Caught in the Akt

Trial drug capivasertib blocks a notorious cancer pathway

Credit: iStock.com/Eloku

Lurking behind prostate cancer’s Public Enemy #1 — the androgen receptor — must be a Public Enemy #2. When we’ve pinned the AR down but cancer rebounds, that’s who we want to come looking for.

A leading candidate for Enemy #2 is a molecular system called the PI3K pathway. While the big-name mutations that rule the rest of the cancer world, like TP53, were found to be rare in prostate cancer, every metastasis in a study of 218 tumors showed mutations in the PI3K pathway. “These data provide strong rationale for exploring the clinical activity of PI3K pathway inhibitors,” the researchers wrote.

Capivasertib¹ is one such drug. When it was mentioned in last week’s AnCan call² none of us had heard of it. It seemed worth looking into.

The PI3K/Akt/mTOR pathway…

The PI3K pathway³ — known also as the PI3K/Akt/mTOR pathway — participates in processes like cell survival, growth, proliferation, metabolism, migration, and formation of blood vessels, and can be triggered by many signals from outside the cell.

It’s not obvious by looking that this path might cause cancer. When cancer is discovered, this pathway is often found to be dysregulated, and when researchers deliberately dysregulate it (in mice!), the result is cancer.

…and PTEN

The PI3K pathway can lead to cancer without any of its genes being mutated; the defect might be in another gene whose role is to keep the pathway under control.⁴ Whether the creek's too high or the levee’s broken, you wind up with the same problem. In the case of prostate cancer (and multiple others including melanoma and glioblastoma), the problem in the PI3K pathway is most often caused by loss of tumor-suppressor gene PTEN⁵, which regulates it.

The AR seesaw

A seesaw relationship has been discovered between the PI3K pathway and the androgen receptor — repressing one upregulates the other. When AR and PI3K therapies were combined, profound tumor regressions resulted — in mice. Results of a human trial appear below.

Think globally, Akt locally

The steps in a pathway offer multiple drug opportunities. Inhibitors for the PI3K pathway have been formulated from PI3K down. As with so many cancer therapies, these drugs walk a tightrope, because they target a process that takes place in normal cells as well. A dose high enough for cancer might also shut down normal activity — a situation called dose-limiting toxicity.

Thought has also been given to providing a PTEN replacement. In general, though, it’s easier to stick a cork in an existing step than to add a missing one.

The leading target so far may be Akt, at least for prostate cancer. Pharmaceutical companies have charged the Akt hill many times unsuccessfully, but capivasertib and ipatasertib are showing promise. Both are still in prostate cancer trials (detailed below), and are being tried for other cancers as well.⁶

Capivasertib is one of at least 18 drugs that have been tried against various points in the PI3K/Akt/mTOR pathway. (The small “i” in the red box headings stands for “inhibitor.”) If you want to trace the pathway: Signals from outside the cell activate PI3K, which turns PIP2 to PIP3. PTEN can reverse this by turning PIP3 back to PIP2. Akt binds with PIP3 and then can be activated by PDK1 and mTORC2. The activated Akt then activates mTORC in a double-negative way — it inhibits molecules TSC1 and TSC2 that inhibit mTORC1. The activated Akt participates in other pipelines as well. Notice the negative feedback through the S6K path. Some details of the Akt-mTORC1 path are omitted, as is the fact that there are different kinds of PI3K and Akt. If cell biology were simpler we might be further along on a cancer cure. (Credit: Turnham et al., The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer.)

Capivasertib plus docetaxel

The phase 2 ProCAID study found that adding capivasertib to docetaxel appeared to improve overall survival for patients who had been taking next-generation drugs like abiraterone or enzalutamide. 

Those results held enough promise to begin a follow-up phase 3 trial, CAPItello-280 (NCT05348577) — this is the trial we heard about last week. Participants must have shown disease progression after at least 3 months on abiraterone, enzalutamide, apalutamide, or darolutamide.

Capitello in Italian is the capital that tops an architectural column. (Credit: Szczebrzeszynski, Wikipedia).

Capivasertib plus abiraterone

CAPItello-281 (NCT04493853) combines capivasertib with abiraterone for a limited population: de novo hormone-sensitive metastatic with PTEN loss, diagnosed within the previous 180 days. Men who’ve had prostate surgery or radiotherapy are ineligible. 

Ipatasertib plus abiraterone

The IPATential 150 trial (NCT03072238) showed an improvement in radiographic progression-free survival only in men with PTEN loss. Not clear where they’ll take this.

Ipataserib plus atezolizumab

This is the IceCAP trial (NCT03673787), now underway. Atezolizumab is a PD-L1 drug similar to pembrolizumab.

Side effects

Common side effects of both drugs include hyperglycemia, diarrhea, and rash.

Natural Akt inhibitors

A diet with cruciferous vegetables (broccoli, brussels sprouts, kale, and others) is believed to lead better prostate cancer outcomes. One possible reason: sulforaphane in these vegetables is an Akt inhibitor.

A surprising number of natural substances are believed to be Akt inhibitors. These include [6]-shogaol from ginger root; herbacetin from flaxseed; reservatrol from grapes, berries, and peanuts; and honokiol from magnolias. I mention these for their conversational value; I am not suggesting you consume them without talking to your doctor. See the this paper for details and a full list of substances.

Companies supplying bio labs try to outdo each other with gloriously intricate pathway posters (this is from Cell Signaling Technology). Akt clearly is a player in many pathways.

1. The official pronunciation, set by the organization that decides generic names, is cap-EYE-va-sertib. “-sertib” is a suffix indicating how the drug works, so va-sertib is better than vasser-tib.

2. If you want to talk treatment, the weekly High Risk/Recurrent/Advanced prostate cancer video support calls run by AnCan are the place to be.

3. A pathway is a domino-like sequence of molecular changes in a cell, each molecule’s change influencing the next. Just as dominos can fan out, a single change can affect multiple molecules downstream, with broad effect.

4. Go-go genes (invariably likened to gas pedals) are called oncogenes, and restraining genes (invariably likened to brake pedals) are called tumor suppressors.

Hate the mutation, not the gene. Elsewhere in your body these genes, in unmutated form, keep you ticking. Thus the go-go genes are more formally called proto-oncogenes in their normal role and oncogenes when they mutate. Tumor suppressors have no other name; their carcinogenic mutation is not to become a monster but to stop working.

5. The protein PTEN is expressed by the gene PTEN (in italics). Gene names are italicized since it’s often the case that the gene and its protein have the same name.

6. Akt inhibitors that have failed clinical trials include GSK690693, uprosertib, aminofurazan, afuresertib, MK-2206, and BAY 1125976. Some of these may be dusted off for another try; MK-2206 is reportedly still a candidate for prostate cancer.

Capivasertib (formerly AZD5363) is from Astra Zeneca; ipatasertib (formerly GDC-0068) is from Genentech.