Prolactin-dependent malignancy- Case Report: Successful Termination of Untreatable Androgen-independent PCa with Cabergoline treatment

[GeorgeGlass]

ncbi.nlm.nih.gov/pmc/articl...

Has anyone here tried Cabergoline to suppress prolactin and slow their prostate cancer growth?

The Intro, Results, Discussion and Conclusions below are short and easy to understand. For more detailed info, you can read below that or click on the embedded link above.

Leslie C. Costello, Renty B Franklin, and George W. Yu

Abstract

Introduction:

Testosterone promotes the initial development of androgen-dependent prostate cancer. This is the basis for androgen ablation treatment, which attenuates, but does not terminate, the malignancy. Instead, it leads to prolactin-dependent malignancy; in which patient death generally occurs within 5 years. This report describes the novel treatment of a patient, which terminated androgen-independent prostate cancer.

Results:

Patient “XY” was diagnosed with prostate malignancy and metastases. He received hormonal androgen ablation treatment, chemotherapy, and radiation treatment. He developed androgen-independent prostate cancer; with expected death in 2–3 years. He was treated with cabergoline (dopamine agonist) treatment, which decreased the plasma prolactin 88%; by inhibiting the pituitary production of prolactin. The subsequent PET scan (positron emission tomography) revealed the absence of malignancy; and the CTC (circulating tumor cells) decreased from count=5.4 to count=0.

Discussion:

The cause of androgen-independent malignancy has been unknown, and an effective chemotherapy did not exist. The activities of normal and malignant prostate cells are regulated primarily by testosterone. When testosterone availability diminishes; prolactin regulation is manifested. This is represented when androgen ablation results in the development of prolactin-dependent malignancy. An effective chemotherapy would be targeted to eliminate the plasma prolactin-manifestation of the androgen-independent malignancy.

Conclusions:

This report of a novel chemotherapy for androgen-independent malignancy corroborates our understanding of the implications of prolactin in its development and treatment. There are about 165,000 cases/year with 25,000 deaths/year in the U.S.; and 1.0 million cases/year with 260,000 deaths/year worldwide. Those patients with androgen-independent prostate cancer can now employ this cabergoline treatment to prevent or terminate this deadly type of prostate cancer.

Keywords: Androgen-Independent Malignancy, Advanced Prostate Cancer, Cabergoline Treatment, Case Report

INTRODUCTION

Advanced prostate cancer accounts for about 25,000 deaths/year in the U.S. and 260,000 deaths/year worldwide [1] Its treatment generally includes hormonal androgen ablation; which leads to androgen-independent malignancy, followed by death generally within 2–5 years. An efficacious treatment does not exist, mainly due to the poor understanding of the factors that are implicated in the development and progression of androgen-independent malignancy. Especially relevant is the issue of the hormonal regulation of normal and malignant prostate acinar epithelial cells. Costello and Franklin [2,3] have provided extensive reviews of these issues.

Testosterone and prolactin regulation of normal and malignant acinar epithelial cells: androgen ablation and the development of prolactin-dependent malignancy

The activities of the normal prostate acinar epithelial cells and their malignant cells are achieved by the dual hormonal regulation of testosterone and prolactin [4]. Generally, testosterone provides the “primary” regulation; and prolactin regulation is manifested when testosterone regulation declines. This relationship exists when testosterone ablation for the treatment of androgen-dependent prostate cancer leads to the development of androgen-independent malignancy; with a life expectancy of up to 5 years.

The cause of androgen-independent malignancy had not been established, which has deterred progress in the development of an effective treatment. This report provides corroborating evidence for our concept [2,3] that androgen-independent prostate cancer is “prolactin-dependent malignancy”. Cabergoline (dopamine agonist) has been employed to suppress the pituitary lactotropic production of prolactin in cases of hyperprolactinemia [5,6]. These relationships provided the basis for our initiation of cabergoline treatment to decrease plasma prolactin, and abort untreatable androgen-independent prostate cancer.

This is the first case report to describe an efficacious treatment of a patient that successfully aborted terminal androgen-independent prostate cancer. Notably, there were no consequential adverse side effects of the treatment. Other patients can now employ cabergoline treatment to terminate this deadly cancer.

Case history of patient “XY”, who presented with terminal androgen-independent prostate cancer

On 8/14/2017 and 9/11/2017, “XY” exhibited a prostate specific antigen (PSA)=21 and PSA= 33, respectively. Prostate biopsy on 10/1/2017 revealed Gleason grade 8 prostate cancer. This was followed by focal laser ablation of the left side of the prostate gland. The subsequent Axumin PET (positron emission tomography) showed the spread of malignancy to the right side of the prostate gland and lymph node metastasis. The oncology diagnosis was the presence of incurable malignancy; and an expected 3-year survival with hormonal androgen ablation and chemotherapy. From about 11/1/2017 – 4/1/2018; “XY” treatment included hormonal androgen ablation, chemotherapy, and radiation therapy. Beginning around 11/01/2017, androgen ablation along with chemotherapy was initiated; which included lupron, casodex, zytiga, prednisone, neulista, and Lu177-PSMA (prostate specific membrane antigen). Prior to androgen ablation, PSAs were ~20–40; and the post-androgen ablation +chemotherapy PSAs<1.0. However, the 4/18/2018 PET revealed prostate gland malignancy and extensive metastases, which represented the development of untreatable androgen-independent malignancy.

On 6/20/2018, “XY” enlisted Dr. Yu as the oncologist and Dr. Costello as the collaborating consultant to manage and treat his androgen-independent malignancy. 3% Clioquinol Cream plus 50mg zinc supplement/day along with Lu177-PSMA radiation therapy was added to the treatment of “XY”. After 8 weeks, a PET scan revealed an arrest of the androgen-dependent malignancy.

However, the persistence of untreatable terminal androgen-independent malignancy presented the major problem. We expected that the development of this malignancy was likely due to the manifestation of prolactin-dependent malignancy; as had been described by Costello and Franklin [2,3]. On 12/8/2018, cabergoline treatment (Dostinex; 0.5mg 2× week) was initiated to inhibit the pituitary production of prolactin; decrease the plasma concentration of prolactin; and terminate the prolactin manifestation of androgen-independent malignancy. After 7 weeks, the plasma prolactin concentration decreased from 11.3 ug/ml (normal prolactin level) to 1.3 ug/ml (extremely low prolactin). The 1/31/2019 MRI and PET revealed the absence of detectable malignancy. A CTCPC (circulating tumor prostate cells count) count = 5.4 on 8/27/2018, which is indicative of ~21 months of survival; and on 2/22/2019, the count=0. This reveals that the imminent death from androgen-independent metastases had been terminated. These collective results following the initiation of cabergoline treatment corroborate our concept that prolactin manifests the development and progression of androgen-independent prostate cancer. This novel case report presents a successful treatment of a patient that successfully aborted terminal androgen-independent prostate cancer.

Additional implications

The terminal androgen-independent malignancy was not aborted by the treatment with Lu177-PSMA, which is consistent with another report [7]. In contrast, the cabergoline treatment did terminate the malignancy. This suggests that the terminal androgen-independent malignant cells might not express detectable levels of PSMA, or the PSMA is mutated and not detectable.

It is also notable that the post-androgen ablation subsequent development of androgen-independent malignancy was not associated with an increase in PSA; thereby indicating that these malignant cells might not express PSA.

Those relationships are consistent with our understanding that the androgen-dependent cells and the androgen-independent cells are different populations of malignant cells.

Acknowledgements:

Studies of LCC and RBF cited in this report were supported in part by NIH grants CA79903 and DK42839.

Footnotes

Disclosures: Clioquinol (3% Clioquinol Cream) and cabergoline (Dostinex) treatments were in conformity with the FDA policy for the “off label use” of a clinical trial safe drug; and in conformity with the “right to try” policy for the use of the safe drug for the treatment of patients with terminal medical conditions.

Article information

Mathews J Case Rep. Author manuscript; available in PMC 2019 Jun 17.

Published in final edited form as:

Mathews J Case Rep. 2019; 4(1): 42.

Published online 2019 May 8.

PMCID: PMC6578577

NIHMSID: NIHMS1019063

PMID: 31211288

Leslie C. Costello,1 Renty B Franklin,1 and George W. Yu2

1Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, and The University of Maryland Greenebaum Comprehensive Cancer Center. Baltimore, Maryland. 21201 USA.

2Department of Urology; George Washington University School of Medicine; 2300 East Street, NW, Washington, DC. 20037 USA.

*Corresponding Author Leslie C. Costello, Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, 650 West Baltimore Street, Baltimore, Md. 21201 U.S.A.

Copyright notice

REFERENCES

1. Siegel RL, Miller KD, Jemal A and Cancer statistics (2016) CA Cancer J Clin. 66: 7–30. [PubMed] [Google Scholar]

2. Costello LC and Franklin RB (2018) Testosterone, prolactin, and oncogenic regulation of the prostate gland. A new concept: Testosterone-independent malignancy is the development of prolactin-dependent malignancy! Oncol Rev. 12: 356. [PMC free article] [PubMed] [Google Scholar]

3. Costello LC and Franklin RB (2018) A proposed efficacious treatment with clioquinol (Zinc Ionophore) and cabergoline (prolactin dopamine agonist) for the treatment of terminal androgen independent prostate cancer. Why and how. J Clin Res Oncol. 1: 1–7. [PMC free article] [PubMed] [Google Scholar]

4. Costello LC and Franklin RB (2002) Testosterone and prolactin regulation of metabolic genes and citrate metabolism of prostate epithelial cells. Horm Metab Res. 34: 417–424. [PMC free article] [PubMed] [Google Scholar]

5. Huang HY, Lin SJ, Zhao WG and Wu ZB (2018) Cabergoline versus bromocriptine for the treatment of giant prolactinomas: A quantitative and systematic review. Metab Brain Dis. 33: 969–976. [PubMed] [Google Scholar]

6. Yarman S, Kurtulmus N and Bilge A (2012) Optimal effective doses of cabergoline and bromocriptine and valvular leasions i n men with prolactinomas. Neuro Endocrinol Lett. 33: 340–346. [PubMed] [Google Scholar]

[Soumen79]

Hi Smurtaw

May I know at what dose and which brand you are taking and what is your prolactin level.

I am high volume Mets, currently doing good, but always of adt independent tumor fear.

My prolactin level is 8 (2-17 is the range) - should I think of taking this?

Any down side of this medicine and low prolactin level.

Thank you!

🙏🙏

[GeorgeGlass]

very thorough response smurtaw. I appreciate it. Which doctor prescribed the cabergoline to you? I’ve mentioned it to two oncologists so far but they don’t know anything about it, as usual.

[MateoBeach]

Thanks for two interesting posts today, GeorgeG. 👍👍

And great rundown of the published data on Cabergoline. I too am keeping it in reserve for when CRPC emerges, or if I start to progress on mBAT.

As for the Clioquinol topical (Zinc ionophore) with 50 mg Zinc, they used it simultaneously with Lu-PSMA treatment. Interesting. I used this for a little while but then realized that good-old Quercetin is also a Zinc ionophore. Trouble is, in my view, that all of the Zn ionophores can only provide a passive concentration gradient for Zinc to enter PC cells. They cannot actively concentrate it to high levels attained by the ZIP-1 transporter which is disabled in PC. So I am skeptical of effectiveness in humans with APC. Any clinical data on that? (Pre-clinical in vitro effects on PC cell lines is never sufficient alone.) Though I see no harm in modest Zinc supplements along with my Quercetin. Paul

[Purple-Bike in reply to MateoBeach]

Oops I haven't seen the evidence of zinc ionophores like quercetin providing a passive concentration gradient for zinc to enter PC cells, but from your last line I infer you still hold some hope....

[MateoBeach in reply to Purple-Bike]

my last line was also a “passive” comment. Since I take Quercetin daily as part of my photochemical regimen for its numerous beneficial mechanisms. And Zinc is in my multi-minerals along with the others.

But I do not think Quercetin, Clioquinol or any other ionophore can provide PC intracelular concentration of Zinc any higher than extra cellular levels since they are all passive carriers into the cells, and not “pumps” like the ZIP-1 transporter that brings high levels into prostate cells. That mechanism is disabled in prostate cancer as an early event in PC development. Too bad we cannot turn it back on!

[Purple-Bike in reply to MateoBeach]

Thanks. With higher extra cellular levels of zinc from supplementing, will there at least be a corresponding increase in PC intracellular concentration, even if doesn't come close to that provided by the ZIP-1 transporter?

[GeorgeGlass in reply to MateoBeach]

No problem Paul. I read your replies. Always good to learn more about our options.

[Soumen79]

Thank your Smurtaw - very precise and comprehensive, thank you!

[GeorgeGlass]

Ok, I'm going to give mine a call soon. Thanks

[jazj]

I am showing classic signs of dopamine deficiency caused my long-term chronic stress. (I should also mention 9 months post treatment my PSA is still undetectable.) So I was going to carefully try to repair my dopamine defficiency so to speak with some very moderate, cycled supplementation of a dopamine agonist such as L-Tyrosine, D-Phenylalanine, or Mucuna Pruriens. Now with any supplement I always cross reference it on Google with Prostate Cancer. L-Tyrosine has some effect on Thyroid so I scratched it off. There was a study in Europe looking back at thousands of patients regarding Amino Acid intake, and there was mild evidence Phenylalanine intake had a positive correlation so I scratched that one off. That left Mucuna Pruriens, the active ingreditent being L-Dopa which is commonly used to increase Dopamine in Parkinsons Disease Patients (usually using Levodopa which also has carbidopa to increase effectiveness..) I would be taking Mucuna Pruriens at levels of L-Dopa being in the 150-300mg range which is very low compared to what a PD patient needs.

At those doses though, there possibly will be a lowering or prolcatin, if it's that signficant or not I have no idea and an associated increase in Testoerone may be possible although I've seen a couple studies that showed at low dose L-Dopa didn't increase Testosterone.

In my research I ran across this same article and was flabbergasted I never discovered it in my hundreds of hours prior researching Prostate Cancer. What I found most interesting was the conclusion: "it is important to recognize that testosterone does not initiate the oncogenic transformation; and is not a cause of malignancy." So Testosterone only comes into play when your are metastatic. Which I assume many in this forum are at that stage hence the use of ADT.

BUT, Conclusion #4 was pretty bold in my opinion:

"Terminal advanced prostate cancer is a “prolactindependent” malignancy. The termination of advanced prostate cancer is best achieved by elimination of plasma prolactin."

So is there solid evidence that being on ADT versus only gabercoline has a major benefit? I don't have time right now to read all of the studies smurtaw links to but has a study been done on the outcome of only eliminating prolactin versus also trying to eliminate testoterone. Could patients be living through the bad side effects of ADT when it doesn't provide any significant and major additional long-term benefit than just only supressing prolactin?

I'm almost wondering, if you have a biochemical recurrence, maybe the best treatment is to obliterate your prolactin to lower the chances of the cancer going metastatic?

It seems like PCa can really present itself in two distinct forms at the same time which you need both ADT and prolactin supressions as it states:

"Those relationships are consistent with our understanding that the androgen-dependent cells and the androgen-independent cells are different populations of malignant cells."

And this is why I missed this information before probably:

"The important role of prolactin in the development of advanced prostate cancer has been largely unrecognized and/or ignored within the medical community; including urologists and oncologists. This is apparent from a PubMed search of “prolactin and androgen-independent prostate cancer”, or a search with “prolactin and castration resistant prostate cancer; which results in only about 12 citations; with only about 5 citations in the recent 10 years. A 2016 extensive review of prostate cancer, which includes over 300 references [9], makes no mention of prolactin."

[jazj]

Oh crap, I already went down this road 9 months ago and just forgot about it. LOL. Still a VERY interesting subject. This makes me wonder if moderate supression of prolactin might lower the chance of malignancy/recurrence?

healthunlocked.com/advanced...