A Pilot Study of Sirolimus (Rapamycin, Rapammune[Registered Trademark]) in Subjects With Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in PTEN
- PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tumor suppressor
gene whose function is frequently lost through genetic and epigenetic mechanisms in
cancer. Loss of PTEN increases activation of the PI3K/Akt/mTOR pathway, which increases
cellular proliferation and survival.
- Germline mutations in PTEN are associated with a number of hamartomatous syndromes, of
which Cowden Syndrome (CS) is the prototype. The set of syndromes that are defined by
germline PTEN mutations has been labeled PTEN Hamartomatous Tumor Syndromes or PHTS.
- Patients with PHTS suffer increased morbidity and mortality. Benign tumors such as
hamartomas occur in virtually every organ, most commonly in the skin and the
gastrointestinal tract, which prompts frequent monitoring and resection and causes
psychological and physical stressors on patients with this condition.
- CS patients develop thyroid, breast, and endometrial cancers at an earlier age than the
general population, and have an overall increased incidence of these cancers compared
to the general population. These patients have increased morbidity from heightened
surveillance and diagnostic procedures.
- No medical therapies exist for PHTS patients.
- Because tumors from PHTS patients show increased activation of the PI3K/Akt/mTOR
pathway, inhibitors of this pathway might have activity in patients with PHTS.
- Sirolimus (rapamycin) is a specific inhibitor of mTOR that is FDA-approved and is
preferentially effective in cells with mutant PTEN.
- We hypothesize that sirolimus will have activity in patients with PHTS, as measured by
biochemical techniques that will assess mTOR inhibition and clinical tests that will
assess the growth and metabolism of benign and malignant tumors.
- The primary endpoint will be inhibition of the mTOR pathway in tissues obtained before
and after therapy, as assessed using immunohistochemistry in benign as well as
- Secondary endpoints will include inhibition of the mTOR pathway in PBMCs as assessed by
immunoblotting, changes and duration of change in benign or malignant tumor size as
assessed by CT, serial digital photography, digital dermoscopy, changes in tumor
metabolism as assessed by PET, changes in lymphocyte counts, as well as changes in
-Adult subjects with documented germline PTEN mutations who meet diagnostic criteria for
Cowden Syndrome by international criteria.
- Subjects will undergo biopsy, imaging, photography, dermoscopy, and neuropsychological
testing prior to and after a course of therapy with sirolimus to assess the efficacy of
- This pilot protocol will test sirolimus at an FDA-approved dose (6 mg PO loading dose/
2mg PO daily) in a group of twenty patients.
- Treatment will last for 56 days (plus 2 - 3 days to allow flexibility for scheduling of
follow-up procedures) for PHTS subjects with benign hamartomatous tumors.
- For PHTS subjects with established malignancy, measurement of disease will be performed
every other cycle and treatment will continue until disease progression or unacceptable
Allocation: Non-Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Biochemical changes (i.e., inhibition of the PTEN/Akt/mTOR pathway) in benign and malignant tumor tissues as assessed by immunohistochemistry.
Giuseppe Giaccone, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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