New paper below [1].
{MAOA has been a promising therapy for 20 years imo.}
"Previous studies have shown that MAOA is clinically associated with prostate cancer (PCa) progression and plays a key role in almost each stage of PCa, including castrate-resistant prostate cancer, neuroendocrine prostate cancer, metastasis, drug resistance, stemness, and perineural invasion.
"Moreover, MAOA expression is upregulated not only in cancer cells but also in stromal cells, intratumoral T cells, and tumor-associated macrophages; thus, targeting MAOA can be a multi-pronged approach to disrupt tumor promoting interactions between PCa cells and tumor microenvironment.
"Furthermore, targeting MAOA can disrupt the crosstalk between MAOA and the androgen receptor (AR) to restore enzalutamide sensitivity, blocks glucocorticoid receptor (GR)- and AR-dependent PCa cell growth, and is a potential strategy for immune checkpoint inhibition, thereby alleviating immune suppression and enhancing T cell immunity-based cancer immunotherapy."
A clinical trial of a MAOA inhibitor (phenelzine sulfate) (2010) was terminated due to poor accrual [2].
But a second trial that also used phenelzine sulfate was completed [3a], with results published in 2021 [3b]:
Discussion:
"In this phase 2 trial involving patients with non-metastatic, castration-sensitive prostate cancer, treatment with phenelzine resulted in a ≥ 50% PSA decline in 10% of subjects. Eleven of 20 patients (55%) had measurable PSA decline compared to baseline with the greatest decline being 74%. Overall, we found phenelzine to be safe and well tolerated in this asymptomatic patient population with most patients (95%) reaching the target dose of 60 mg/ day for an average duration of treatment of 350 days (±263 days). The most common treatment related adverse events reflected the known MAOI related central nervous system effects including dizziness, fatigue, and somnolence. In general, these remained mild (grade 1) and were managed with dose adjustments. However, in two patients, grade 1 treatment related toxicity of dizziness led to subject withdrawal before completing 2 cycles.
"A particular concern associated with the use of irreversible and MAOA/MAOB non-selective MAOIs such as phenelzine is the occurrence of transient hypertension associated with high dietary tyramine intake (termed the “cheese effect”) (24). Perhaps not as well-known is transient hypotension which may also be associated with these agents (25). In this trial, regular evaluation for cardiovascular signs and symptoms (generally every 4–6 weeks) and patient education cards were used to minimize cardiovascular risks and avoid exposure to high-tyramine foods. However, we did observe cardiovascular adverse events on trial which included grade 4 hypertension (1 subject) and grade 3 syncope (2 subjects) requiring subject withdrawal. All of these significant cardiovascular adverse events occurred without obvious dietary indiscretion and after more than 3 months of therapy. As these events were both rare and reversible and the median duration of treatment on the trial approached one year (326, range 40–954, days), we conclude that phenelzine is safe to administer to prostate cancer patients without pre-existing psychiatric or neurologic diseases when used with close monitoring in this setting with emphasis that educating patients about dietary restrictions is key to safety.
"As MAOIs are best known as anti-depressants with a recommended therapeutic dose range of 60–90 mg daily, we used the HADS questionnaire to explore mood effects associated with phenelzine treatment in patients in the absence of an overt psychiatric disorder. At baseline, potentially clinically significant anxiety (HADS-A>7) was observed in 7 of 20 subjects (35%). Anxiety relating to PSA laboratory values has been associated with screening and treatment decision making in prostate cancer (26, 27). Interestingly, we observed a significant decrease in the HADS-A index following 3 months of treatment with phenelzine. In this open-label trial, it is impossible to determine if the decrease in anxiety was a direct pharmacologic effect of MAOI treatment or a non-specific placebo effect related to clinical trial participation. Regardless, the data does suggest that anxiety is prevalent in patients with biochemically recurrent prostate cancer and additional studies may be needed to address more fully this as an important quality of life issue in prostate cancer patients following primary therapy.
"The main limitations of this study include lack of a placebo control group and the small sample size. Biochemical recurrent prostate cancer is notoriously heterogeneous in clinical course with a very long natural history that can extend for many years from the time PSA elevation to the development of overt metastatic disease. It is possible that the short-term effects observed on PSA levels may not translate to significant delays in clinically significant endpoints such as metastatic progression or overall survival. In general, an appropriately powered randomized clinical trial would be required to demonstrate effects on time to progression endpoints.To our knowledge, this study represents the first clinical trial to demonstrate activity of a MAOI in human cancer. Additional studies are planned to identify biomarkers of clinical benefit and to explore how MAOI based therapy may be best applied to the treatment of men with prostate cancer."
Wikipedia [4]: "Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A(MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, especially for treatment-resistant depression and atypical depression.They are also used to treat panic disorder, social anxiety disorder, Parkinson's disease, and several other disorders."
Also of interest, published this year [5] (full text):
"Monoamine oxidase A: An emerging therapeutic target in prostate cancer"
Abstract:
"Monoamine oxidase A (MAOA), a mitochondrial enzyme degrading biogenic and dietary amines, has been studied in the contexts of neuropsychiatry and neurological disorders for decades, but its importance in oncology, as best exemplified in prostate cancer (PC) to date, was only realized recently. PC is the most commonly diagnosed non-skin cancer and the second deadliest malignancy for men in the United States. In PC, the increased expression level of MAOA is correlated with dedifferentiated tissue microarchitecture and a worse prognosis. A wealth of literature has demonstrated that MAOA promotes growth, metastasis, stemness and therapy resistance in PC, mainly by increasing oxidative stress, augmenting hypoxia, inducing epithelial-to-mesenchymal transition, and activating the downstream principal transcription factor Twist1-dictated multiple context-dependent signaling cascades. Cancer-cell-derived MAOA also enables cancer-stromal cell interaction involving bone stromal cells and nerve cells by secretion of Hedgehog and class 3 semaphorin molecules respectively to modulate the tumor microenvironment in favor of invasion and metastasis. Further, MAOA in prostate stromal cells promotes PC tumorigenesis and stemness. Current studies suggest that MAOA functions in PC in both cell autonomous and non-autonomous manners. Importantly, clinically available monoamine oxidase inhibitors have shown promising results against PC in preclinical models and clinical trials, providing a great opportunity to repurpose them as a PC therapy. Here, we summarize recent advances in our understanding of MAOA roles and mechanisms in PC, present several MAOA-targeted strategies that have been nominated for treating PC, and discuss the unknowns of MAOA function and targeting in PC for future exploration."
-Patrick
[1] pubmed.ncbi.nlm.nih.gov/370...
[2] clinicaltrials.gov/ct2/show...
[3a] clinicaltrials.gov/ct2/show...
[3b] ncbi.nlm.nih.gov/pmc/articl...
