Mitochondrial DisordersNCT00406445
Role of p53 Gene in Metabolism Regulation in Patients With Li-Fraumeni Syndrome
An observational study of Mitochondrial Disorders and Li-Fraumeni Syndrome, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 100 yearsHealthy volunteers can take part
- Conditions the study is for
- Mitochondrial Disorders, Li-Fraumeni Syndrome, Carriers of p53 Mutation
- How many people
- 82 participants
- Where
- 1 siteUnited States
- Study dates
- 23 Jan 2007to 22 Mar 2021
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
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
Who may be able to join
- At least 18 years of age and able to give informed consent
- In overall good physical and mental health;
- Able to exercise on a treadmill (if participating in the treadmill exercise portion).
- 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
Who cannot join
- Cancer patients undergoing or requiring systemic treatment
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: 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.
Read the 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.
- Keywords
- p53 Mutation, Li-Fraumeni Syndrome, Aerobic Metabolism, Magnetic Resonance Spectroscopy
- Medical subject headings
- Mitochondrial Diseases, Li-Fraumeni Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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 being measured
The primary outcome is the main question the study is designed to answer.
Non-invasively measure aerobic exercise capacity and metabolism
Because an interim analysis has confirmed our hypothesis, the aim of the primary endpoint has been achieved.
Measured: ongoing
Secondary outcomes (2)
Non-invasively measure markers of mitochondrial function by magneticresonance spectroscopy (MRS) in response to transient ischemic stress
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.
Measured: ongoing
Measure oxygen consumption, protein and RNA levels of p53-regulated mitochondrial genes using blood cells and other tissue samples if available.
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.
Measured: ongoing
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Dec 2006 (estimated)
- Study start23 Jan 2007
- Primary completion22 Mar 2021
- Study completion22 Mar 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Mitochondrial DisordersStudies of the same condition, open and under way.
- More trials run by National Heart, Lung, and Blood Institute (NHLBI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 82 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Paul M Hwang, M.D., Principal investigator, National Heart, Lung, and Blood Institute (NHLBI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00406445
- Sponsor's protocol ID
- 070030
- Other IDs
- 07-H-0030
- Status last verified
- Nov 2021
- First submitted
- 25 Nov 2006
- Last updated
- 22 Nov 2021
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Arena R, Myers J, Abella J, Peberdy MA. Influence of heart failure etiology on the prognostic value of peak oxygen consumption and minute ventilation/carbon dioxide production slope. Chest. 2005 Oct;128(4):2812-7. doi: 10.1378/chest.128.4.2812.
PubMed 16236959Brown BW, Costello TJ, Hwang SJ, Strong LC. Generation or birth cohort effect on cancer risk in Li-Fraumeni syndrome. Hum Genet. 2005 Dec;118(3-4):489-98. doi: 10.1007/s00439-005-0016-x. Epub 2005 Nov 12.
PubMed 16284780Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest. 1981 Dec;68(6):1456-67. doi: 10.1172/jci110398.
PubMed 7033284Wang PY, Li J, Walcott FL, Kang JG, Starost MF, Talagala SL, Zhuang J, Park JH, Huffstutler RD, Bryla CM, Mai PL, Pollak M, Annunziata CM, Savage SA, Fojo AT, Hwang PM. Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome. J Clin Invest. 2017 Jan 3;127(1):132-136. doi: 10.1172/JCI88668. Epub 2016 Nov 21.
PubMed 27869650Wang PY, Ma W, Park JY, Celi FS, Arena R, Choi JW, Ali QA, Tripodi DJ, Zhuang J, Lago CU, Strong LC, Talagala SL, Balaban RS, Kang JG, Hwang PM. Increased oxidative metabolism in the Li-Fraumeni syndrome. N Engl J Med. 2013 Mar 14;368(11):1027-32. doi: 10.1056/NEJMoa1214091.
PubMed 23484829
Study at a glance
From the registry record, last updated by the sponsor on 22 Nov 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Metabolic Regulation by Tumor Suppressor p53 in Li-Fraumeni Syndrome
- ClinicalTrials.gov ID
- NCT00406445
- Acronym / sponsor ID
- 070030
- Keywords
- p53 Mutation, Li-Fraumeni Syndrome, Aerobic Metabolism, Magnetic Resonance Spectroscopy
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 82 participants (actual)
- Lead sponsor
- National Heart, Lung, and Blood Institute (NHLBI)US National Institutes of Health
- Study start
- 23 Jan 2007 (actual)
- Primary completion
- 22 Mar 2021 (actual)
- Study completion
- 22 Mar 2021 (actual)
- First posted
- 4 Dec 2006 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| 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 |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- 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
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (1 listed)
- Cancer patients undergoing or requiring systemic treatment
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
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.
2 secondary outcomes
Non-invasively measure markers of mitochondrial function by magneticresonance spectroscopy (MRS) in response to transient ischemic stress
Time frame: 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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Nov 2021.
- Background: PubMed 16236959Arena R, Myers J, Abella J, Peberdy MA. Influence of heart failure etiology on the prognostic value of peak oxygen consumption and minute ventilation/carbon dioxide production slope. Chest. 2005 Oct;128(4):2812-7. doi: 10.1378/chest.128.4.2812.
- Background: PubMed 16284780Brown BW, Costello TJ, Hwang SJ, Strong LC. Generation or birth cohort effect on cancer risk in Li-Fraumeni syndrome. Hum Genet. 2005 Dec;118(3-4):489-98. doi: 10.1007/s00439-005-0016-x. Epub 2005 Nov 12.
- Background: PubMed 7033284Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest. 1981 Dec;68(6):1456-67. doi: 10.1172/jci110398.
- Derived from this study: PubMed 27869650Wang PY, Li J, Walcott FL, Kang JG, Starost MF, Talagala SL, Zhuang J, Park JH, Huffstutler RD, Bryla CM, Mai PL, Pollak M, Annunziata CM, Savage SA, Fojo AT, Hwang PM. Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome. J Clin Invest. 2017 Jan 3;127(1):132-136. doi: 10.1172/JCI88668. Epub 2016 Nov 21.
- Derived from this study: PubMed 23484829Wang PY, Ma W, Park JY, Celi FS, Arena R, Choi JW, Ali QA, Tripodi DJ, Zhuang J, Lago CU, Strong LC, Talagala SL, Balaban RS, Kang JG, Hwang PM. Increased oxidative metabolism in the Li-Fraumeni syndrome. N Engl J Med. 2013 Mar 14;368(11):1027-32. doi: 10.1056/NEJMoa1214091.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paul M Hwang, M.D. principal investigator
National Heart, Lung, and Blood Institute (NHLBI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Mitochondrial Disorders and Li-Fraumeni Syndrome, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Non-invasively measure aerobic exercise capacity and metabolism (time frame: ongoing). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00406445, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Nov 2021.