Drug Repurposing: Antidepressants, MAOIs, and Prostate Cancer Treatment
Featuring: Mitchell Gross, MD, PhD
In short
A common antidepressant called phenelzine — one of the oldest MAO inhibitors — is being studied as a possible treatment for prostate cancer, particularly for patients whose cancer has come back or stopped responding to standard therapies. In a small pilot trial, 24% of patients saw a PSA decline and about a third had no disease progression. Researcher Mitchell Gross, MD, PhD, explains why the enzyme MAOA is a promising target, which cancer types may benefit, and what it would take to access this approach today.
- •MAOIs like phenelzine are not an approved cancer treatment — if you're interested, ask your oncologist about the experimental, off-label nature of this approach before pursuing it.
- •This research may be most relevant if you have high-grade, recurrent, or treatment-resistant prostate cancer, where MAOA tends to be highly expressed.
- •Search ClinicalTrials.gov for ongoing trials investigating MAOIs in cancer to see if you might be eligible to enroll.
- •Patients taking MAOIs must avoid certain foods high in tyramine — such as aged cheeses and some fermented foods — so discuss diet restrictions and drug interactions with your care team.
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Repurposing an Antidepressant Against Prostate and Other Cancers” Brad Power and Marianna Hernandez July 10, 2024 “I led a clinical trial testing phenelzine. It’s one of the oldest MAOIs, but clinically available and used. What I found was that 24% of the patients had a PSA decline. That was definitely encouraging.
Meeting Summary
Cancer researchers are constantly searching for unique characteristics of cancer cells and cancer evolution that they might be able to target with drugs. One such unique characteristic in prostate cancer and treatment-resistant cancers is high expression of an enzyme, monoamine oxidase A (MAOA). MAOA acts like a garbage disposal for certain chemicals which transmit signals between nerve cells in the brain.
It turns out that MAOA also plays a role in promoting cancer growth, metastasis, and drug resistance. Elevated MAOA expression in cancer cells is associated with poorer survival. If we could inhibit MAOA, perhaps we could inhibit the growth of cancer.
Mitchell Gross, MD, PhD, Faculty and Senior Director, Clinical Translational Program, and Associate Professor, USC Keck School of Medicine at the Ellison Institute of Technology Los Angeles, is uniquely qualified to talk about the potential of MAOA inhibitors in cancer care. His group recently published the results of the first clinical trial demonstrating clinical activity of a MAOA inhibitor in patients with recurrent prostate cancer.
They have also recently identified new chemical structures and drugs designed to specifically target MAOA enzyme activity outside of the central nervous system to avoid the potential for brain-related adverse effects which may be associated with these treatments.
His overall research interest focuses on applying modern techniques relating to the study of genes and proteins (genomics and proteomics) on the clinical problems faced in treating patients with prostate cancer. A particular interest relates to the androgen receptor and related proteins and pathways as key driving forces behind the development and treatment of prostate cancer.
As a medical oncologist, his clinical activities are focused on therapeutic clinical trials incorporating both molecularly targeted and conventional therapies to the care of patients with prostate cancer. He serves as primary investigator on many multicenter phase 1 and 2 clinical trials. Dr. D. Molecular Biology).
He completed a residency in internal medicine and a fellowship in hematology and medical oncology at the UCLA Center for the Health Sciences. Why is MAOA a promising targeted approach for multiple cancer types, particularly prostate cancer?
•MAOA is highly expressed in high-grade prostate cancer, and is upregulated in treatment-resistant cancers. It helps to control the balance of chemicals inside cells and also helps to control how genes are switched on and off. Research has shown that MAOA plays a role in promoting cancer cell growth, metastasis, and immune evasion in prostate cancer.
•MAOA inhibitors, like phenelzine, a medication primarily used to treat depression, have been shown to decrease cancer growth in animal models. It can be combined with other treatments, like androgen deprivation therapy or immune checkpoint inhibitors, to enhance anti-cancer effects.
•Phenelzine has the potential of hitting multiple targets, and it has shown to have activity in several cancer types.
•Repurposing an existing drug, like phenelzine, reduces the time and costs associated with drug development. What additional preclinical research is needed to better understand the anti-cancer mechanisms of MAOIs and optimize MAOI use in cancer treatment?
•Detailed molecular mechanism studies to see how these medications interfere with the processes that make cancer cells run, and how they might change the cell's ability to produce energy.
•Comprehensive genomic and transcriptomic analysis to identify specific cancer subtypes most likely to respond to this treatment.
•Combination studies with existing cancer treatments to understand potential synergistic effects, such as immune modulation and their interaction with immune checkpoint inhibitors.
•How nerves outside the brain and spinal cord connect to and affect different kinds of cancer.
•More targeted variants that can minimize side effects while maintaining anti-cancer efficacy. For which cancer patients might MAOIs be relevant?
•Patients with prostate cancer, lung cancer, breast cancer, colon cancer, glioblastoma (brain cancer), colorectal cancer, melanoma, and Hodgkin's lymphoma.
•Patients with treatment-resistant cancers, especially those with high-grade or recurrent prostate cancer. Can you access MAOIs for cancer treatment today?
•MAOIs are not a standard approved cancer treatment. Dr. Gross's research is still preliminary, with a small pilot study of 24 patients showing some potential benefits for biochemical recurrent prostate cancer.
•While the drug exists, it's not widely available for cancer treatment. If you are interested in this approach, you would need to consult your oncologist and discuss the experimental nature of using MAOIs off-label. Repurposing an Antidepressant Against Prostate and Other Cancers” (Mitchell How can you learn more about using MAOIs as a cancer treatment?
•Review Dr. Mitchell Gross's published research on monoamine oxidase inhibitors (MAOIs) in prostate cancer; contact Dr. Gross at mgross@emilaorg
•Consult with oncologists specializing in prostate cancer who are familiar with repurposing drugs and with your medical team
•Follow clinical trials investigating MAOIs in cancer treatment
•Explore databases like ClinicalTrials.gov for ongoing research The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Cancer Patient Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action. You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health. Repurposing an Antidepressant Against Prostate and Other Cancers” Meeting Notes KEYWORDS Monoamine oxidase inhibitors, cancer, prostate cancer,, repurposing, anti cancer effect, mao, brain, medicines SPEAKERS Mitchell Gross (68%), Allen Morris (10%), Brad Power (6%), Richard Anders (5%), Rochelle Prosser (4%), Brian McCloskey (4%), Michelle Sager (2%) SUMMARY Dr. Mitchell Gross discussed the potential of repurposing drugs for cancer treatment, including off-label use of antidepressants, phenelzine, and Monoamine oxidase A (MAOA). He shared his research on using antidepressants to combat prostate cancer and discussed the potential of targeting the MAOA pathway in prostate cancer patients with biochemical recurrence (a rise in PSA levels after initial prostate cancer treatment, indicating a potential return of the cancer). The challenges and opportunities involved in repurposing drugs were highlighted, including the need for funding and the potential negative effects on micronutrients. The potential of monoamine oxidase inhibitors (MAOIs) in cancer treatment was also discussed, including their location and specificity. Speakers explored the potential of using historical databases to identify interactions between MAOA inhibitors and cancer, and discussed the development of new medicines that combine the benefits of MAOIs while minimizing their adverse effects. OUTLINE Introductions
•Brian McCloskey connected with Dr. Gross for prostate cancer treatment through repurposed drugs.
•Dr. Gross presented his research on antidepressants combating prostate cancer. Monoamine oxidase inhibitors and their relation to prostate cancer.
•Dr. Gross discussed monoamine oxidase inhibitors and their relation to prostate cancer and other cancers. Monoamine oxidase A and its role in prostate cancer, including its upregulation in high-grade cancer and its potential as
•Dr. Gross explained the function of monoamine oxidase inhibitors in the body, including their role in regulating neurotransmitters.
•Monoamine oxidase A and B have different expressions in different parts of the body, and inhibitors can be specific to one or both forms. Repurposing an Antidepressant Against Prostate and Other Cancers”
•Dr. Gross discussed monoamine oxidase A (MAOA) and its relation to prostate cancer, highlighting its high expression in high-grade prostate cancer and its potential as a target for treatment.
•Research shows that MLA is upregulated in treatment-resistant prostate cancer, including in animal models, and may be a promising target for overcoming resistance to Enzalutamide therapy. Monoamine oxidase inhibitors in prostate cancer treatment.
•Dr. Gross discussed the potential of monoamine oxidase inhibitors (MAOIs) in treating cancer, particularly in combination with other drugs.
•There is a long history of MAOIs in medicine, including their use in treating depression, and their relatively rare use in modern psychiatry.
•Clinical trial results on monoamine oxidase inhibitors for prostate cancer show 24% of patients experiencing PSA decline and 33% showing no progression.
•Patients on phenelzine/MAOIs have to avoid aged avocados and Mexican food due to tyramine interaction. Using monoamine oxidase inhibitors to treat cancer, with a focus on phenelzine and prochlorperazine.
•Researchers found that combining phenelzine with immune checkpoint inhibitors significantly accelerated anti-cancer effects in various cancer models.
•Dr. Gross along with other researchers at USC are trying to redesign MAO inhibitors to target peripheral activity (outside of the brain) for cancer treatment. Safety and efficacy of MAO inhibitors in psychiatry.
•Dr. Gross explains the long-term safety of monoamine oxidase inhibitors in psychiatry, citing animal studies and human trials. Off-label drug use for cancer treatment, with a focus on phenelzine and its potential benefits and risks.
•Dr. Gross discussed a preliminary pilot study on using phenelzine in cancer treatment, emphasizing the need to balance risks and benefits.
•Off-label drug use and personalized medicine highlight the need for genomics data to understand treatment efficacy.
•Dr. Sager discussed MAOA as a potential immune modulator for cancer treatment, with challenges in delivering it across the blood-brain barrier. Monoamine oxidase inhibitors and their potential effects on cancer cells and the nervous system.
•Dr. Gross discussed mechanisms of MAOA in peripheral cancer tissues, including its role in regulating redox potential and cell differentiation.
•He raised a question of whether MAOA’s effects on the nervous system could be desirable in cancer treatment, despite lack of knowledge on the topic. Repurposing an Antidepressant Against Prostate and Other Cancers”
•He discussed the potential side effects of a drug, including a tyramine surge in the bloodstream, and the importance of separating the two effects to understand them better.
•He also mentioned that an MAOA inhibitor could be used to reduce the toxicity of the drug, and there is a literature on this in psychiatry dating back to the 1970s. Repurposing drugs for cancer treatment, including challenges and potential solutions.
•Richard Anders asked about using the Medicare database for cancer research, and Dr. Gross mentioned unpublished real-world evidence from other countries.
•Dr. Gross discussed repurposing existing drugs, including safety considerations and Brian's involvement in the topic.
•Dr. Gross mentioned a nonprofit called Reboot that repurposes drugs, but faces challenges in getting them through the regulatory system.
•Brian McCloskey suggests working with Dr. Gross to update the NCCN guidelines with evidence supporting drug repurposing.
•Rochelle Prosser discussed potential micronutrient interactions with targeted therapies, including FGFR drugs and their impact on survivorship. Using ADT in combination with Enzalutamide for BCR patients.
•Allen Morris presented a theory that women are in a better immune state than men, based on observations of autoimmune diseases, cancer, and COVID-19 outcomes.
•Morris suggests ADT class drugs, which are proven treatments for high risk BCR patients, if phenelzine is used off-label for BCR, should still be given. And highlights Dr. Gross’ research that suggests synergy. Repurposing an Antidepressant Against Prostate and Other Cancers”
Full transcript
Brad Power This is the Cancer Patient Lab. Let me quickly cover our standard housekeeping items before we get started. The first is that this is not medical advice. This is for information purposes only. Everything that you hear is with a goal of allowing you to take some of these ideas to your medical team for consideration in your care. We are a patient-led learning community.
We would appreciate any donations that you might make, which you could do through our website, using the donate button. Brian, can you introduce Dr. Gross and describe how we got connected and your background with him? Brian McCloskey 1:06 Our paths go back many years. I was diagnosed with prostate cancer in 2016. Dr. Gross was part of my clinical team very early on, I think, as early as 2017. He's been a part of my care team really ever since.
But I got interested in repurposing drugs and reached out to a company called “Reboot Rx”. I don't think Laura Kleiman is on this call. But long story short, I put Laura in touch with Dr. Gross, because he is an expert in the repurposing of drugs. Laura had a very interesting AI methodology for identifying drugs that could be repurposed. But of course, it requires clinical scrutiny.
So I don't think that we're going to be talking about that so much. But we are going to be talking about antidepressants and the amazing research that Dr. Gross has Repurposing an Antidepressant Against Prostate and Other Cancers” done with antidepressants in combating prostate cancer and other cancers as well. So Dr. Gross, thank you so much for accepting the offer to be here.
We look forward to your lecture, and very active discussion from the community as well. Mitchell Gross 2:22 That's great. Yeah. Thank you again, Brian and Brad for inviting me to speak. What I thought I would do here was talk about the story of monoamine oxidase inhibitors (MAOIs), and how I propose that that's related to prostate and other cancers, and show you some data in prior publications that led me to this conclusion.
First, we'll talk about monoamines and monoamine oxidase inhibitors (MAOIs). Then we'll talk about how these are related to prostate cancer and other cancers. Then we'll talk about some next steps. Repurposing an Antidepressant Against Prostate and Other Cancers” Monoamines are a class of natural signaling molecules in the body. There are many of these that are really important for many functions, especially in the brain.
We know a lot of these in popular literature, there's what we call “epinephrine” (or “adrenaline”), that's a monoamine. Other ones are called “serotonin”, “dopamine”, or “histamine". These are all monoamines. These are very important molecules for lots of processes in the body that have to do with signaling, basically, telling one cell or another cell what to do. So some examples of some of these monoamines and their diseases include depression.
Low serotonin levels in certain areas of the brain are related to depression, and we use drugs that try to raise those levels. The main problem in Parkinson's is a deficiency of dopamine in one particular brain area. Again, we use medicines to raise those. We know about what's called adrenaline, or epinephrine, the “fight or flight” response.
That's also driven by a monoamine, by epinephrine, which has to do with blood pressure and heart rate and attention and all sorts of things. That's the function of the monoamines in the body. Some examples of that. What are monoamine oxidase inhibitors (MAOIs)? Well, every time you have an “on switch” in the body, you also have an “off switch”. The MAOIs or monoamine oxidases are the “off switch”.
Repurposing an Antidepressant Against Prostate and Other Cancers” We see a diagram of the monoamine system, like two neurons talking to each other. The purple triangles represent monoamines, and they go between the cells. But then on the left, the monoamine oxidases will turn off and will inhibit those.
It helps to regulate the right amount of the neurotransmitter (chemical messengers of the body that communicate across different cells in different parts of the body), as they're communicating to each other. That's the picture on the right. On the far right is: if you have a MAOI, what you do is you prevent or block the inhibition or the degradation of those purple triangles.
The purple triangles build up, you get more monoamines, more purple triangles, more signaling to the other neurons. Basically, that's what monoamine oxidase does: it helps to regulate this very important system in the body that has lots and lots of different aspects of it. The other part to go into is there's what's called monoamine oxidase A (MAOA) and monoamine oxidase B (MAOB). These are two forms.
The important thing is that they're expressed in different parts of the body, different parts of the brain, other body parts as well, but also, the chemical inhibitors that we develop can be specific to one or both of these. There’s MAOA and MAOB, they have different areas, they have different functions. The inhibitors also have different activities, different functions.
Most of the MAOIs, certainly the ones that are used somewhat in psychiatry now – but not so commonly used to be – are nonspecific inhibitors. They inhibit both the A and B forms. There's another MAOB inhibitor, which is much more commonly used in Parkinson's disease, called “selegiline”. It's either a patch or pill, used in some patients with Parkinson's, that's very specific for MAOB.
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