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Autoantibodies directed against α1-adrenergic receptor and endothelin receptor A in patients with prostate cancer
Gerd Wallukat1, Burkhard Jandrig2, Niels-Peter Becker1
1Berlin Cures GmbH, Knesebeckstraße 59-61, 10719, Berlin, Germany.
Background:
For prostate cancer, signaling pathways induced by over-boarding stimulation of G-protein coupled receptors (GPCR) such as the endothelin, α1- and β-adrenergic, muscarinic and angiotensin 1 receptors were accused to support the carcinogenesis. However, excessive receptor stimulation by physiological receptor ligands is minimized by a control system that induces receptor sensitization and down-regulation. This system is missing when so-called "functional autoantibodies" bind to the GPCR (GPCR-AAB). If GPCR-AAB were found in patients with prostate cancer, uncontrolled GPCR stimulation could make these autoantibodies an additional supporter in prostate cancer.
Methods:
Using the bioassay of spontaneously beating cultured rat neonatal cardiomyocytes, GPCR-AAB were identified, quantified and characterized in the serum of 25 patients (aged 56-78 years, median 70 years) with prostate cancer compared to 10 male patients (aged 48-82 years, median 64) with urinary stone disorders (controls).
Results:
Of the cancer patients, 24 (96%) and 17 (68%), respectively, carried autoantibodies directed against the α1-adrenergic receptor (α1-AAB) and endothelin receptor A (ETA-AAB). No patient was negative for both GPCR-AAB. In contrast, ETA-AAB and α1-AAB were absent in all (100%) and 9 (90%) of the 10 control patients, respectively. While α1-AAB targeted a specific epitope of the first extracellular loop of the α1-adrenergic receptor subtype A, an epitope of the second extracellular loop of the ETA receptor was identified as a target of ETA-AAB. As demonstrated in vitro, the functional activity of both autoantibodies found in prostate cancer can be neutralized by the aptamer BC007.
Conclusions:
We hypothesized that α1-AAB and ETA-AAB, which are highly present in prostate cancer patients, could by their functional activity support carcinogenesis by excessive receptor stimulation. The in vitro demonstrated neutralization of α1- and ETA-AAB by the aptamer BC007 could open the door to complement the treatments already available for prostate cancer.
Insights
Functional autoantibodies targeting G-protein coupled receptors (GPCR-AAB) are prevalent in prostate cancer patients, potentially driving cancer growth. The aptamer BC007 effectively neutralizes these autoantibodies in vitro, offering a potential new therapeutic avenue.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Prostate cancer progression may involve overstimulation of G-protein coupled receptors (GPCRs).
- A natural control system normally prevents excessive receptor stimulation, but this is impaired by functional autoantibodies (GPCR-AAB).
- GPCR-AAB in prostate cancer patients could contribute to carcinogenesis through uncontrolled receptor signaling.
Purpose of the Study:
- To investigate the presence and characteristics of GPCR-AAB in prostate cancer patients.
- To assess the potential role of GPCR-AAB in prostate cancer development.
- To evaluate the efficacy of the aptamer BC007 in neutralizing these autoantibodies.
Main Methods:
- A bioassay using cultured rat neonatal cardiomyocytes was employed to detect and quantify GPCR-AAB.
- Serum samples from 25 prostate cancer patients and 10 control patients were analyzed.
- Autoantibody targets and epitopes were characterized, and in vitro neutralization by BC007 was assessed.
Main Results:
- Autoantibodies against the α1-adrenergic receptor (α1-AAB) and endothelin receptor A (ETA-AAB) were found in 96% and 68% of prostate cancer patients, respectively.
- These autoantibodies were largely absent in control patients.
- α1-AAB targeted an epitope on the first extracellular loop of the α1-adrenergic receptor subtype A, while ETA-AAB targeted an epitope on the second extracellular loop of the ETA receptor. Both were neutralized by BC007 in vitro.
Conclusions:
- The high prevalence of α1-AAB and ETA-AAB in prostate cancer suggests they may support carcinogenesis via excessive receptor stimulation.
- In vitro neutralization of these autoantibodies by the aptamer BC007 presents a potential complementary treatment strategy for prostate cancer.
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