While we all use PSA and PSMA as markers for PCa, any hope for a longer term “cure” will only be achieved through therapies that obliterate these nasty little stem creatures. Also, if we could keep any cells out there in a AR+ or resensitize AR-the current SOC would result in much longer life expectancies. The current approach is like the game Whack-a-Mole. Anyways, has anyone seen anything helpful is this regard? Research is hampered by the fact that these are a minority population and that mouse models are short-term and anything that is likely to be effective won’t be effective overnight. The only research I find is addressing natural items but the findings are often more suggestive than conclusive. I am okay with anything that has promise.
Stem-like cells and transcription to AR- - Advanced Prostate...
Stem-like cells and transcription to AR-
You had me at "whack-a-mole" 😂. Anyways, just as a speculative engagement, here is the question I put in to Google search:
GOOGLE SEARCH:
"estrogen axis" metastatic prostate cancer resistance "stem cells"
GOOGLE INLINE AI ANSWER:
"The estrogen receptor alpha (ERα) signaling pathway plays a role in regulating prostate cancer stem cells (PCSCs) and may contribute to prostate cancer resistance. PCSCs are a small population of cells that are responsible for tumor recurrence, metastasis, and treatment failure."
FWIW.
Interesting how many things prostate cancer has “in common” with breast cancer. Somewhat related are studies that identify Prolactin acts as a replacement for T in advanced PCa. The good news here is that there are readily available antagonists for Prolactin. The bad news is that it has only been tested in tubes and Mickey Mouse (ever wonder how he could still be alive?) It somewhat answers why AR- prostate cancer can grow so well with low T even though increased receptor expression and self-synthesis provides a partial answer.
DeepSeek said
(excuse DeepSeek because I didn't feed him everything)
Ah, the estrogen axis in prostate cancer! This is a fascinating (and underrated) angle in the "whack-a-mole" game of treatment resistance. Let’s unpack the AI’s answer and dive deeper into why this matters for prostate cancer stem cells (PCSCs) and therapy evasion:
---
### **1. Estrogen Signaling in Prostate Cancer: Not Just an Androgen Show**
While prostate cancer is androgen-driven, estrogen receptors (ERs)—specifically **ERα**—play a sneaky role in fueling aggression and stemness:
- **ERα vs. ERβ**:
- **ERα** (the "bad cop"): Promotes proliferation, inflammation, and stem cell maintenance. Found in PCSCs and linked to castration resistance.
- **ERβ** (the "good cop"): Often tumor-suppressive, but its expression declines in advanced disease.
- **CSC Connection**: ERα activates pathways like **Wnt/β-catenin** and **Notch**, which drive PCSC self-renewal and survival. It also upregulates **ALDH1** (your CSC marker buddy) and **SOX2**, key for stem cell identity.
---
### **2. How Estrogen Axis Fuels Resistance**
- **AR-Independent Survival**: When androgen receptor (AR)-targeted drugs (e.g., Enzalutamide) suppress the AR pathway, ERα signaling can compensate, keeping PCSCs alive.
- **Inflammatory Feedback**: ERα interacts with **NF-κB** and **IL-6**, creating a pro-inflammatory niche that protects CSCs from therapy.
- **Metastasis**: ERα enhances EMT (epithelial-mesenchymal transition), helping PCSCs break free and colonize new sites.
---
### **3. Targeting the Estrogen Axis: Existing & Experimental Strategies**
- **SERMs (Selective Estrogen Receptor Modulators)**:
- **Tamoxifen** (blocks ERα): Preclinical data shows it reduces PCSC populations, but human trials in prostate cancer are sparse.
- **Raloxifene**: A safer SERM with anti-CSC activity in models, but no prostate-specific trials yet.
- **Aromatase Inhibitors** (e.g., **Letrozole**): Block estrogen synthesis. Mixed results in prostate cancer—may help in ERα+ subsets.
- **ERβ Agonists**: Drugs like **LY500307** reactivate ERβ to counteract ERα, but clinical development stalled.
- **Dual AR/ER Inhibitors**: Experimental drugs (e.g., **TOK-001**) aim to hit both pathways simultaneously.
---
### **4. Why This Matters for Your Approach**
- **Metformin**: Indirectly impacts estrogen signaling by lowering insulin/IGF-1, which can suppress ERα activity. Synergy potential!
- **Doxycycline**: Inhibits mitochondrial metabolism in CSCs, which may overlap with ERα’s metabolic reprogramming.
- **Mebendazole**: While paused, its microtubule disruption could theoretically interfere with ERα nuclear shuttling.
---
### **5. Speculative but Actionable Ideas**
- **Test for ERα Expression**: If your tumor or circulating tumor cells (CTCs) express ERα, targeting it becomes more rational.
- **Repurpose SERMs**: Discuss low-dose tamoxifen/raloxifene with your oncologist—if ERα is active, it’s worth a trial.
- **Combine with AR Therapies**: Pairing an ERα inhibitor (e.g., **fulvestrant**, though not prostate-approved) with Enzalutamide could block escape routes.
- **Watch This Space**: Trials like [NCT03785210](clinicaltrials.gov/ct2/show... (tamoxifen + Enzalutamide) are exploring this axis.
---
### **The Big Picture**
The estrogen axis is a backup orchestra for PCSCs when the AR pathway is silenced. Targeting it could prevent the "adaptive whack-a-mole" resistance you’re wisely trying to outmaneuver. That said, human data is thin—proceed with biomarker-guided caution and a side of clinical trial enrollment.
Need help digging into ERα inhibitors or trials? Let me know!
DeepSeek said
Cool stuff..thanks. Docs in the US are scared silly of prescribing anything off label. We jailed people for suggesting anything for COVID that did directly from Dr. Fauci’s lips (our all-knowing COVID czar at the time.) The good news is that Metformin isn’t impossible to get for the silly reason people are taking it for low cost weight loss.
We have better drugs for weight loss now. Metformin is also good for dementia not just for weight loss.
Weight loss is not so "silly" if you are really overweight.
My sister is 135kg.
Whoops. Didn’t really mean that weight loss is silly. I was thinking of my niece who took Ozempic and never even tried to reduce otherwise and then had stomach problems. She stopped taking it and changed her diet and voila she is healthy again. I realize it isn’t always so easy.
No magic bullet?
DeepSeek said
A. **Short Answer:** Nope, no magic bullet—*yet*. Prostate cancer stem cells (PCSCs) are master escape artists, wired for survival through redundancy (multiple signaling pathways), plasticity (switching identities), and dormancy (hiding out). But the hunt is heating up. Here’s the state of play:
---
### **Why PCSCs Dodge Every Bullet**
1. **Heterogeneity**: PCSCs aren’t a single population. Subtypes use different survival tricks:
- **AR-low/ERα-high**: Rely on estrogen signaling (your Google AI hint).
- **Neuroendocrine**: Ditch AR entirely, activate ASCL1/SOX2.
- **Treatment-emergent**: Evolve new mutations (e.g., BRCA2 loss) post-therapy.
2. **Adaptive Signaling**: Block one pathway (AR), and another (ERα, Wnt, Notch) takes over. It’s like cutting off a hydra’s head.
3. **Dormancy**: PCSCs can “hibernate” for years, evading drugs targeting proliferating cells.
4. **The Microenvironment**: Bone marrow/lymph nodes shield PCSCs via cytokines (IL-6, TGF-β) and immune suppression.
---
### **Current "Bullets" (and Why They’re Not Magic)**
| **Approach** | **Promise** | **Problems** |
|------------------------|----------------------------------------------|-----------------------------------------------|
| **Metformin** | Targets CSC metabolism (AMPK/mTOR). | Weak potency; CSC-specific dosing unclear. |
| **SERMs (Tamoxifen)** | Blocks ERα→Wnt crosstalk in PCSCs. | No prostate-specific trials; risk of blood clots. |
| **Immunotherapy** | CAR-T/NK cells targeting CSC markers (CD44). | PCSCs suppress MHC-I/PD-L1 → immune evasion. |
| **Epigenetic Drugs** | Demethylate silenced tumor suppressors. | Blunt tools; off-target effects. |
| **Antibiotics** | Disrupt mitochondrial metabolism (e.g., doxy). | Risks microbiome carnage + resistance. |
---
### **The Estrogen Axis Wildcard**
The ERα pathway is a **backup driver** when AR is suppressed. Targeting it *could* help, but:
- **Selective targeting is hard**: ERβ (good) vs. ERα (bad) are structurally similar.
- **Crosstalk with AR**: ERα upregulates **PSA** (yes, PSA!) via non-classical pathways, muddying PSA as a biomarker.
- **No approved ERα inhibitors for prostate cancer**: Tamoxifen is breast-cancer-centric, with limited prostate data.
---
### **What’s Missing (and What You Can Do)**
1. **Biomarkers to Guide Therapy**:
- Test tumor/CTC samples for **ERα, ALDH1, CD44** to identify dominant CSC subtypes.
- Use **liquid biopsies** to track PCSC-driven clones (e.g., AR-V7, ERα mutations).
2. **Rational Combinations**:
- **Metformin + Enzalutamide**: Preclinical synergy (AMPK inhibition + AR blockade).
- **Doxycycline + Statin**: Hit mitochondria + cholesterol in CSCs.
- **SERM + Immunotherapy**: Unmask PCSCs to the immune system.
3. **Clinical Trials to Watch**:
- **NCT04815876**: Bipolar androgen therapy (flooding testosterone to disrupt AR/ER crosstalk).
- **NCT03829930**: Pembrolizumab + epigenetic drug (guadecitabine) for CSC-rich tumors.
- **NCT04736992**: ERα inhibitor (GDC-0927) in metastatic prostate cancer.
---
### **Bottom Line**
PCSCs are the ultimate survivors, but their Achilles’ heels are slowly being mapped. For now:
- **Your cocktail (metformin/statin/doxy)** has mechanistic plausibility but unproven efficacy.
- **Prioritize trials** over off-label experiments—PCSC-targeting therapies are finally entering clinics.
- **Monitor aggressively**: PSA *plus* circulating tumor cells (CellSearch®) or exosome-based CSC markers.
The magic bullet might be a **“silver buckshot” approach**: hitting PCSCs from multiple angles while keeping the rest of the tumor in check. Stay tuned—the next 5 years will be explosive for CSC research.
DeepSeek said
Cancer stem cells have been identified in most cancers and probably exist in all cancers. They typically make up 1 to 10% of the entire population of cancer cells in a tumor. They are chemo resistant and radiation resistant. This is a problem with these SOC treatments because they select for these stem cells. This paradigm seems to fit with observations in that the tumor initially shrinks because the majority of the non cancer stem cells are killed off but the percentage of these stem cells has now increased dramatically. So now you have a largely resistant tumor.
It’s a bit like hair loss with chemotherapy. You loose your hair initially but the hair stem cells repopulate the somatic hair cells and it grows back. In other words they survived the treatment. Don’t see why a tumor should be any different.
There are various markers used to identify them. One such marker is ALDH 1 whereby the stem cells are positive whilst the remaining population is mostly negative .
New personalised immunotherapy technologies might be effective at killing these cells. Research is ongoing.
In the meantime 2 drugs that apparently act against the prostate cancer stem cells are Sertraline and Metformin and I have been taking them since my RP for this very reason.
pubmed.ncbi.nlm.nih.gov/327...
nature.com/articles/pcan201535
Thanks! May I ask dosage you are using and how did you get a doctor to write it? I get snorted at when I ask about adjunct therapies by my oncologist. He screwed up his face and said “Oh, you want to take a horse dewormer?”
I figure/guess/accept I face CSCs at my very low stable range for past seven years - 0.03X for nearly four years now, no ADT. I am taking some supplements knowing may be flushing my monies but not aware of any risks. I found a doc, a DO, who was willing to scribe Sertraline and Metformin, but was not compelled. MrProstate what compelled you?
I spent several months reading paper after paper.
I’ve known about the cancer stem cell theory ever since my sisters breast cancer back in 2008 when I acted as her advocate throughout her treatment. Spent months visiting and talking to researchers.
Finally spent time reading about the usage of these drugs by several prostate cancer patients. Anecdotal to be sure but until modern medicine comes up with something useful why not try it?
Thanks! I'll look again. (A few members call my treatment path anecdodtal - well the most popular "SOC" ones don't seem to be delivering what I want. Anecdotal precedes "popular science"). All the best!
Anectodal originates from the Greek word that directly translates to unpublished. It dates from the time that publishing was only considered as printing on paper, hence, got the complementary meaning of "by word of mouth" and by extension "unreliable". Today, electronic media publishing is as good if not better to printing and as so calling anectodal something that has been posted multiple times only shows the language deficit of those using this term.
My MO believes that Metformin plus statins are useful in prostate cancer treatment.
He sounds like an arrogant dill. Something to do with god syndrome? I take 100mg Sertraline and 500mg Metformin daily.
Thanks!
I am using Metformin between 1g to 2g per day plus rosuvastatin, doxycycline 100 mg per day in order to kill cancer stem cells.
I was also using mebendazole 200 mg per day for around 4 months in order to prevent the development of androgen receptors resistance to Enzalutamide or Bicalutamide etc. I stopped that mainly because I didn't see any drop on PSA and to minimise any potential side effects. (Every medication has side effects.)
DeepSeek said
Your approach to targeting cancer stem cells (CSCs) and preventing treatment resistance involves a combination of repurposed medications. Below is a breakdown of the rationale, evidence, and considerations for each drug, along with key recommendations:
---
### **1. Metformin (1–2g/day)**
- **Rationale**:
- Preclinical studies suggest metformin may inhibit CSC self-renewal via AMPK activation and mTOR suppression, potentially sensitizing tumors to therapy. Observational data link metformin use to reduced prostate cancer risk and improved outcomes.
- **Evidence**:
- Limited clinical trials specifically targeting prostate CSCs. A phase II trial (NCT01433913) showed metformin + ADT delayed progression in non-diabetic men, but CSC-specific effects remain unproven.
- **Considerations**:
- Generally safe, but monitor for GI side effects (diarrhea, nausea) and vitamin B12 deficiency with long-term use.
---
### **2. Rosuvastatin (Statin)**
- **Rationale**:
- Statins may disrupt cholesterol-dependent CSC membrane synthesis and inhibit RAS/MEK pathways. Some observational studies associate statins with reduced prostate cancer mortality.
- **Evidence**:
- No randomized trials confirm statins specifically target CSCs. Effects on prostate cancer are inconsistent across studies.
- **Considerations**:
- Watch for muscle pain (myopathy) or elevated liver enzymes. Drug interactions (e.g., with doxycycline) may increase myopathy risk.
---
### **3. Doxycycline (100mg/day)**
- **Rationale**:
- Antibiotics like doxycycline may impair mitochondrial function in CSCs, which rely on oxidative metabolism. Preclinical studies show CSC inhibition in breast and ovarian cancers.
- **Evidence**:
- No prostate cancer-specific clinical data for CSC targeting. Long-term antibiotic use risks microbiome disruption and antimicrobial resistance.
- **Considerations**:
- GI upset, photosensitivity, and esophageal irritation are common. Discuss duration limits with your oncologist.
---
### **4. Mebendazole (200mg/day for 4 months)**
- **Rationale**:
- Antiparasitics like mebendazole disrupt microtubules, potentially blocking androgen receptor (AR) nuclear translocation and slowing resistance to Enzalutamide/Bicalutamide.
- **Evidence**:
- Preclinical studies show activity in prostate cancer models, but no clinical trials support its use in humans. Lack of PSA decline may reflect CSC dormancy or insufficient dosing.
- **Considerations**:
- Liver toxicity and neutropenia are risks. Stopping due to unclear benefit is reasonable.
---
### **Key Concerns & Recommendations**
1. **Lack of Clinical Evidence**:
- These drugs have preclinical rationale but no robust human data for CSC targeting in prostate cancer. PSA stability/decline is not a validated CSC biomarker.
2. **Drug Interactions & Side Effects**:
- **Rosuvastatin + Doxycycline**: May increase muscle toxicity. Monitor CPK levels.
- **Metformin + Doxycycline**: Both cause GI distress; stagger dosing if tolerable.
3. **PSA Monitoring**:
- PSA is not a direct CSC marker. Persistent PSA stability could reflect CSC dormancy or treatment effect, but progression warrants re-evaluation.
4. **Next Steps**:
- Discuss **clinical trials** targeting CSCs (e.g., immunotherapy, NOTCH inhibitors).
- Consider **liquid biopsies** (CTC/DNA analysis) to detect CSC-driven resistance early.
- Prioritize **standard therapies** (e.g., Enzalutamide) with proven survival benefits.
---
### **Conclusion**
Your proactive approach is understandable, but combining repurposed drugs carries risks without proven efficacy. Work closely with your oncologist to:
- Validate strategies with biomarkers (e.g., circulating tumor cells, ALDH1+ cells).
- Balance experimental approaches with evidence-based treatments.
- Explore CSC-focused trials (e.g., NCT04497974 for metformin in prostate cancer).
Let me know if you’d help searching for trials or reviewing specific studies!
DeepSeek said
DeepSeek said
**Cancer Stem Cells (CSCs) and Treatment Resistance: Key Insights**
1. **CSC Characteristics & Role in Resistance**
- CSCs constitute 1–10% of tumor cells, exhibiting chemo/radiation resistance due to mechanisms like enhanced DNA repair, drug efflux pumps, and quiescence.
- Standard therapies shrink tumors by killing non-CSCs but enrich residual CSCs, leading to relapse—akin to hair follicle stem cells surviving chemotherapy to regrow hair.
2. **CSC Markers (e.g., ALDH1)**
- ALDH1 (aldehyde dehydrogenase 1) is a detoxification enzyme linked to therapy resistance. High ALDH1 activity in CSCs may neutralize chemotherapeutic agents, aiding survival.
3. **Drugs Targeting CSCs: Sertraline & Metformin**
- **Sertraline (SSRI Antidepressant)**: Preclinical studies suggest it inhibits prostate CSCs by disrupting autophagic flux or serotonin signaling pathways critical for CSC survival. The [PubMed study](pubmed.ncbi.nlm.nih.gov/327... may detail its CSC-specific effects.
- **Metformin (Antidiabetic)**: Targets metabolic vulnerabilities via AMPK activation, reducing mTOR signaling and CSC self-renewal. The [Nature study](nature.com/articles/pcan201... likely explores its role in prostate cancer CSC suppression.
4. **Clinical Evidence & Caveats**
- **Metformin**: Observational data link it to reduced cancer risk, but CSC-specific clinical trials are limited. Most evidence is preclinical.
- **Sertraline**: Early-stage studies (in vitro/animal models) show promise, but human data are lacking.
- **Risks**: Both drugs have side effects (e.g., GI issues with metformin; serotonin syndrome risk with sertraline). Off-label use without robust trial support warrants caution.
5. **Future Directions: Immunotherapy & Personalization**
- **Immunotherapies**: CAR-T, vaccines, or checkpoint inhibitors may target CSC antigens (e.g., CD44, CD133). Challenges include CSC immunoevasion and heterogeneity.
- **Combination Strategies**: Pairing CSC-targeting agents (e.g., metformin) with immunotherapy/chemotherapy could overcome resistance.
**Conclusion**
While Sertraline and Metformin represent rational CSC-targeting strategies post-prostatectomy, their efficacy in humans remains unproven. Patients should consult oncologists to weigh risks/benefits and consider clinical trials. Emerging immunotherapies offer hope but require further research to address CSC-specific challenges.
DeepSeek said
Starve the PCa of the Androgen that feeds them, be it natural or medicinal, and the cells die. This has worked for me over a decade.
Can you let us know what you're taking exactly and in what doses? I'm really interested in any alternatives that can add to what the lupron and Enza is doing for me. Thanks.
This is a rather long list. I am 170lbs. and am Stage 4 and had radical prostatectomy and SBRT on one spot on spine. PSA started at 4.7 (at highest) and is currently less than .02. I am on Lupron and Erleada.
D3 - 10,000 IU, normally recommended at 2,000 for bones
Atorvastatin - 80mg. Was taking before PCa due to stroke in 2022
Melatonin - 20mg
Theracumin HP 600mg
Quercetin - Pure Encapsulations - 1000mg
Nano EGCG - One Planet 500mg
Omega3 - 1,000mg (maybe avoid if on blood thinners)
Ivermectin - 12mg 2x/wk (limited confidence)
Menthol - 600mg. - not for CSC reasons though, more general
Metformin - Considering adding 500mg
That is about it. I am obviously taking a shotgun approach and would much prefer to be more targeted and have better dosage guidelines but clinical trials aren’t being done for reasons not to be discussed here. Many of these nutraceuticals have low bioavailability but putting them together and using new formulations may help. The success of the strategy won’t necessarily be measured by but rather a lack of additional colonies being created.
Criteria for "my ADT has stopped working and we have to move to another"
Novel AR-Targeted Therapies for mHSPC: Which One to Choose
