Scientists in Germany have discovered additional ways that hormone therapy using steroid synthesis inhibitor abiraterone acetate (AA) could deliver great help in treating advanced prostate cancer (PC) patients.
The study by researchers from University Medicine Greifswald and University Hospital of Würzburg, Germany, found that “AA’s multi-targeting characteristics could offer further anticancer treatment options in different settings of PC,” reported lead researcher Robert Mandelkow and his colleagues in the latest issue of the gold open-access peer-reviewed journal of Advances in Modern Oncology Research (AMOR).
Prostate cancer is the most commonly diagnosed malignancy and one of the leading causes of oncological mortality in men in the Western hemisphere.
Abiraterone acetate is a hormone therapy drug used to treat metastasized castration-resistant prostate cancer patient – those whose malignancy has spread to other parts of their body and who are no longer responding to conventional medical or surgical treatments in lowering the levels of androgens, the male hormones responsible for stimulating the growth of prostate cancer cells.
The once-daily oral medication AA (marketed as Zytiga, Abiratas, Abretone and Abirapro) is “a potent inhibitor of steroid hormone anabolism,” according to the research team, and the drug is already known to interfere with the CYP17A1 enzymes required in the body’s production of androgens.
The AA interference essentially decreases the amount of androgens produced and stops the testes, the adrenal glands, as well as the tumor itself from manufacturing testosterone, which either slows the growth of prostate cancer or shrinks it altogether.
In addition, AA also impairs expressions of androgen receptors (AR) which mediate the biological effects of androgens. “In PC therapy, the AA anticancer activity essentially arises from the inhibition of androgen receptor signaling, which is the primary growth-stimulating pathway in prostatic epithelial cells,” their report stated.
The German researchers’ goal was to investigate the drug’s effects on other pathways, which could offer new insights on alternative ways of treating prostate cancer.
“Owing to AA’s anti-proliferative efficacy, even in the absence of androgen receptor, the molecular mode of action is suspected to be a result of simultaneously targeted cellular factors,” the team explained.
“Since AA allows inhibitory activity even on castration-resistant patients with androgen-insensitive PC tissues, we hypothesized that additional proliferative pathways can be targeted during AA treatment,” they continued.
The research specifically aimed to characterize AA’s efficacy on lysophosphatidic acid receptor (LPAR) expressions, according to their study.
Lysophosphatidic acid (LPA) is a signaling molecule which can stimulate cell propagation, and therefore has been linked to cancer initiation and progression. In addition, LPA is a pivotal growth-stimulating factor in hormone-regulated tissues such as mammary, endometrial, ovarian and prostatic tissues.
“In PC cells, LPA controls proliferation, cell motility and survival via the modulation of various downstream targets (e.g., transcription factors, growth factors and mitogen-activated protein kinases),” the scientists described.
“The secreted lipase autotaxin hydrolyzes lysophospholipids to LPA, which subsequently binds to its receptors LPAR1-LPAR6. Therefore, LPAR stimulation controls numerous cellular responses,” they added.
“In various malignancies including prostate cancer, the autotaxin enzyme is over-expressed compared to the adjacent non-malignant tissues,” their study stated.
Based on the hypothesis of steroid dependency of the proliferation-stimulating LPAR, the researchers assessed the expressions of LPAR1 to LPAR6 in the presence of AA by propagating prostate cancer cell lines, namely PC-3 (highly metastatic) and LNCaP (low metastatic potential).
The scientists’ research found that AA has an inhibitory effect even on prostate cancer cells that are AR-negative, indicating that AA’s effect is androgen-independent.
“AA possesses anti-proliferative properties even on AR-negative PC-3 cells, which points to an alternative, AR-independent molecular mode of action in AA anti-cancer activity,” they observed.
AA treatment was also verified to also target proliferative factors LPAR1, LPAR3, LPAR4, LPAR5 and LPAR6.
“Diminished levels of steroid hormones achieved by AA treatment,” the researchers observed, “affected the differential expression of LPAR isoforms specifically in PC cells.” Their report added, “The study demonstrated a differentially regulated expression of proliferative LPAR isoforms in AR-positive LNCaP cells incubated with AA.”
The study surmised, “This may underline a more global role of AA in PC cell physiology, and that AA’s molecular mode of action may be a result of simultaneously targeted steroid-dependent factors.”
The German team members include Daniela Brunnert from University Hospital of Würzburg along with Martin Weiss, Martin Burchardt and Matthias B Stope from University Medicine Greifswald, Germany.