Intemittent hormone therapy with orgovyx (relugolex) plus nubequa and avodart

[rococo]

Anyone doing this and what’s your protocol and how are you doing. Iam going on my third month this Friday. Psa went from 3,5 to .8 in the first mo.

[deepsci]

I'm planning to start BAT in the next few months, and hope to get more info from Johns Hopkins about their experience reported in a recent poster session of the Prostate Cancer Foundation's recent conference in my area:

Alternating high testosterone with Xtandi gives better “Bipolar Androgen Therapy” results, by upregulating the number of androgen receptors and downregulating “MYC”.

Prostate cancer androgen receptor activity dictates efficacy of bipolar androgen therapy through MYC

Laura A Sena1†, Rajendra Kumar1†, David E Sanin1, Elizabeth A Thompson1, D Marc Rosen1, Susan L

Dalrymple1, Lizamma Antony1, Yuhan Yang1, Carolina Gomes-Alexandre1, Jessica L Hicks1, Tracy Jones1,

Kiara A Bowers1, Jillian N Eskra1, Jennifer Meyers1, Anuj Gupta1, Alyza Skaist1, Srinivasan

Yegnasubramanian1, Jun Luo1, W Nathaniel Brennen1, Sushant K Kachhap1, Emmanuel S Antonarakis1,2,

Angelo M De Marzo1, John T Isaacs1, Mark C Markowski1‡, Samuel R Denmeade1‡

1 The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University; Baltimore, MD, USA.

2 Current address: University of Minnesota, Masonic Cancer Center; Minneapolis, MN, USA.

Background: Testosterone is the canonical growth factor of prostate cancer but can paradoxically suppress its growth when present at supraphysiological levels. We have previously demonstrated that the cyclical administration of supraphysiological androgen (SPA), termed Bipolar Androgen Therapy (BAT), can result in tumor regression and clinical benefit for patients with castration-resistant prostate cancer. However, predictors and mechanisms of response and resistance have been ill-defined.

Methods: We used matched sequential patient biopsies and models of prostate cancer to interrogate predictors and mechanisms of response and resistance to BAT.

Results: Growth inhibition of prostate cancer models by SPA required high androgen receptor (AR) activity and was driven in part by downregulation of MYC. Using matched sequential patient biopsies, we show that high pre-treatment AR activity predicted downregulation of MYC, clinical response, and prolonged progression-free and overall survival for patients on BAT. BAT induced strong downregulation of AR in all patients, which is shown to be a primary mechanism of acquired resistance to SPA. Acquired resistance could be overcome by alternating SPA with the AR inhibitor enzalutamide, which induced adaptive upregulation of AR and re-sensitized prostate cancer to SPA

. Conclusions: This work identifies high AR activity as a predictive biomarker of response to BAT and supports a new treatment paradigm for prostate cancer involving alternating between AR inhibition and activation.

More details, from dm5migu4zj3pb.cloudfront.ne...

… we used a patient-derived xenograft (PDX) model derived from a metastasis298

of a patient with CRPC that was adapted to grow in a castrated mouse (SkCaP-1R) (33). This PDX,299

which expresses high AR and the AR splice-variant AR-V7 and is resistant to the second300

generation androgen signaling inhibitors abiraterone and enzalutamide (33), initially regressed in301

response to SPA, but acquired resistance after about 5 months (Figure 7F). Regression was302

associated with an almost complete loss of MYC expression, while acquired resistance was303

associated with a decrease in AR and return of MYC expression (Figure 7G-H). SPA suppressed304

mRNA expression of AR and AR-V7 as early as 21-30 days (Figure 7G-I). Notably, when SPA was305

alternated every 21 days with enzalutamide (SPA-ENZA), this PDX did not acquire resistance306

after 160 days of observation (Figure 7F). Subcutaneous tissues from the animals that received307

SPA-ENZA for 160 days were analyzed histologically and nests of cancer cells were observed,308

but these cells lacked significant staining for the proliferation marker Ki-67 (Figure 7H). These309

data suggest that repeat cycling of SPA and AR inhibition may prevent the development of310

acquired resistance and lead to more durable growth inhibition of prostate adenocarcinoma.

Remarks from my summary of the book, How To Starve Cancer, as to how to downregulate MYC:

Every cancer is driven by different metabolic and genetic changes -- which is why there can never be one specific recommendation. For cancers with an overexpressed MYC gene, which are more glutamine driven, a more vegan diet (cutting out protein) may be important.

Notch (a signaling pathway) is associated with cervical cancer and is combatted by the natural flavonoid luteolin. A proper dose is important because it is also a SREPB-2 inhibitor. Sulforaphane, delta tocotrienol, orodonin and quercetin also target Notch. It is associated with an alteration in the surrounding fibroblasts and the gene c-MYC, both of which may make cancer especially aggressive.

Note: if you really want to dive deeply, see the 18,454 compounds tested against MYC, listed at pubchem.ncbi.nlm.nih.gov/ge...

My plan is to use both "Zytiga with food" (details on request), and finasteride with the Xtandi during the low-T phase, because they wash out quickly, with the Xtandi -- which should promote formation of more androgen receptors. Then hit it with high T, with none of these three drugs present. I won't use dutasteride because it persists. I want both high T and high DHT during the "fire hose" phase to drown the cancer. Tentatively alternating months, but perhaps two months of starving followed by a fire hose month.