Clinical Trial: Sirolimus to Treat Cowden Syndrome and Other PTEN Hamartomatous Tumor Syndromes

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Pilot Study of Sirolimus (Rapamycin, Rapamune[Registered Trademark]) in Subjects With Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in PTEN

Brief Summary:

Background:

People with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) hamartomatous tumor syndromes (PHTS) have a mutation in one of their genes called PTEN that can lead to benign tumors called hamartomas throughout the body. This puts them at increased risk for breast, thyroid and endometrial cancer.

People with a PTEN mutation have increased activity of proteins such as protein kinase B (AKT) and mammalian target of rapamycin (mTOR), which may be responsible for tumor growth and their increased risk of these cancers.

Experiments show that a drug called sirolimus, which is used to prevent the immune system from rejecting transplanted organs, can inhibit cancer cell growth by blocking the mTOR protein.

Objectives:

To test the ability of sirolimus to decrease the activity of proteins that are regulated by mTOR in both benign and cancerous tumor tissue.

Eligibility:

People 18 years of age and older with Cowden syndrome or other PHTS.

Design:

Sirolimus treatment. Patients take sirolimus once a day in 28-day treatment cycles. Patients who do not have cancer take the drug for a total of two cycles (56 days) unless they develop unacceptable side effects. Those who have cancer may continue sirolimus beyond cycle 2 until their disease worsens or they develop unacceptable side effects.

Evaluations. Patients come to the clinic for a history and physical examination on day 1 of every treatment cycle, then every month for th

Detailed Summary:

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 phosphoinositide 3-kinase (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.
  • Cowden syndrome (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 Food and Drug Administration (FDA)-approved and is preferentially effective in cells with mutant PTEN.
  • We hypothesize that sirolimus will h
    Sponsor: National Cancer Institute (NCI)

    Current Primary Outcome:

    • Biochemical Changes in Benign and Malignant Tumor Tissues as Assessed by Immunohistochemistry. [ Time Frame: Baseline, day 14, and day 56 ]
      A biochemical change is defined as a decrease in certain protein levels (e.g. P-AKT (phosphorylated AKT), total S6, P-S6, and P-4E-BP1) important in cell growth. These are measured by collecting tissue samples which stained and protein levels are measured under the microscope. Scoring will be based on distribution and intensity of staining. Distribution will be scored as 0 (0%), 1 (1% to 50%), and 2 (51% to 100%) to indicate the percentage of positive cells of interest in a single core. The intensity of the signal will be scored as 1 (weak), 2 (moderate), and 3 (strong). The distribution score and intensity score will be summed into a total score (TS).
    • Number of Participants With Adverse Events [ Time Frame: 47 months ]
      Here is the number of participants with adverse events


    Original Primary Outcome: To determine whether sirolimus, an mTOR inhibitor, will alter the activation of status of components in the PTEN/Akt/mTOR pathway in benign and malignant tissues derived from PHTS subjects.

    Current Secondary Outcome:

    Original Secondary Outcome: To explore inhibition of mTOR pathway in PBMCs, to explore inhibition of benign and malignant tumor growth and/or induction of tumor regression using serial dermoscopy, photography, PET.

    Information By: National Institutes of Health Clinical Center (CC)

    Dates:
    Date Received: September 3, 2009
    Date Started: July 2008
    Date Completion:
    Last Updated: September 29, 2015
    Last Verified: July 2013