Role of p53 Gene in Metabolism Regulation in Patients With Li-Fraumeni Syndrome

November 18, 2021 updated by: National Heart, Lung, and Blood Institute (NHLBI)

Metabolic Regulation by Tumor Suppressor p53 in Li-Fraumeni Syndrome

This study will examine metabolic and biological factors in people with Li-Fraumeni syndrome, a rare hereditary disorder that greatly increases a person's susceptibility to cancer. Patients have a mutation in the p53 tumor suppressor gene, which normally helps control cell growth. This gene may control metabolism as well as cancer susceptibility, and the study findings may help improve our understanding of not only cancer but also other conditions, such as cardiovascular function.

Healthy normal volunteers and patients with the Li-Fraumeni syndrome and their family members may be eligible for this study. Candidates must be at least 18 years of age, in overall good health and cancer-free within 1 year of entering the study. Participants undergo the following procedures:

  • Blood tests for routine lab values and for research purposes.
  • ECG and echocardiogram (heart ultrasound) to evaluate heart structure and function.
  • Resting and exercise metabolic stress testing: The subject first relaxes in a chair wearing the facemask and then exercises on a stationary bicycle or treadmill while wearing the mask. This test uses the facemask to measure oxygen usage by the body to determine metabolic fitness. Electrodes are placed on the body to monitor the heart in an identical manner to a standard exercise stress test.
  • Magnetic resonance imaging of metabolism: The subject lies on a bed that slides into a large magnet (the MRI scanner) for up to 60 minutes. During scanning, the arm or leg muscles are stressed by inflating a blood pressure cuff and by exercising the limb for several minutes. Subjects may be asked to squeeze a rubber ball or exercise with a foot pedal. Immediately afterwards, the pressure in the cuff is released and remains deflated for 10 to 15 minutes. No more than three 5-minute episodes of blood flow stoppage are performed.
  • Standard MRI scan of exercised limb to determine muscle volume.
  • Brachial artery reactivity test to measure blood vessel function: Before the exercise stress testing, subjects lie on a stretcher while the brachial artery (artery in the forearm) is imaged using a noninvasive ultrasound method. Artery size and blood flow velocity are measured before and after inflating a blood pressure cuff on the forearm. Vessel size and flow velocity measurements are repeated after 15 minutes and again after administration of nitroglycerin under the tongue.
  • Oral glucose tolerance testing to test for diabetes: To assess sugar metabolism, subjects drink a sugar solution. Blood samples are collected before drinking the solution and 1 and 2 hours after drinking the solution.
  • Muscle biopsy (optional according to subject preference): Subjects may be given small amounts of sedation for the procedure. A small area of skin over a leg muscle is numbed and a small amount of muscle tissue is surgically removed.

Study Overview

Status

Completed

Conditions

Detailed Description

We have previously reported that TP53 (encoding p53 protein), one of the most frequently mutated genes in human cancers, dose dependently modulates the balance between the utilization of oxidative and glycolytic pathways for energy generation in human colon cancer cells and mouse liver mitochondria. Though morphologically similar to their wild-type littermates, mice deficient in p53 display a gene dose-dependent decrease in aerobic exercise capacity, implying that p53 has functions beyond its well characterized cell cycle activities. These current findings have broad implications in fields ranging from cancer and aging research to cardiovascular physiology.

In the Li-Fraumeni familial cancer syndrome (LFS), affected individuals harbor a germline mutation in TP53, hence they are heterozygous with reduced wild-type p53 activity. We hypothesize that the heterozygous individuals will display alterations in aerobic capacity and metabolism that previously has been unappreciated. This IRB proposal translates our experimental observation to human subjects in collaboration with extramural groups studying this rare familial syndrome. The results may not only help clarify why mutations of p53 gene are so common in cancers by potentially conferring metabolic advantages in tumorigenesis, but they may also give us an opportunity to understand a fundamental regulatory mechanism in cellular energy generation relevant to other processes.

Study Type

Observational

Enrollment (Actual)

82

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 96 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

96 carrier LFS family members 60 non-carrier LFS family members or normal 30 normal controls for MR spectroscopy study 20 subjects with mitochondrial disorders 20 non-carrier mitochondrial disorder family members or normal controls

Description

  • INCLUSION CRITERIA:

    1. At least 18 years of age and able to give informed consent
    2. In overall good physical and mental health;
    3. Able to exercise on a treadmill (if participating in the treadmill exercise portion).
    4. Able to perform hand or leg exercises (if participating in the MRS portion)

Able to undserstand and sign consent

Have been diagnosed with the Li-Fraumeni Syndrome or have a family member with the Li-Fraumeni Syndrome or have been diagnosed with mitochondrial disorder or be a healthy volunteer

EXCLUSION CRITERIA:

Cancer patients undergoing or requiring systemic treatment

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Control
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
carrier LFS family members
96 carrier LFS family members
non-carrier LFS family members or normal
60 non-carrier LFS family members or normal
non-carrier mitochondrial disorder family members or normal controls
20 non-carrier mitochondrial disorder family members or normal controls
normal controls for MR spectroscopy study
30 normal controls for MR spectroscopy study
subjects with mitochondrial disorders
20 subjects with mitochondrial disorders

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Non-invasively measure aerobic exercise capacity and metabolism
Time Frame: ongoing
Because an interim analysis has confirmed our hypothesis, the aim of the primary endpoint has been achieved.
ongoing

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Non-invasively measure markers of mitochondrial function by magneticresonance spectroscopy (MRS) in response to transient ischemic stress
Time Frame: ongoing
This will serve to facilitate bench-to-bedside studies to investigate metabolic and other associated changes in LFS with the goal of deriving mechanistic insights that may lead to new strategies forcancer prevention.
ongoing
Measure oxygen consumption, protein and RNA levels of p53-regulated mitochondrial genes using blood cells and other tissue samples if available.
Time Frame: ongoing
This will serve to facilitate bench-to-bedside studies to investigate metabolic and other associated changes in LFS with the goal of deriving mechanistic insights that may lead to new strategies forcancer prevention.
ongoing

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

  • Principal Investigator: Paul M Hwang, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 23, 2007

Primary Completion (Actual)

March 22, 2021

Study Completion (Actual)

March 22, 2021

Study Registration Dates

First Submitted

November 25, 2006

First Submitted That Met QC Criteria

December 1, 2006

First Posted (Estimate)

December 4, 2006

Study Record Updates

Last Update Posted (Actual)

November 22, 2021

Last Update Submitted That Met QC Criteria

November 18, 2021

Last Verified

November 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 070030
  • 07-H-0030

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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