The history of Hormone Therapy by Brian Mannion

Monday, September 28, 2026 4:12:00 AM

Prostate Cancer and the Evolution of Hormone Therapy.

Medical oncologist Dr. Brian Mannion reviews the evolution of hormone therapy for prostate cancer, tracing its history from early discoveries involving testosterone to modern pharmacological treatments. He explains the biological mechanisms of androgen receptors and how cellular mutations eventually cause current therapies to fail. Additionally, the presentation explores future strategies such as degraders and alternative signaling pathways to overcome treatment resistance. Finally, Dr. Mannion addresses patient questions regarding precision medicine, side effects, and ongoing clinical trials.

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The Original presentation:

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⭐ 1. Drugs that LOWER testosterone

These medications stop the body from making testosterone.

A. GnRH agonists & antagonists (Lupron, Eligard, Firmagon, Orgovyx)

  • They shut down the signal from the brain that tells the testicles to make testosterone.

  • Result: Testicles stop producing ~90% of your testosterone.

B. CYP17 inhibitors (Abiraterone/Zytiga)

  • They block a key enzyme needed to turn cholesterol into testosterone.

  • Result: Stops testosterone production everywhere — testicles, adrenal glands, and even cancer cells.

C. 5‑alpha reductase inhibitors (Finasteride, Dutasteride)

  • They don’t lower testosterone itself.

  • They block the conversion of testosterone → DHT, a much stronger androgen.

  • Result: Less potent androgen signaling.

⭐ 2. Drugs that BLOCK the androgen receptor (AR)

These medications don’t care how much testosterone you have — they stop cancer cells from using it.

A. First‑generation blockers (Casodex, Flutamide)

  • They sit on the androgen receptor and block testosterone from attaching.

B. Second‑generation blockers (Xtandi, Erleada, Nubeqa)

They block the receptor much more completely:

  1. Stop testosterone/DHT from binding

  2. Stop the receptor from entering the nucleus

  3. Stop the receptor from turning on growth genes

Result: Cancer cells can’t receive the “grow” signal.

⭐ 3. New & emerging approaches

These target the receptor in more advanced ways:

A. AR degraders (ARV‑110)

  • They cause the cell to destroy the androgen receptor entirely.

B. N‑terminal domain blockers (EPI‑7386)

  • They block a different part of the receptor — useful for mutated receptors that don’t respond to normal drugs.

C. AKT/PI3K pathway inhibitors (Capivasertib/AZD5363)

  • They shut down backup growth pathways cancer uses when AR is blocked.

⭐ The simplest way to think about all of this

You can stop prostate cancer by either:

1️⃣ Removing the fuel (testosterone)

or

2️⃣ Disabling the engine (androgen receptor)

Every drug fits into one of those two strategies.

Prostate cancer cells develop resistance to hormone therapy primarily because cancer cell DNA is inherently unstable and mutates at a high rate. Under the selective pressure of continuous hormone deprivation, the rare mutant cells that can survive without testosterone are selected for and gradually become the dominant tumor population.

Dr. Brian Mannion outlines several specific mechanisms through which cancer cells achieve this resistance:

  • Androgen Receptor (AR) Overexpression: The cell begins producing 5- to 10-fold more Androgen Receptors. Through sheer numbers, even trace amounts of testosterone left in the body are enough to overwhelm anti-androgen drugs and activate the receptors.

  • Androgen Receptor Mutations: Over 600 point mutations in the AR protein have been identified. These structural alterations allow other hormones (such as cortisol, progesterone, or estrogen)—and sometimes even former anti-androgen drugs like bicalutamide (Casodex)—to bind and activate the receptor instead of blocking it.

  • Truncated AR Variants (e.g., AR-V7): Mutations or splicing changes cause the cell to produce truncated versions of the AR (like AR-V7 or v567) that lack the ligand-binding domain entirely. Without this binding domain, the shortened receptor stays permanently stuck in the "on" position inside the nucleus, driving cancer growth without needing testosterone or any hormone at all.

  • Alternative Signaling Pathways (AKT/PI3K Pathway): As cells become resistant, they increasingly rely on alternative pathways—such as the AKT / PI3K signaling pathway (especially common in cells with P10 gene mutations)—to activate the AR or drive cell survival independently of testosterone.