Molecule Thought Cancer Foe Actually Helps Thyroid Tumors Grow

A molecule widely believed to fight many forms of cancer actually helps deadly thyroid tumors grow, and cancer therapies now being tested in humans might boost the activity of this newly revealed bad guy, researchers at Mayo Clinic in Florida say.

The study found that in anaplastic thyroid cancer, the Forkhead transcription factor, FOXO3a, is not the helpful tumor suppressor everyone thought it was, but, instead, is a lethal promoter of tumor growth. When FOXO3a was silenced in laboratory models of human anaplastic thyroid cancer, the cells grew slowly, but when it was added, they grew much faster.

"This result is exactly the opposite of what we expected," says senior author John A. Copland, Ph.D., a Mayo cancer biologist. "We were more than surprised. We were concerned."

FOXO3a is known as a suppressor of tumor growth because it responds to all forms of cell stress, including that produced in cancer, by turning on genes inside the nucleus that trigger the cell's death. Cancer, in turn, is known to shut down FOXO3a by sending it out of the nucleus and into the cell's cytoplasm, where it is degraded. The molecule that ships FOXO3a out of the nucleus is Akt, which tries to keep cancer cells alive.

The research team used an Akt blocker -- similar to the ones now being used in human cancer clinical trials -- expecting to increase nuclear FOXO3a and suppress cancer growth in anaplastic thyroid cancer. They were trying to find a treatment for one of the deadliest known cancers, which accounts for just 2 percent of thyroid cancer cases in the U.S. but is responsible for about 40 percent of thyroid cancer deaths.

Foxo3a drives proliferation in anaplastic thyroid carcinoma via transcriptional regulation of cyclin A1: A paradigm shift that impacts current therapeutic strategies

The Forkhead transcription factor, FoxO3a, is a known suppressor of primary tumor growth via transcriptional regulation of key genes regulating cell cycle arrest and apoptosis. In many types of cancer, in response to growth factor signaling, FoxO3a is phosphorylated by Akt, resulting in its exclusion from the nucleus. Here we show that FoxO3a remains nuclear in anaplastic thyroid carcinoma (ATC). This correlates with lack of Akt phosphorylation at S473 in ATC cell lines and patient ATC tissues, providing a potential explanation for nuclear FoxO3a. Mechanistically, nuclear FoxO3a promotes cell cycle progression by transcriptional upregulation of cyclin A1, promoting proliferation of human ATC cells. Silencing FoxO3a with a reverse genetics approach leads to down-regulation of CCNA1 mRNA and protein. This combined data implicates an entirely novel function for FoxO3a in ATC promotion by enhancing cell cycle progression and tumor growth via transcriptional upregulation of cyclin A1. This is clinically relevant since we detected highly elevated CCNA1 mRNA and protein levels in ATC patient tumor tissues. Our data indicate therapeutic inactivation of FoxO3a may lead to attenuation of tumor expansion in ATC. This new paradigm also suggests caution related to current dogma focused upon reactivation of FoxO3a as a therapeutic strategy against cancers harboring active PI3-K and Akt signaling pathways.

Beware of Occam's razor when you don't know what you don't know.

I am a male with very aggressive papillary carcinoma.

You have my sympathy and prayers.

I will be entering a LBH589 research project next week.

If it's a double blind placebo controlled test, you could get the placebo.

What are my chances?

It depends on its stage. Here's 2 links:

Papillary Carcinoma Prognosis

"papillary carcinoma" mortality survival

Just remember the survival and mortality rates at particular intervals are group averages. It's near impossible to make predictions for individuals. Have hope and good luck!

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