Some Promising News

[~MaryO~]

http://www.acurian.com/link.js....ewshtml

 

Cushing's Syndrome Pituitary Tumor Cells Found to Express Large Amounts of PPAR-Gamma Source: Cedars-Sinai Medical Center

10/29/2002    

 

While most cases of a hormonal disorder called Cushing's Syndrome are caused by non-cancerous pituitary tumors that secrete too much of a particular hormone resulting in high cortisol levels, the disorder can ultimately lead to an early death for many patients whose tumors cannot be removed surgically.

 

Now, researchers at Cedars-Sinai Medical Center have found that pituitary tumors express an abundance of a specific protein receptor and report that treatment with a common diabetes drug was effective in shrinking tumor size and reducing hormone production in Cushing's pituitary tumors in mice. The findings, reported in the November 2002 issue of the journal, Nature Medicine, may lead to a new way to treat patients who have Cushing's Syndrome.

 

"Now that we know that this protein receptor plays a role in the pituitary tumors that cause Cushing's syndrome, we may have found a drug that can effectively treat this disease," said Dr. Anthony Heaney, lead author of the study and Assistant Professor and Medical Director of the Neuroendocrine Tumor Center at Cedars-Sinai Medical Center. "We will soon begin a clinical trial to test the effectiveness of this antidiabetic drug in patients with Cushing's syndrome who have pituitary tumors."

 

The most common type of Cushing's syndrome is caused by prolonged high-level exposure of a hormone called ACTH (adrenocorticotropin), which is secreted in excess by tumors of the pituitary gland, situated at the base of the brain and, which controls growth, metabolism and reproduction. Although the disorder is rare, it affects more women than men by a ratio of 5:1. Symptoms include weight gain with rounding of the face; increased fat in the neck; thinning skin; excess hair growth on the face neck, chest abdomen and thighs; muscle weakness and bone loss (osteoporosis); high blood sugar; diabetes; and high blood pressure. These effects are caused by high levels of adrenal steroids, or cortisol. The disorder is commonly treated with surgery to remove the tumor, but tumors are not always completely removed, either because they are too small to detect or have spread to parts of the brain that cannot be accessed via surgical procedures. Further, even if the tumor is successfully removed initially, about 50 percent of patients' experience a recurrence sometime after surgery.

 

The protein receptor, called PPAR-gamma (peroxisome proliferator-activated receptor), is a member of the steroid family and functions to regulate other genes involved in growth and metabolism. For example, the protein plays a role in the body's ability to respond to insulin, which lowers blood sugar. In fat cells, PPAR-gamma regulates sugar metabolism.

 

In view of the relationship between excess steroid hormones and obesity, the investigators first examined normal human pituitary tissue to determine which pituitary cells expressed PPAR-gamma. Their analysis revealed that PPAR-gamma was present selectively on normal ACTH-secreting pituitary cells, leading them to examine tumor specimens that secreted too much ACTH. In this analysis, they evaluated six ACTH-secreting pituitary tumors that had been surgically removed. They found that PPAR-gamma was abundantly expressed in all six tumors, as compared to modest expression in the normal pituitary tissue samples.

 

"The over-expression of this receptor on pituitary tumor cells indicates that PPAR-gamma may play a major role in the causation of Cushing's syndrome," said Dr. Shlomo Melmed, senior author of the study and Sr. Vice President of Academic Affairs and Professor and Director of the Burns and Allen Research Institute at Cedars-Sinai Medical Center.

 

Based on these findings, the investigators tested whether pituitary tumor cells would respond to drugs called thiazolidinediones (TZDs), which are commonly used in the treatment of diabetes and work by activating gamma. To do this, they first treated pituitary tumor cells with two different types of TZD drugs called troglitazone or rosiglitazone. They found that both drugs caused pituitary tumor cells to die, and inhibited secretion of ACTH hormone from the tumor cells.

 

Given that the TZD's were effective to induce tumor-cell death and slow the secretion of ACTH in cell cultures, the investigators subsequently tested the drugs in mice with ACTH-secreting pituitary tumor cells, which were then randomly selected to receive food containing rosiglitazone or normal food. After four weeks, the investigators found that four of the five untreated mice developed large, visible pituitary tumors, and the typical Cushing's features of a "moon shaped" face and large neck. In comparison, only one of the five rosiglitazone treated mice developed a small pituitary tumor. The investigators also found that ACTH and other steroid hormones were considerably lower in the treated mice as compared to those not receiving treatment.

 

"These results indicate that TZDs may be effective in slowing tumor growth in humans," said Dr. Heaney.

 

Cedars-Sinai Medical Center is one of the largest non-profit academic medical centers in the Western United States. For the fifth straight two-year period, Cedars-Sinai has been named Southern California's gold standard in health care in an independent survey. Cedars-Sinai is internationally renowned for its diagnostic and treatment capabilities and its broad spectrum of programs and services, as well as breakthrough in biomedical research and superlative medical education. Named one of the 100 "Most Wired" hospitals in health care in 2001, the Medical Center ranks among the top 10 non-university hospitals in the nation for its research activities.

[Guest Lynne Clemens I]

WOW!

[CindyRPT]

This post is nearly 5 years old. In 2002 it was experiemental...I was just wondering if it has been approved by now, and if anyone has received this type of treatment post surgery.

I find it amazing that they say 50% of surgical patients have a recurrence of symptoms. I have noted that many people on the boards here have had to have more than one surgery & yet they are still dealing with Cushing's symptoms. It would be nice to be able to take a medication that would kill the remaining tumor cells that they missed!

 

If anyone has any updated info on this, please let us know!

 

Thanks!

Cindy

[Kristy]

The drug is Avandia... and with all of the new warnings about it... I expect they are looking for another way.

http://www.fda.gov/bbs/topics/NEWS/2007/NEW01636.html

[CindyRPT]

I'm wondering about Actos. It's also a TZD. I just recently found some research published by JAMA just last week regarding Actos. Here's the link:

 

http://www.medscape.com/viewarticle/562715

 

It's mode of action is a little different than the TZD's they used in the Cedar's Sinai Study, I'm just wondering if it could be helpful.

Edited September 21, 2007 by CindyRPT

[staticnrg]

I'm wondering about Actos. It's also a TZD. I just recently found some research published by JAMA just last week regarding Actos. Here's the link:

 

http://www.medscape.com/viewarticle/562715

 

It's mode of action is a little different than the TZD's they used in the Cedar's Sinai Study, I'm just wondering if it could be helpful.

 

 

Hi, Cindy....If anyone will know it's Kristy. I do have this article in my files, though: http://jcem.endojournals.org/cgi/reprint/9...1340.pdf?ck=nck

 

Bottom line.... " We conclude that short-term therapy with pioglitazone [Actos] therapy is unlikely to modulate the HPA axis in subjects with Cushing's disease. However, further studies with more potent PPAR agonists for longer durations of treatment may be warranted."

[CindyRPT]

Great... so in a nutshell, the TZD that isn't harmful is not helpful, and the TZD's that showed promise will kill you! We just can't catch a break here can we?!

[Kristy]

Nope... just can't seem to find that magic bullet. What I have noticed though, is patients who were suspected of cushings who took avandia and actos, that it did take alot longer to have their cushings diagnosed. Unfortunately, one of the side effects of the medicines was weight gain... so it seems to me that it may have helped biochemically, but when you are trying to tell your doctor that something is terribly wrong...

 

Never mind... you all know where I am going.

 

[MCF]

The problem with the edema caused by that class of drugs isn't just weight and congestive heart failure. The edema is system wide so there are vision problems/damages, etc.

 

Now that these drugs are being advised against for DMs, expect them to be hunting around for new indications to keep them profitable.