The Gene Expression Studies of the Role of Tumor Microenvironments in Tumor Progression
Summary
The purpose of this study is to analyze the gene expression patterns associated with various microenvironmental stresses in tumors to understand their roles in tumor progression and treatment responses. To achieve this goal, we will perform gene expression analysis of the tumor samples collected from an IRB-approved study (IRB #: 4516-05-2R2) International Phase III Study of Chemoradiotherapy versus Chemoradiotherapy Plus Hyperthermia for Locally Advanced Cervical Cancer directed by Dr. Mark Dewhirst. We will correlate the gene expression signatures of different microenvironmental stresses with the measured physiological parameters to understand their role in tumor progression, treatment response and clinical outcomes.
Description
In the first part of the proposal, we will determine the cellular responses to various microenvironmental factors (such as lactosis, acidosis, hypoxia, glucose deprivation) in cultured epithelial cells (commercially obtained) making use of DNA microarray analysis. From the analysis of these microarray assays, we will obtain the gene signatures reflecting how cells respond to these environments stresses. These gene signatures will be used to analyze and annotate the gene expression patterns in the tumor samples and whether hyperthermia will affect the physiological parameters and the corresponding gene signatures.
In the second part of the proposal, we will work with Dr. Dewhirst to perform gene expression study of cervical cancer samples from a phase III, multicenter, randomized clinical trial (IRB 4516-05-2R2). The subjects will de-identified and we will not obtain directly the PHI of the subjects in this trial. Subjects will be randomized to chemoradiotherapy alone or chemoradiotherapy + hyperthermia. For subjects randomized to hyperthermia, heat treatments will be administered concurrently with chemotherapy once weekly during the course of external beam radiation. In the hyperthermia suite, catheters will be placed in the cervical os, vagina and rectum for internal temperature monitoring. Hyperthermia will be given externally to the pelvis and abdomen using the BSD Sigma 60 ,Sigma Eye or Sigma Ellipse systems. Initial power will be limited to less than 1500 watts with phase and amplitude adjusted for equal surface electric fields in each quadrant of the applicator. Heating will continue for 60 minutes after average cervical os or interstitial temperatures of 40°C have been achieved, or for a maximum total duration of 90 minutes, whichever is longest. The bolus temperature will be 37° at initiation of power and will be reduced as necessary for patient comfort and/or to help maintain oral temperature of 38.5C. Power will also be reduced or treatment will be stopped at the patient request, or due to intractable pain, nausea or vomiting, if normal tissue temperature rises to 44°C, pulse > 160, BP > 180/100 or < 90/50, altered mental status, or systemic temperature > 38.5°C.
A. The research materials will include the tumor biopsy obtained before and after HT treatments to be used for gene expression studies as well as for the IHC and ISH studies to the findings from our microarray analysis. We will also obtain the information on the tumor physiological parameters information measured in these tumors.
B. The data of the tumor physiological parameters measured and the response to treatments and other clinical outcomes of these patients will also be acquired.
C. Only the physicians taking care of the patients will have access to the patient identifies and other Protected Health Information (PHI). All information will be de-identified and remain anonymous during the studies.
D. The specimens will be collected when the patients undergo medical care for their respective diseases. No new materials or data will need to be collected specifically for this proposal. These biopsies and physiological measurements are included in the original proposed clinical trials.
Study Design
Observational Model: Cohort, Time Perspective: Cross-Sectional
Conditions
Hypoxia
Location
Duke Medical Center
Durham
North Carolina
United States
27708
Status
Not yet recruiting
Source
Duke University
Results (where available)
Links
- Source: http://clinicaltrials.gov/show/NCT00638040
- Information obtained from ClinicalTrials.gov on July 15, 2010
Medical and Biotech [MESH] Definitions
Brain Ischemia
Localized reduction of blood flow to brain tissue due to arterial obstruction or systemic hypoperfusion. This frequently occurs in conjunction with brain hypoxia (HYPOXIA, BRAIN). Prolonged ischemia is associated with BRAIN INFARCTION.
Hypoxia-inducible Factor 1
A basic helix-loop-helix transcription factor that plays a role in APOPTOSIS. It is composed of two subunits: ARYL HYDROCARBON RECEPTOR NUCLEAR TRANSLOCATOR and HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT.
Hypoxia-ischemia, Brain
A disorder characterized by a reduction of oxygen in the blood combined with reduced blood flow (ISCHEMIA) to the brain from a localized obstruction of a cerebral artery or from systemic hypoperfusion. Prolonged hypoxia-ischemia is associated with ISCHEMIC ATTACK, TRANSIENT; BRAIN INFARCTION; BRAIN EDEMA; COMA; and other conditions.
Hypoxia-inducible Factor 1, Alpha Subunit
Hypoxia-inducible factor 1, alpha subunit is a basic helix-loop-helix transcription factor that is regulated by OXYGEN availability and is targeted for degradation by VHL TUMOR SUPPRESSOR PROTEIN.
Hypoxia, Brain
A reduction in brain oxygen supply due to ANOXEMIA (a reduced amount of oxygen being carried in the blood by HEMOGLOBIN), or to a restriction of the blood supply to the brain, or both. Severe hypoxia is referred to as anoxia, and is a relatively common cause of injury to the central nervous system. Prolonged brain anoxia may lead to BRAIN DEATH or a PERSISTENT VEGETATIVE STATE. Histologically, this condition is characterized by neuronal loss which is most prominent in the HIPPOCAMPUS; GLOBUS PALLIDUS; CEREBELLUM; and inferior olives.
Clinical Trials
Hypoxia Impairs Endothelial Function in HAPEs
Aim of the study is to investigate the function of the systemic vascular endothelium in individuals susceptible to high-altitude pulmonary oedema during normoxia and normobaric hypoxia.
The purpose of this study is to look for low levels of oxygen (hypoxia) in prostate cancer using a special x-ray test called a positron emission tomography (PET)scan. Hypoxia may have an e...
Cerebral Blood Flow and Metabolism During Hypoxia and Endotoxemia
The objective of the present protocol is to study whether a low level of oxygen in the blood will affect the immune response to as well as cerebral blood flow and metabolism during an infe...
DAHANCA 24: Prognostic Value of 18F-FAZA in Head and Neck Squamous Cell Carcinoma (HNSCC)
Solid tumours contain varying degrees of hypoxia. Studies show hypoxia to be associated with poor local control and survival, as hypoxia is a cause of resistance to radio- and chemotherapy...
Catecholamines Can Attenuate Intermittent Hypoxia-Induced Expression of TNF in Human Monocytes
Specific aim To examine the effect of catecholamines on the modulation of intermittent hypoxia induced TNF- in human monocytes from both healthy subjects and OSA patients (2). To map th...
PubMed Articles
Development of a novel chronic intermittent hypoxia chamber.
OBJECTIVE: To develop a novel chronic intermittent hypoxia chamber for rat models. DESIGN: The intermittent hypoxia chamber included two animal cabins (28 × 20 × 15 cm) and a hypoxia chambe...
Hypoxia Is Increasing in the Coastal Zone of the Baltic Sea.
Hypoxia is a well-described phenomenon in the offshore waters of the Baltic Sea with both the spatial extent and intensity of hypoxia known to have increased due to anthropogenic eutrophication, howev...
Cardiac atria are the primary source of ANP release in hypoxia-adapted rats.
AIMS: Atrial natriuretic peptide (ANP) is released from the heart in response to hypoxia and helps mitigate the development of pulmonary hypertension. However, the mechanism of hypoxia-induced ANP rel...
This review deals with emerging evidence of an association between systemic or local hypoxia and inflammation in a variety of diseases. The evidence points to new ways of treating inflammatory disorde...
Skeletal muscle adaptation to chronic hypoxia includes loss of oxidative capacity and decrease in fiber size. However, the diaphragm may adapt differently since its activity increases in response to h...
