Monday, October 24, 2011

Two studies of the mTOR inhibitor everolimus in Peutz-Jeghers syndrome

Two studies of the mTOR inhibitor everolimus in Peutz-Jeghers syndrome
A patient-view report by Stephanie Sugars

Dear PJS friends,

I apologize for my long absence from the group. I’ve continued my medical research, but been focused on metastatic breast cancer, rather than PJS, because it’s of immediate, personal concern.

Recent reports from the metastatic breast cancer world have shown improved disease response in patients treated with the mTOR inhibitor everolimus.

I’ve been posting about mTOR and LKB1 (the PJS gene) for eight years now and have followed the research as closely as I can – I’m “only” a PJS patient, not a researcher or medical professional though, so apologize in advance for any inaccuracies in my reporting.

Today I posted an updated version of a January 2009 series I wrote about the then upcoming Salt Lake City trial of everolimus (aka RAD001 or Afinitor) in PJS patients. 

Pilot Study of mTOR Inhibitor Therapy in Peutz-Jeghers Syndrome

The study has since been reported in the following article.

Fam Cancer. 2011 Sep;10(3):469-72.

A rationale for mTOR inhibitors as chemoprevention agents in Peutz-Jeghers syndrome.

Kuwada SK, Burt R.

University of Hawaii, John A. Burns School of Medicine, Honolulu, HI, USA,

Peutz-Jeghers patients frequently develop clinically significant complications, namely hemorrhage and bowel obstruction, from small intestinal hamartomatous polyps that frequently require surgery. In addition, many PJS patients develop epithelial malignancies in a variety of organs. The vast majority of PJS is due to germline alterations in the STK11 gene that encodes a protein that modulates PI3-kinase signaling, a key regulator of cell survival and growth. One of the major downstream mediators of PI3-kinase signaling is mTOR, the mammalian target  of rapamycin. Several drugs that inhibit the PI3-kinase signal transduction pathway are in development and one, RAD001 (everolimus), an mTOR inhibitor, was recently approved for the treatment of renal cell carcinoma. Effective chemoprevention of intestinal polyps would be a first step in simplifying and improving the management of PJS patients. We present here, the rationale for the first human PJS chemoprevention trial using an mTOR inhibitor.

PMID: 21826537 

I hope those interested in the topic will read the full article, but for those who want the quick report, here’s an excerpt:

“The hypothesis of the trial, which was launched at the University of Utah is that mTOR inhibition by RAD001 (everolimus) will cause regression of gastrointestinal polyps in patients with Peutz-Jeghers syndrome. Unfortunately the study was ended due to a high prevalence of concurrent cancers in the patient pool available for recruitment. Three patients completed 12 months of open-label treatement with RAD001 (everolimus) at 10 mg po daily. All three developed stomatitis causing dose-reductions to 10 mg po every day. No other serious adverse events were noted. Unfortunately there was insufficient polyp burden to draw any statistical analysis from. The ability of these patients to tolerate RAD001 (everolimus) without serious side effects suggests that it or other similar drugs could be used in future clinical trials in PJS patients.”

I think there must be a typo and that the dosage was reduced from 10 mg daily to 10 mg every other day…but  that’s a guess on my part.

So, some of the patients who could have enrolled in the study were diagnosed with cancer and were excluded from the study. The three who enrolled and stayed in the study for a full year didn’t have enough polyps to be measured in a statistically significant manner.

And the authors conclude that the lack of serious side effects suggests future clinical trials.


Well, here is a future clinical trial from the Netherlands:

Study of Everolimus in the Treatment of Advanced Malignancies in Patients With Peutz-Jeghers Syndrome (EVAM)

The study investigators don’t consider our gastrointestinal polyps worthy of intervention with mTOR inhibitors. Nor do they consider early stage PJS-related cancers worthwhile. Instead, they are focused on those of us with advanced cancers. The study’s Principal Investigator, Klümpen, is co-author of this medical journal article.

J Clin Oncol. 2011 Feb 20;29(6):e150-3. Epub 2010 Dec 28.

mTOR inhibitor treatment of pancreatic cancer in a patient With Peutz-Jeghers syndrome.

Klümpen HJ, Queiroz KC, Spek CA, van Noesel CJ, Brink HC, de Leng WW, de Wilde RF, Mathus-Vliegen EM, Offerhaus GJ, Alleman MA, Westermann AM, Richel DJ.

PMID: 21189378
free full text available at:
Here's some backstory from the article: 

The authors reported a 46-year-old man with PJS who’d been diagnosed with pancreatic cancer at age 45. He’d also had multiple polyps removed, a liposarcoma, anemia, pancreatitis, diabetes and recurrent intussusception. His original pancreatic mass was 15 cm mass that was surgically removed. A CT scan 7 months later revealed a 9 cm mass. Five months after that he was treated with 9 mg daily of everolimus for 9 months. Treatment was well tolerated (grade 1 myalgia/arthralgia after 6 months of treatment). “A partial response was confirmed by CT scan 3 and 6 months after the start of treatment with everolimus. However, after 9 months of treatment, progressive disease was found. A colonoscopy 8 months after the start of treatment and 15 months after the last colonoscopy did not show any large (larger than 1 cm) colon polyps (in contrast to all previous colonoscopies).”

“We were able to induce shrinkage of the tumor while avoiding the classic chemotherapy adverse effects, but speculate that the observed progressive disease, which occurred after 9 months of mTOR inhibition was a result of either development of treatment-resistant cancer cells with other pathway mutations as the main driver of proliferation, or was caused by hperactivation of an alternative pathway such as the AKT pathway.”


I must mention, as an aside, that everolimus is expensive $7000-$9000 for a month’s supply. Also, in another inherited cancer syndrome, tuberous sclerosis, mTOR inhbitors only work while being administered, once the patient stops the drugs the old problems soon return.

While I’m encouraged that mTOR inhibitors might help some of the people some of the time, they won’t help all of the people all of the time. I still don’t think they make sense for those whose polyps can be controlled with scopes and surgery. Nor would I wish them on a child who has, potentially, many years of life ahead. Not many will be able to afford the costs - financial or side effects. But those who have plenty of resources and who are willing to take risks, might want to keep informed.

Love and good wishes,

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