The discovery of functionally active autoantibodies (GPCR-AAB) in the blood of patients that bind to GPCR for uncontrolled stimulation, which explains the perpetuation of pathogenically important downstream effects inside cells, has introduced a new class of autoimmune diseases denoted as functional autoantibody diseases. The bioassay of spontaneously beating cultured neonatal rat cardiomyocytes [23] , is the most commonly used analytical tool for the identification and characterization of GPCR-AAB found in human serum.
Having recently shown with this bioassay that patients with BPH/LUTS carry functional autoantibodies, such as ETA-AAB, we used in the present study this tool to demonstrate that patients with prostate cancer also carry GPCR-AAB, but positive chronotropic α1-AAB in addition to the negative chronotropic ETA-AAB.
ETA-AAB were found in the majority (68%) of patients with prostate cancer, targeting the second extracellular receptor loop, an epitope located in the middle region of the loop. This is insignificantly different from our findings with a 60% ETA-AAB positivity in patients with BPH/LUTS in whom the ETA-AAB target was comparably localized [20].
In contrast to patients with BPH/LUTS, where ETA-AAB were the only GPCR-AAB, nearly all patients with prostate cancer additionally carried α1-AAB which targeted the first extracellular loop, and specifically an epitope localized near the loop’s N-terminus. α1-AABs were also frequently found in patients with idiopathic pulmonary hypertension, diabetes mellitus, drug-induced cancer [16,17], psoriasis [25] and dementia [19], where the α1-AAB targeted the second extracellular receptor loop. However, α1-AAB targeting the first extracellular loop were found in dementia patients [26].
GPCR-AAB were not found in our control group, except one control who carried α1-AAB. Interestingly, this man suffered from psoriasis in which α1-AAB positivity was described 27.
Regarding the mechanisms to be considered for ETA-AAB- and α1-AAB-induced pathologies, many of these with the potency of generalization were discussed for ETA-AAB focused on systemic sclerosis [27] and for α1-AAB focused on Alzheimer’s disease [26].
For ETA-AAB in prostate cancer must be considered that their target, the ETA receptor, was identified in the prostate in the 1990s [28,29], where its expression increased with tumor stage, grade and recurrence [30]. Overstimulation of the endothelin receptor A led to pathogenic effects involved in tumor growth, epithelial mesenchymal transition, apoptosis, metastasis, angiogenesis, and drug resistance, thus probably contributing to prostate carcinogenesis [2-5].
Unfortunately, a meta-analysis of clinical trials of ETA receptor antagonists for the treatment of hormone refractory prostate cancer did not show a significant benefit for overall or progression-free survival. However, patients benefited from a reduction in cancer-related bone pain and skeletal events [31].
To approximate the carcinogenic effects of α1-AAB, several arguments for the effects of α1-adrenergic receptor-mediated signaling on the development, progression and prevention of prostate cancer were summarized in [7].
The α1-adrenergic receptor subtype A is localized in the prostate [32,33] and mRNA and receptor increase were found in the aging gland [34,35]. Proliferation in prostate cancer epithelium was demonstrated after α1-adrenergic receptor stimulation [36]. Due to potentially carcinogenic effects seen after stimulation of the α1-adrenergic receptor in prostate cell lines, suitable blockers have been proposed for the treatment of prostate cancer [37]. Retrospective cohort and observational studies did indeed show a reduced incidence of prostate cancer if patients treated with α1- adrenergic receptor blockers for hypertension and/or benign prostate hyperplasia; in the latter patients the blockers increased the apoptotic index and reduced the vascularity of the prostate tumor [36].
For some antitumor effects of the α1-adrenergic receptor antagonists, however, in addition to the patient benefit discussed as a result of the α1-adrenergic receptor antagonization, a DNA breaking activity of the blockers, which leads to mitotic arrest of the cell cycle and mitochondrial damage, must be considered [37].
By combining ETA-AAB and α1-AAB in prostate cancer with the downstream effects after agonist binding and the lack of prevention of GPCR over-stimulation after GPCR-AAB binding [15], we postulate the establishment of GPCR-AAB/GRCR axes that should be more potent than the physiological axes in over-stimulation and induction of pathologies.
As illustrated in Fig. 4 (using data published in [38-40]), the different binding sites were considered the reason for the discrepancy between physiological agonists and GPCR-AAB in GPCR stimulation and control. While physiological agonists bind in a hydrophobic pocket of GPCR, GPCR-AAB binds to the extracellular loops and, due to the bivalent nature of IgG, crosslink the GPCR to realize the functional activity of GPCR-AAB without control.
It remains speculative, however, whether the postulated creation of the α1-AAB/α1-adrenergic and ETA-AAB/ETA receptor axes in prostate cancer patients overpowers the drug-induced receptor antagonization that was intended to benefit patients.
However, it should not be concealed that, derived mainly from studies of cardiovascular diseases associated with GPCR-AAB, there were convincing data that demonstrated a more pronounced patient benefit if antagonist treatment was combined with an attack on the GPCR-AAB [41].
In case future studies manifest the pathogenic roles of α1-AAB and ETA-AAB in prostate cancer, a treatment strategy targeting the GPCR-AAB should be considered. As a first step of such treatment strategy, we demonstrated the in vitro neutralization of the prostate cancer associated GPCR-AAB with the drug BC 007.
The recently successfully completed phase 1 clinical trial with BC 007 in combination with the successful demonstration of GPCR-AAB neutralization in humans [42,43] could open the door for studies to evaluate in vivo GPCR-AAB neutralization with BC 007 as a new complementary therapeutic strategy for patients with prostate cancer.