Sirolimus to Treat Cowden Syndrome and Other PTEN Hamartomatous Tumor Syndromes

• Biochemical changes (i.e., inhibition of the PTEN/Akt/mTOR pathway) in benign and malignant tumor tissues as assessed by immunohistochemistry. [ Designated as safety issue: No ]
  

• Biochemical changes (i.e., inhibition of the mTOR pathway) in peripheral blood mononuclear cells as assessed by immunoblotting [ Designated as safety issue: No ]
  
• Changes in tumor size and duration of change as assessed by CT scan, digital photography, and digital dermoscopy [ Designated as safety issue: No ]
  
• Changes in tumor metabolism as assessed by PET scan [ Designated as safety issue: No ]
  
• Changes in lymphocyte counts [ Designated as safety issue: No ]
  
• Changes in neuropsychological function as assessed by a battery of neuropsychological tests (WASI, Yields Verbal IQ, Performance IQ, Full Scale IQ, Beck Depression Inventory, Hopkins Verbal Learning Test, Brief Visuospatial Memory Test-Revised [ Designated as safety issue: No ]
  

Radiation: fludeoxyglucose F 18
N/A
Drug: sirolimus
N/A

Background:

• 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.

Objectives:

• 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 malignant tumors.
• 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 neuropsychological testing.

Eligibility:

-Adult subjects with documented germline PTEN mutations who meet diagnostic criteria for Cowden Syndrome by international criteria.

Design:

• 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 treatment.
• 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 toxicity.