Monday, October 24, 2011

My 2009 report on mTOR inhibitors in PJS

Drug directions in PJS – RAD001 (aka everolimus and Afinitor), an mTOR inhibitor
A patient-view report by Stephanie Sugars 
January 17, 2009  

Part one of three: These are the thoughts of a PJS patient, not a medical professional. I'm thinking like a patient advocate and wondering what we might want to consider about using these drugs and participating in clinical trials for them. 

I don't mean to discourage anyone who'd like to participate in a clinical trial, it's a sacrifice that some will have to make to determine whether new drugs are both safe and effective for other patients. 

I do want us to consider possible risks and benefits and not get carried away in the excitement of a new era of chemoprevention in PJS.  

I've been following mTOR, rapamycin and RAD001 (everolimus) in PJS and our gene, LKB1 for many years. I heard about the Salt Lake City trial ( in October 2007 at the Collaborative Group of Americas on Inherited Colorectal Cancer conference.

One of our members asked them about it when she went to SLC for treatment in autumn 2008. The trial is open only to local folks, but is well worth watching.

Clinical trials are the place to match patients with drugs, then to follow the effects of those drugs on patients. I much prefer clinical trials to off-label prescribing, which we saw with COX-2 inhibitors in PJS earlier this decade. 2011 - the trial terminated due to lack of enrollment. I will report on a medical journal article about the trial in a separate post.

I have very mixed feelings/thoughts about this drug and its use in PJS people.

Rapamycin and its analogs (like RAD001) are mTOR inhibitors, have been around for about a decade and have historically been used as immunosuppressants in transplant patients. Since 2002 researchers have become interested in using these drugs in advanced cancer patients. There has been some success in advanced renal (kidney) cancer patients and those with progressive neuroendocrine tumors of pancreatic origin.

 Here's a press release from Novartis, the drug company: Everolimus (RAD001) Significantly Extends Progression-Free Survival in Advanced Kidney Cancer Patients After Failure of Other Targeted Therapy -

Do note, this significant improvement is a median progression-free survival of 4.0 months vs 1.9 months. (1)

 This is great if you have advanced renal cancer. But I'm not sure we can compare the situations of those with PJS to those with a probably fatal disease.

There are many clinical trials for use of RAD001 in advanced cancer ( Most of these trials are Phase I or Phase II trials, not Phase III trials. 2011 update – 60 of the 684 studies are Phase III or Phase IV trials.

 "Many people imagine that a new drug is developed in the lab, tested in human beings, and approved—boom: a new treatment. Few realize how excruciatingly slowly cancer research moves.

 "A drug ready to be tested in human beings is first used in a Phase I trial, in which perhaps two dozen people, in groups of three, take varying doses to establish a maximum safe dose. Then another small group receives it in a Phase II trial to test the drug's effectiveness. If at this stage it looks promising (and it often does not), the drug will enter a randomized Phase III trial, involving hundreds, perhaps thousands, of patients at several hospitals, typically over three to five years. A Phase III trial is considered a success (and few are) if the new drug extends median survival by 25 percent, which might be as little as three months." The Clinical Trials Bottleneck by Francine Russo.

 References: (1) Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22. PMID: 18653228

 Part two of three:

To continue, here's a 2009 abstract about how rapamycin, an mTOR inhibitor, helped mice bred with a PJS mutation to have a lower and slower rate of polyp growth.

 Cancer Lett.
2009 Jan 13.
 Chemopreventive efficacy of rapamycin on Peutz-Jeghers syndrome in a mouse model.
 Wei C, Amos CI, Zhang N, Zhu J, Wang X, Frazier ML.
 Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, 1155 Pressler Boulevard, Houston, TX 77030, USA.

 Germline mutations in LKB1 cause Peutz-Jeghers syndrome (PJS), an autosomaldominant disorder with a predisposition to gastrointestinal polyposis and cancer.

Hyperactivation of mTOR-signaling has been associated with PJS. We previously reported that rapamycin treatment of Lkb1(+/-) mice after the onset of polyposis reduced the polyp burden. Here we evaluated the preventive efficacy of rapamycin on Peutz-Jeghers polyposis. We found that rapamycin treatment of Lkb1(+/-) mice initiated before the onset of polyposis in Lkb1(+/-) mice led to a dramatic reduction in both polyp burden and polyp size and this reduction was associated with decreased phosphorylation levels of S6 and 4EBP1. Together, these findings support the use of rapamycin as an option for chemoprevention and treatment of PJS.
 PMID: 19147279
Free full text at:

Unfortunately this reminds me of COX-2 inhibitors (Vioxx, Celebrex, Bextra), which were pretty widely prescribed to prevent polyps in PJS people, until it was found that those drugs increased risk of heart and vascular events.

 "Why did NCI suspend the use of celecoxib in the Adenoma (polyp) Prevention with Celecoxib (APC) Trial?
 "The use of celecoxib in the APC Trial was suspended on Dec. 17, 2004, because an initial analysis by an independent Data Safety and Monitoring Board (DSMB) showed that the risk of major fatal and non-fatal cardiovascular events (cardiovascular death, heart attack, stroke, or heart failure) was 2.5 times higher for participants taking the drug compared to those on a placebo. Investigators in the APC Trial immediately suspended study drug use, although the participants were observed for the planned remainder of the trial."
Read more about it at:

 PJS people were prescribed COX-2 inhibitors based on mouse models, one small study of PJS people in Finland (2 of 6 participants had positive response) and their use in people with FAP (familial adenomatous polyposis, another inherited polyp and cancer syndrome). It seemed like good common sense at the time, but the failure of the APC trial led most PJS patients & their doctors away from COX-2 inhibitors.

Now we're being offered RAD001, is it any better (safer and more effective)?

Part three of three:

 To continue my thoughts, I have to wonder whether rapamycin/sirolimus and its analogues like RAD001/everolimus will safely and effectively reduce our polyp burden (and possibly cancer risk).

 My sense from reading the safety data and reports from patients, that it's possibly overkill.

 These are serious drugs and though there's much "buzz" around them, it's unclear that they'll prove to be of use in PJS or even advanced cancers other than renal cell. By 2011, RAD001/everolimus is approved for three medical conditions: Progressive Neuroendocrine Tumors of Pancreatic Origin (PNET) in unresectable, locally advanced or metastatic disease; Subependymal Giant Cell Astrocytoma (SEGA) associated with Tuberous Sclerosis (TS) that cannot be surgically removed; and Advanced Renal Cell Carcinoma after Failure of Treatment with Sunitinib or Sorafenib.

I've pasted info on side effects below.

I hope participants in the SLC trial will be well informed and well followed for side effects.

I could write many more pages, but will hope for some feedback from you all.

warm regards, Stephanie 

From the Novartis for Afinitor/everolimus website: Important Safety Information Common side effects: Common side effects of AFINITOR include mouth ulcers; feeling weak or tired; cough, shortness of breath; diarrhea; rash, dry skin, and itching; nausea and vomiting; fever; loss of appetite; swelling of arms, hands, feet, ankles, face or other parts of the body; abnormal taste; inflammation of lining of the digestive system; headache; nose bleeds; and pain in arms and legs. Patients should not take AFINITOR if they are allergic to AFINITOR or to any of its ingredients. Patients should tell their healthcare provider before taking AFINITOR if they are allergic to sirolimus (Rapamune®) or temsirolimus (Torisel®). AFINITOR can cause serious side effects including lung or breathing problems, infections and kidney failure, which can even lead to death. If patients experience these side effects, they may need to stop taking AFINITOR for a while or use a lower dose. Patients should follow their healthcare provider's instructions. Lung or breathing problems: In some patients lung or breathing problems may be severe, and can even lead to death. Patients should tell their healthcare provider right away if they have any of these symptoms: new or worsening cough, shortness of breath, chest pain, difficulty breathing, or wheezing. Infections: AFINITOR may make patients more likely to develop an infection, such as pneumonia, or a bacterial, fungal, or viral infection. Viral infections may include reactivation of hepatitis B in people who have had hepatitis B in the past. In some people these infections may be severe, and can even lead to death. Patients may need to be treated as soon as possible. Patients should tell their healthcare provider right away if they have a temperature of 100.5°F or above, chills, or do not feel well. Symptoms of hepatitis B or infection may include the following: fever, skin rash, joint pain and inflammation, tiredness, loss of appetite, nausea, pale stool or dark urine, yellowing of the skin, or pain in the upper right side. Kidney Failure: AFINITOR may cause kidney failure. In some people this may be severe and can even lead to death. Patients should have tests to check their kidney function before and during their treatment with AFINITOR. Mouth ulcers: AFINITOR can cause mouth ulcers and sores. Patients should tell their healthcare provider if they have pain, discomfort, or open sores in their mouth. Their healthcare provider may tell them to use a special mouthwash or mouth gel that does not contain alcohol or peroxide. Blood tests: Patients will have regular blood tests before they start AFINITOR and as needed during their treatment. These will include tests to check the patient's blood cell count, kidney and liver function, and blood sugar levels. Other medicines/food and AFINITOR: AFINITOR may affect the way other medicines work, and other medicines can affect how AFINITOR works. Using AFINITOR with other medicines can cause serious side effects. Patients should tell their healthcare provider about all of the medicines they take, including prescription and non-prescription medicines, vitamins, and herbal supplements such as: St. John's Wort and medicine for fungal infections, bacterial infections, tuberculosis, seizures, HIV-AIDS, heart conditions or high blood pressure, and medicines that suppress their immune system. Patients should not drink grapefruit juice or eat grapefruit during their treatment with AFINITOR as it may make the amount of AFINITOR in their blood increase to a harmful level. Patients should not take AFINITOR tablets which are broken or crushed. Patients should not chew or crush the tablets. Liver Problems & Other Medical Conditions: The amount of AFINITOR in the blood was increased in patients who had liver problems. Patients should tell their healthcare provider about all their medical conditions including if they have or have had liver problems, diabetes or high blood sugar, high cholesterol levels, infections, hepatitis B, or other medical conditions. Vaccinations: Patients should tell their healthcare provider if they are scheduled to receive any vaccinations. Patients should not receive a live vaccine or be around people who have recently received a live vaccine during treatment with AFINITOR. Use in pregnancy: It is not known if AFINITOR will harm an unborn baby. Women should use effective birth control while using AFINITOR and for 8 weeks after stopping treatment. Patients should tell their healthcare provider if they have any side effect that bothers them or does not go away. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit, or call 1-800-FDA-1088. Full Prescribing Information about Afinitor. Sutent®, Rapamune® and Torisel® are registered trademarks of Pfizer Inc. Nexavar® is a registered trademark of Onyx Pharmaceuticals, Inc. and Bayer HealthCare Pharmace

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