Role of p53 Gene in Metabolism Regulation in Patients With Li-Fraumeni Syndrome
| Status: | Enrolling by invitation |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/6/2019 |
| Start Date: | March 25, 2008 |
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.
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.
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.
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.
- 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
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 800-411-1222
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