High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice

[pjoshea13]

A new Finnish-Swedish paper (with no mention of NATO) [1]

Dr. Myers has said that the purpose of ADT is to deny PCa access to dihydrotestosterone [DHT]. A minority of men produce DHT via the alternative pathway that does not involve testosterone [T]. Myers was one of the few doctors who checked DHT levels. (Most doctors assume that castrate T = castrate DHT.)

However, when PCa is on the road to CRPC, cells may discover the alternative pathway. A blood test will not detect DHT in those cells. So, some men cover that possibility by taking the 5alpha-reductase inhibitor Dutasteride [Avodart].

"Using xenografts of VCaP cells we showed that growth of antiandrogen resistant CRPC tumors were characterized by a higher intratumor dihydrotestosterone (DHT) concentration than that of treatment responsive tumors."

The mice had been castrated, so the presumed origin of the hormones leading to DHT was the adrenal glands [2].

"... the slow tumor growth after adrenalectomy was associated with a low intratumor DHT concentration."

"... intratumor DHT concentration and expression of several androgen-dependent genes in CRPC lesions is an indication of enzalutamide treatment resistance and an indication of the need for further androgen blockade."

Abiraterone is a CYP17A1 inhibitor. The CYP17A1 enzyme acts upon pregnenolone and progesterone to produce downstream hormones that include androgens.

"The presence of an androgen synthesis, independent of CYP17A1 activity, has been shown to exist in prostate cancer cells, and thus, novel androgen synthesis inhibitors are needed for the treatment of enzalutamide-resistant CRPC tumors that do not respond to abiraterone."

However, from what I know, Avodart will inhibit the final step that results in DHT.

How often is Enzalutamide [Xtandi] resistance due to intratumor DHT? I don't know, but Avodart is an inexpensive safety play. imo

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/355...

iScience

. 2022 Apr 25;25(5):104287. doi: 10.1016/j.isci.2022.104287. eCollection 2022 May 20.

High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice

Riikka Huhtaniemi 1 , Petra Sipilä 1 , Arttu Junnila 1 , Riikka Oksala 2 , Matias Knuuttila 1 , Arfa Mehmood 3 , Eija Aho 2 , Teemu D Laajala 1 4 5 , Tero Aittokallio 4 5 , Asta Laiho 3 , Laura Elo 3 1 , Claes Ohlsson 6 7 , Malin Hagberg Thulin 6 , Pekka Kallio 2 , Sari Mäkelä 1 8 , Mika V J Mustonen 2 , Matti Poutanen 1 6

Affiliations collapse

Affiliations

1 Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland.

2 Orion Corporation, Orion Pharma, Turku, Finland.

3 Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.

4 Department of Mathematics and Statistics, University of Turku, Turku, Finland.

5 Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

6 Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

7 Region Västra Götaland, Sahlgrenska University Hospital, Department of Drug Treatment, Gothenburg, Sweden.

8 Functional Foods Forum, University of Turku, Turku, Finland.

PMID: 35573198 PMCID: PMC9097697 DOI: 10.1016/j.isci.2022.104287

Abstract

Antiandrogen treatment resistance is a major clinical concern in castration-resistant prostate cancer (CRPC) treatment. Using xenografts of VCaP cells we showed that growth of antiandrogen resistant CRPC tumors were characterized by a higher intratumor dihydrotestosterone (DHT) concentration than that of treatment responsive tumors. Furthermore, the slow tumor growth after adrenalectomy was associated with a low intratumor DHT concentration. Reactivation of androgen signaling in enzalutamide-resistant tumors was further shown by the expression of several androgen-dependent genes. The data indicate that intratumor DHT concentration and expression of several androgen-dependent genes in CRPC lesions is an indication of enzalutamide treatment resistance and an indication of the need for further androgen blockade. The presence of an androgen synthesis, independent of CYP17A1 activity, has been shown to exist in prostate cancer cells, and thus, novel androgen synthesis inhibitors are needed for the treatment of enzalutamide-resistant CRPC tumors that do not respond to abiraterone.

Keywords: Cancer; Endocrinology.

[2] en.wikipedia.org/wiki/Adren...

[Hidden]

I don't think that this picture has been posted before.

DHT pathways

[LearnAll in reply to Hidden]

Thanks. That's a nice picture and explains a lot. Blocking DHT by Finasteride/Dutasteride can certainly help many men. And so is reducing lipids by Statins. Not to forget Metformin/Berberin.

[Hidden in reply to LearnAll]

Zytiga inhibits CYP17. But then there is the backdoor pathway that Patrick discusses.

[Kuanyin]

High Patrick. I think we should also mention foods that help block 5-Alphas Reductive--Edamame

--Green Tea

--Coconut (Lauric Acid)

--Onions

--Flax (seeds, not oil which is too volatile)

Supplements

--Quercitin

--Calcium d-Glutarate and others

[Hidden in reply to Kuanyin]

Does anyone have any experimental data for these? Baseline DHT, supplements/foods, subsequent DHT?

I have data but only for dutasteride/finasteride and there are plenty of studies that show the reduction amount so my data is rather moot (good for me personally of course).

[EdBar]

Yep, I continue to take dutasteride daily per Dr. Myers while on ADT. I’ve been taking it for about 8 years now, my PSA continues to be <0.1. Myers was so far ahead of his time on many “outside the box” treatments he prescribed.

Ed

[elkmt]

TA has informed me that trials on use 0f avodart were not favorable. i think erleada suppresses adrenal production.