Pilot Study of mTOR Inhibitor Therapy for Treatment of Intestinal Polyps in Peutz-Jeghers Syndrome
Peutz-Jeghers Syndrome is a hereditary polyposis condition in which hamartomatous tumors
develop in many tissues of the body. These tumors are benign but frequently cause
gastrointestinal obstruction and bleeding beginning in the 2nd-3rd decades of life
necessitating surgical intervention. Unfortunately, a recent study showed that the lifetime
risk of cancers that arise in Peutz-Jeghers Syndrome is 85% by age 70 years and is 60% by
age 60 years (Hearle et al., 2006).
A working definition of PJS has been suggested by Giardiello et al ,1987(www.genetests.com):
- For individuals with a histopathologically confirmed hamartoma, a definite diagnosis of
PJS requires two of the following three findings:
- Family history consistent with autosomal dominant inheritance
- Mucocutaneous hyperpigmentation (although this can fade with age)
- Small-bowel polyposis
- For individuals without histopathologic verification of hamartomatous polyps, a
probable diagnosis of PJS can be made based on the presence of two of the three
clinical criteria above.
- For individuals without a family history of PJS, diagnosis depends upon the presence of
two or more histologically verified Peutz-Jeghers-type hamartomatous polyps (Tomlinson
& Houlston 1997).
- For individuals with a first-degree relative with PJS, presence of mucocutaneous
hyperpigmentation is sufficient for presumptive diagnosis.
Recently, rapamycin (Rapamune, Wyeth), an FDA-approved drug for use in orthotopic transplant
recipients, was successfully used in an off-label study of 5 individuals with a related
condition called tuberous sclerosis in which the patients had subependymal giant cell
astrocytomas that caused significant and insidious neurological problems such as
hydrocephalus and seizures (Franz, et al. 2006). All astrocytoma lesions exhibited
regression with treatment of oral rapamycin and in one case, necrosis. Treatment was well
tolerated and may offer an alternative to operative therapy in tuberous sclerosis. Tuberous
sclerosis is caused by germline mutations in the tuberous sclerosis 1 or 2 genes. These
genes encode proteins that function downstream of STK11, the gene that is mutated in
Peutz-Jeghers Syndrome. Mutations of STK11 or TSC1/2 leads to activation of mTOR (mammalian
target of rapamycin). Dysregulation of mTOR has been demonstrated in several types of
cancers and clinical trials are underway to see if inhibition of mTOR will be of benefit to
a variety of cancer patients. A recent trial showed efficacy of everolimus in advanced
renal cancer (Hudes, et al. 2007).
All of these studies will be performed on an outpatient basis.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
The Size of Intestinal Polyps
Randall W Burt, MD
Huntsman Cancer Institute
United States: Food and Drug Administration
|Huntsman Cancer Institute||Salt Lake City, Utah 84112|