programmed cell death, or inducible autophagy [6]. Additionally, carboxypeptidase-D and nitric oxide levels are upregulated by PRL and testosterone in vitro, which favors survival of prostate cancer cells. However, inhibition of PRLR and the androgen receptor (AR) prevented carboxypeptidase-D and nitric oxide production in this setting, which implies that combined blockade of PRLR and AR may have a role in the treatmentof prostatecancer [7]. It has beennoted thathuman epidermal growth factor 2 (HER2)-positive breast cancers are more likely to proliferate and metastasize in the presence of autocrine PRL, which suggests that PRLR and HER2 interact to promote tumorigenesis and breast cancer progression. Therefore, investigators studied the combination of the monoclonal antibody trastuzumab and G129R in two PRLexpressing human breast cancer cell lines (T-47D and BT-474) withvarying levelsofHER2andPRLRexpression.Thecombination of trastuzumab and G129R additively inhibited cellular proliferation in vitro and in vivo as measured by inhibition of the growth of both cell line xenografts in athymic nude mice [8]. Therefore, targeting prolactin signaling appeared to be a logical strategy for further study in breast and prostate cancer.