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Works: 171 works in 356 publications in 1 language and 356 library holdings
Publication Timeline
Targeting HER-2/neu Overexpression By Suicide Ribozyme In Breast Cancer( Book )

4 editions published between 1997 and 1998 in English and held by 2 WorldCat member libraries worldwide

Breast cancer represents a major cause of death for women in the United States. Overexpression of HER- 2/neu oncogene was found in approximately 30% of breast tumor tissues and shown to be a marker indicating poor prognosis for breast cancer patients. HER-2/neu overexpression in cancer cells is also known to enhance cancer metastasis and to induce chemoresistance to certain anti-cancer drugs and repression of HER-2/neu expression reduces malignancy of the cancer cells. Therefore, HER-2/neu overexpression serves as an excellent target for development of breast cancer therapy. Ribozymes have been successfully used to control gene expression. We have designed a novel suicide ribozyme that will allow a gene of interest (such as a toxin gene) to be expressed specifically in the HER-2/neu- overexpressing breast cancer cells, and therefore, will kill only the HER-2/neu-overexpressing cells. This report describes the progress in the following specific aims: I) Design of the suicide ribozyme and proof of concept in vitro; 2) Proof of concept in vivo: a reporter gene regulated by the suicide ribozyme will be expressed only in cells overexpressing HER-2/neu mRNA. 3) Application of concept in vivo: a toxin gene regulated by the suicide ribozyme will preferentially inhibit the growth of breast cancer cells that overexpress HER-2/neu
Breast Cancer Metastasis: Prognosis and Monitoring of Metastatic Disease( Book )

6 editions published between 1995 and 1998 in English and held by 2 WorldCat member libraries worldwide

Approximately, 1/10 women will develop breast cancer and of these, a large number will succumb to their disease. Although there are many reasons for treatment failure, it is partly due to the inability of current clinical methods to detect disease progression. Since the production of several enzymes including the type IV collagenases and heparanase partly contribute to breast cancer invasion and metastases, we hypothesized that their measurement may provide a means of detecting the early onset of disease progression. This would be useful in two settings. First, if metastatic lesions could be detected by measuring the levels of these enzymes prior to the onset of clinical manifestations which mark this phenomenon, it may be possible to aggressively treat these patients. Second, by measuring these enzymes we hope to detect the relapse of patients being treated with chemotherapeutic drugs/anti-estrogens again prior to the onset of clinical manifestations. Such patients could be rapidly switched over to alternate therapeutic strategies with the objective of controlling disease progression. Accordingly, we undertook studies to develop assays to measure type IV collagenases and heparanase and used these assays to measure these enzymes in serial serum samples from breast cancer patients
Multiple Genetic Alterations in Breast Cancer( Book )

4 editions published between 1995 and 1998 in English and held by 1 WorldCat member library worldwide

Overexpression of HER-2/neu (a member of the EGF receptor family) and inactivation of estrogen receptor (ER) or the tumor suppressor gene, Rb, are known to be involved in the development of human breast cancer. Expression of HER-2/neu can be regulated by ER or Rb. In addition, expression of other EGF receptor family genes (EGF receptor, HER-3 and HER-4) and Heregulin, a ligand for the HER-3 and HER-4 encoded receptor has also been found in some breast cancer cells and may contribute to malignant transformation of breast cancer. The current progress report focuses on the role of the EGF receptor family genes, Heregulin, ER, Rb, and their interrelationship in breast cancer. The technical objectives are: (1) Systematic studies on the expression of EGF receptor family genes, Heregulin, and ER in breast tumor specimens and correlation of the expression with tumor stages and patient survival; (2) Potential paracrine and autocrine loops for EGF receptor family molecules and Heregulin; (3) Effects of ER on malignant transformation phenotypes breast cancer cells; and (4) Effects of Rb on malignant transformation phenotypes breast cancer cells. Expression of EGF receptor family genes, Heregulin, and ER in the same breast tumor specimens were examined by immunohistochemical staining, and western blotting. The relationship between expression of these molecules, tumor grades, and patient's survival will be evaluated Using gene transfer technique, Heregulin, ER or Rb gene are being introduced into HER-2/neu-expressing breast cancer cells. The effect on their malignant transformations will be examined. This project may help to develop a more reliable molecular prognostic strategy and to understand how interactions among multiple genetic factors are involved in the development of breast cancer
Profiling of Resistance Patterns & Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax and Therapeutic Target Identification( Book )

3 editions published between 2008 and 2010 in English and held by 1 WorldCat member library worldwide

We will develop a high throughput therapeutic-target focused (TTF) profiling platform and will combine this with tumor genome wide mRNA profiling and with serum or plasma profiling of phosphopeptides and DNA. We will use these molecular profiles to help define how various molecular factors alone and in combination relate to resistance to therapy, to prognosis, and to metastatic patterns at relapse. Using tumor and blood samples from non-small cell lung cancer (NSCLC) patients as well as NSCLC cell lines with defined chemotherapy resistance patterns, we will examine how molecular profiles may confer resistance and will identify new, potential therapeutic targets. The PROSPECT approach will be novel in that we will assess tumors from NSCLC patients undergoing surgical resection after having received neoadjuvant therapy as a model of resistance. Tumor surviving neoadjuvant therapy would be expected to be enriched for resistant cells. We will define what combinations of targeted therapies are most effective against resistant cell lines with similar molecular profiles, and this will drive later clinical trials (beyond the scope of this Program). Similar studies will be conducted in patients with mesotheliomas undergoing surgical resection of tumor after neoadjuvant therapy with the new Src inhibitor dasatinib
The p16 Pathway In Breast Cancer and Senescence Control( Book )

4 editions published between 1997 and 2000 in English and held by 1 WorldCat member library worldwide

The main hypothesis of this proposal is that breast cancer cells utilize various alternative mechanisms to circumvent a major restriction point in the G1 phase of cell cycle progression. Furthermore, we speculate that the sum of the various subsets of tumors with abnormalities in either player of the cell cycle inhibitor p16 pathway, accounts for a very significant number of breast cancers. It is a main objective of this research project to elucidate the overall extent of p16 involvement in the tumorigenesis of the breast. An additional major goal is to evaluate whether p16 fulfills all the criteria to be considered a senescence control gene
Liposomal Sphingolipids to Target Breast Adenocarcinoma Apoptosis( )

4 editions published between 2000 and 2003 in English and held by 0 WorldCat member libraries worldwide

We have observed that certain sphingolipids (e.g., dimethyl-sphingosine: DMSP) induce apoptosis in vitro in tumor cells despite the over-expression of HER-2/neu and other resistance mechanisms relevant to breast cancer. In these studies, we translated formulation and toxicity studies of liposomal-DMSP (L-DMSP) to proof-of-principle efficacy studies in the nude mouse/human HER-2/neu over-expressing MDA-MD-361 breast adenocarcinoma model. In the first tier efficacy experiments, mice were treated with a multiple-dose MTD regimen of L-DMSP administered i.v. beginning either one-week after - tumor implantation or when tumors grew to 4-5 mm diameter. Early treatment caused a delay in or reduced subsequent tumor growth, but was rarely curative; the tumor growth curve was suggestive of stasis. Treatment initiated at the later timepoint was also efficacious, but less so; the response appeared to be primarily very brief stasis, with slight growth occurring through treatment, followed by a slower growth rate than for controls. In the second tier efficacy experiments using the later timepoint only, the effect of PEG in the liposomal formulation was evaluated, and the i.p. and i.v. routes of administration were compared. The PEG formulation appeared superior to the non-PEG, and the i.p. route did not prove efficacious
The BESCT Lung Cancer Program (Biology, Education, Screening, Chemoprevention, and Treatment)( )

8 editions published between 2002 and 2009 in English and held by 0 WorldCat member libraries worldwide

Our long-term objectives are to define the molecular processes contributing to lung cancer development and progression in order to recognize genetic and phenotypic changes early enough to be reversed with molecularly-targeted therapy and to develop innovative therapeutic approaches to lung cancer. Therefore, the specific goals of this program are to understand molecular alterations in lung cancer, develop lung cancer prevention strategies, and implement experimental molecular approaches to lung cancer. We report herein that enolase-alpha down-regulation is common in NSCLC and associated with a poor clinical outcome; IL-10 expression is lost in a subset of NSCLC and such loss predicts a poor clinical outcome in patients with stage I NSCLC; the combination of the COX-2 inhibitor Celecoxib and the retinoid 4HPR results in more effective growth inhibition than each agent alone; lack of PTEN expression in NSCLC may be related to promoter methylation and is of prognostic importance in stage I NSCLC; Farnesyl Transferase Inhibitors down-regulate phosphorylated RAF and AKT and induce the ubiquitination of AKT protein
Chemoprevention of Ovarian Cancer( )

4 editions published between 2003 and 2006 in English and held by 0 WorldCat member libraries worldwide

The overarching hypothesis of this program project is that 4-HPR (a synthetic vitamin A) and oral contraceptives (OCP) induce apoptosis, possibly through induction of TGFb production by stromal cells, as well as by direct interaction with the surface epithelial cells and these two cell types may act synergistically. In Project 1, 18 adult Rehesus monkeys were give 4-HPR1 OCP, the combination or no medication for 3 months. There were consistent differences in the absolute fluorescence intensities and relative contributions noted between pre- and post-drug measurements in each drug group. A second study involving 30 Cynomolgus macacues and using a crossover design has been completed; immunohistochemical analysis of several biomarkers and analysis of the fluorescence spectroscopy data are ongoing. Project 2 has been transferred to the University of Arizona with the relocation of Dr. Molly Brewer. Now that a supply of 4-HPR has been obtained from the NCI, this study should be ready for patient accrual within the next few weeks pending final approval of revisions by HSRRB. In Project 3, we have focused on understanding the mechanism of action of 4-HPR in tissue culture using both normal and immortalized epithelial cells. Studies are ongoing, and results to date are inconclusive
The Role of MEKK3 Signaling of Pathway in the Resistance of Breast Cancer Cells to TNF-(Alpha)-Mediated Apoptosis( )

4 editions published between 2003 and 2006 in English and held by 0 WorldCat member libraries worldwide

With the support from the DOD Breast Cancer Research Program, the research conducted in the past three years has tested the hypothesis that the NF-kB activation and MAPK activation by MEKK3 plays a critical role in breast cancer growth and survival in response to anti-cancer drugs and to cytokine treatment. We used dominant interfering forms of MEKK3 mutant to examine how perturbation of the MEKK3 pathway may affect breast cancer growth, survival and responses to cytokines. We found that MEKK3 is essential for cytokine induced NF-kB and MAPK activation in fibroblasts. We also developed small interference (si) RNA strategy to inhibit MEKK3 expression in breast cancer cells and used MEKK3 specific antibodies to examine the MEKK3 expression and activation in normal mammary gland cells and in breast cancer cells. Our studies revealed that MEKK3 signaling pathway may be a key regulator for breast cancer cell growth, survival and migration. Our studies also suggest that too little MEKK3 activity may cause cancer growth retardation and affect its migration potential, while too much activity may lead to cell death. These studies will allow us to reveal novel targets and to develop new strategies to treat and prevent breast cancer
Tumor Specific Regulation of C-CAM Cell Adhesion Molecule in Prostate Cancer Carcinogenesis( )

4 editions published between 1999 and 2004 in English and held by 0 WorldCat member libraries worldwide

Down-regulation of carcinoembryonic antigen-related cell adhesion molecule (CEACAM1) tumor suppressor gene expression is common in several malignancies including prostate. The mechanism that mediates this down-regulation is not known. We propose to elucidate the mechanism of loss of CEACAM1 tumor suppressor expression in prostate cancer. We found that down-regulation of CEACAM1 expression in prostate tumors is mainly due to transcriptional down-regulation of CEACAM1 gene. We have identified two transcription factors, i.e. AP-2 and androgen receptor, that are involved in the up-regulation of CEACAM1 gene expression and one transcription repressor, i.e. Sp2, that specifically down-regulates CEACAM1 promoter activity in tumor cells. The identification of Sp2 as a transcriptional suppressor of CEACAM1 gene is a novel finding. We found that Sp2 represses CEACAM1 gene expression by recruiting histone deacetylase activity to the CEACAM1 promoter. Thus, loss of CEACAM1 tumor suppressor gene expression in prostate cancer is due to aberrant chromatin acetylation. Results from this study will allow us to better understand the regulation of CEACAM1 gene during tumorigenesis and this may lead to design new therapy strategies to alter tumor progression or to implement early detection and prevention strategies
Wilms' Tumor 1 (WT1) as Novel Molecular Target in Breast Cancer( )

4 editions published between 2003 and 2006 in English and held by 0 WorldCat member libraries worldwide

High levels of Wilms' Tumor 1 (WT1) mRNA in breast tumors have been linked with poor prognosis for breast cancer patients. However, the function of WT1 protein in breast cancer was not known. We reported the expression of WT1 protein in 9 out of 10 human breast cancer cell lines. The levels of WT1 protein were increased by the HER2/neu oncogene and 17 -estradiol. We demonstrated that WT1 protein is vital to the proliferation of breast cancer cells since down regulation of WT1 protein expression led to breast cancer growth inhibition and apoptosis, which was correlated with decreased cyclin D1 and Bcl-2 levels. WT1 has been shown to undergo two splicing events, which result in four different isoforms. Stable transfection of the different WT1 isoforms was performed in MCF-7 cells. Our data indicate that the WT1 isoforms enhance the in vitro proliferation of MCF-7 breast cancer cells, but do not modulate the sensitivities of MCF-7 cells to doxorubicin, taxol, or tamoxifen. WT1 protein enhances breast tumorigenesis induced by other oncogenes or growth factors, such as HER2/neu and estradiol, but its over expression alone is not sufficient to induce breast tumorigenesis. 14. SUBJECT TERMS 15. NUMBER OF PAGES 9 Proliferation, apoptosis, chemoresistance, signal transduction 16
Epitope Specific T-Cell Immunity to Breast Cancer( )

4 editions published between 1998 and 2002 in English and held by 0 WorldCat member libraries worldwide

We analyzed the ability of T cells from PBMC of breast cancer patients to recognize HBR-2/neu (HER-2) peptides. We found that 13/18 patients responded by proliferation to at least one of the HER-2 peptides tested. Of these peptides, one designated G89 (HER-2:777-789) was recognized by T cells from 10 patients. 7/9 responding patients were HLA- DR4+, suggesting that this peptide is recognized preferentially in association with HLA-DR4. Analysis of the specificity and restriction of the cytokine responses by G89-stimulated T cells revealed that these cells secreted significantly higher levels of IFN-gamma than lL-4 and IL-lO suggesting priming for a T helper 1 (Thl) response. The same pattern of responses was observed to the intracellular domain (ICD) of HER-2 suggesting that G89-stimulated T cells recognized epitopes of the HER-2 protein in association with HLA-DR4. Since HLA-DR4 is present in 25% of the humans, characterization of MHC-class II restricted epitopes inducing Thl responses may provide a basis for the development of multivalent HER-2 based vaccines against breast and ovarian cancer
Vasculature-Specific Adenovirus Vectors for Gene Therapy of Prostate Cancer( )

4 editions published between 2005 and 2008 in English and held by 0 WorldCat member libraries worldwide

In Year 2 of the project we have completed Task 2 (as per approved Statement of Work) by characterizing the binding specificity of the Ad fiber proteins designed to bind IL-11Ralpha. In Task 3 of the project we identified the most promising fiber ligand constructs and designed Ad genomes that incorporate the genes for these proteins in addition to the reporter expressing gene cassettes
Evaluation of Novel Agent Which Target Neovasculature of Breast Tumors( )

4 editions published between 2003 and 2006 in English and held by 0 WorldCat member libraries worldwide

Biological studies examining the development of the vascular tree in normal development and in disease states have identified numerous cytokines and their receptors responsible for triggering and maintaining this process (1-7). Tumor neovascularization is central not only to the growth and development of the primary lesion but appears to be a critical factor in the development and maintenance of metastases (8-12). Clinical studies in bladder cancer (9) have demonstrated a correlation between micro-vessel density and metastases. In addition, studies of breast cancer metastases by Fox et al. and Aranda et al. (11-12) have demonstrated that microvessel count in primary tumors appears to be related to the presence of metastases in lymph nodes and micrometastases in bone marrow. The cytokine vascular endothelial growth factor-A (VEGF-A) and its receptors Flt-1 and KDR have been implicated as one of the central mediators of normal angiogenesis and tumor neovascularization (13-20). Up-regulation or over-expression of the KDR receptors or the VEGF-A ligand itself have been implicated as poor prognostic markers in various clinical studies of colon, breast and pituitary cancers (21-23). Recently, Padro et al. (24) have suggested that both VEGF-A and KDR may play a role in the neovascularization observed in bone marrow during AML tumor progression and may provide evidence that the VEGF/KDR pathway is important in leukemic growth
Epigenetic Silencing and Resistance to Imatinib Mesylate in CML( )

4 editions published between 2004 and 2007 in English and held by 0 WorldCat member libraries worldwide

We performed analyses of DNA methylation data reported in the final report with clinical outcome of CML patients. DNA methylation significantly correlated with survival. CML patients with average methylation zscore values above zero had significantly shorter survival than patients with z-scores below zero (median 10 months vs 59 months, P<0.0001). This was true also within CP (median survival of 44 months for patients with high methylation vs median not reached in patients with low methylation, P=0.02) and AP (median survival of 11 months for patients with high methylation vs 27 months in patients with low methylation, P=0.009). Changes in gene silencing by DNA methylation may play a role in developing alternative routes for cells to circumvent the effects of imatinib
A High Resolution Clinical PET with Breast and Whole Body Transfigurations( )

4 editions published between 2003 and 2006 in English and held by 0 WorldCat member libraries worldwide

Despite advances in the last decade, the radiographic diagnosis of breast cancer remains uncertain. Of the annual 600,000 cases referred for biopsy by mammograms each year, 400,000 are unnecessary, costing $2 billion annually. The diagnosis of breast cancer in young women and women with silicone implants continues to be difficult. Accurate detection of small breast tumors (2-3 mm) is still to be achieved. Positron emission tomography (PET) has the potential to reduce this high healthcare cost, unnecessary painful anxiety, and to improve diagnosis and survivability for women of all ages. We have developed the detector and electronic technology for building an ultrahigh resolution PET camera. We propose to use such technology to construct an ultrahigh resolution PET that has a dedicated breast-diagnosis mode that has 13-26 times higher detection sensitivity than regular PET and an ultrahigh image resolution of 3mm compared to the 4.5-6 mm in today?s PET cameras. We have already developed a scaled-down engineering prototype PET to confirm the feasibility that 3 mm tumor can be detected accurately. We propose to construct a scaled-up clinical version of the design so that it can be used for clinical human trials to confirm the clinical utility
Cyclin E, a Powerful Predictor of Survival in Breast Cancer - A Prospective Study( )

4 editions published between 2003 and 2006 in English and held by 0 WorldCat member libraries worldwide

Aberrations in expression of cyclin E, a positive cell cycle regulator at the G1 to S transition, may affect the biological behavior of breast cancer. In a retrospective analysis of tumor specimens from 395 breast cancer patients, we found that overexpression of the full-length cyclin E protein and its LMW isoforms was a very strong predictor of breast cancer death regardless of whether patients had lymph node-negative disease or lymph node-positive disease (p <0.0001). Our hypothesis is that dysregulation of cyclin E is a powerful prognostic indicator of outcome in early stage breast cancer. Specifically we will: 1: use cyclin E antibody as a prognostic marker for stage I and II breast cancer in a PROSPECTIVE study, 2: examine the cyclin E associated activity and its immunecomplex formation with key cell cycle regulators in freshly resected tumor samples, and 3: develop an immunohistochemical (IHC) assay for specifically detecting the LMW forms of cyclin E in Breast Cancer. We will correlate the cyclin E alterations in samples with the expression of key cell cycle regulators and clinical biomarkers. If we prospectively confirm cyclin E overexpression correlates with poor outcome, clinicians can more appropriately tailor aggressive systemic treatment to those at greatest risk for systemic metastases
Targeting Human Breast Cancer Cells that Overexpress HER-2/neu mRNA by an Antisense Iron Responsive Element( )

4 editions published between 2000 and 2003 in English and held by 0 WorldCat member libraries worldwide

Amplification and overexpression of the HER-2/neu gene were found in 20-30% of patients with breast cancer, and is an indicator for poor prognosis of the disease. To target the breast cancer cells-overexpressing HER-2/neu mRNA, a novel approach was developed. We combine the antisense principle and the biochemical property of a translation regulator, an iron responsive element (IRE) to preferentially express therapeutic gene in HER-2/neu overexpressing breast cancer cells. Briefly, IRE, when placed 5 to a gene, functions as a negative translation regulator in that IRE interacts with iron-regulatory proteins (IRPs) and this protein-RNA complex blocks translation. One way to alleviate this translation inhibition is to prevent the IRE/IRP interaction by disrupting the IRE stem-loop structure via a sense-antisense hybrid. Thus, we designed a HER-2/neu antisense IRE (AS-IRE) that possesses the IRE consensus sequence and functions as a translation inhibitor. When placed 5 to a reporter gene, AS-IRE could direct the reporter gene expression in breast cancer cells that overexpress HER-2/neu mRNA, because the AS-IRE-mediated translation inhibition can be overcome by the overexpression of HER-2/neu mRNA. In this project, we attempt to demonstrate the utility of this novel approach in vitro and in vivo by specifically directing gene expression in HER-2/neu-overexpressing breast cancer cells
Radiation-Induced Chemosensitization: Potentiation of Antitumor Activity of Polymer-Drug Conjugates( )

4 editions published between 2001 and 2004 in English and held by 0 WorldCat member libraries worldwide

This study was aimed at evaluating the enhanced antitumor response to radiotherapy by poly(L-glutamic acid)- paclitaxel (PG-TXL) conjugate. We compared the ability of paclitaxel and PG-TXL to sensitize radioresponse using both tumor growth delay and tumor curability as the end points. Furthermore, the effect of treatment schedule on the radiosensitizing activity of PG-TXL as well as the effect of PG-TXL on the sensitivity of normal tissues to radiation was also studied. Our data demonstrate significant synergistic interaction between PG-TXL and tumor radiation. Compared to paclitaxel, PG-TXL enhanced the response of tumors to radiation for approximately 4 folds. Importantly, the enhanced antitumor activity was achieved without apparent effect on the normal tissues. Our results also suggest that PG-TXL may exert its radiosensitizing effect through multiple mechanisms, one of which being sustained release of paclitaxel in the tumor from PG-TXL. This study has lead to a National Cancer Institute-sponsored clinical study that will be initiated at the University of Texas M.D. Anderson Cancer Center upon regulatory approval
Training Program in Breast Cancer Research at the University of Texas M.D. Anderson Cancer Center( )

4 editions published between 2000 and 2004 in English and held by 0 WorldCat member libraries worldwide

Under support from the US Army I DOD the training program in breast cancer research at MDACC has had a successful first year. The training grant has supported four predoctoral and four postdoctoral fellows (two of these trainees were included in the program due to their outstanding qualifications, but are supported by funds from the BCRP at MDACC). Each trainee has made notable progress as evidenced by publications and presentations at national meetings. Significant strides have been made within the scope of the original specific aims in the following research areas: 1) Therapeutic approaches for breast cancer through regulation of oncogene and tumor suppressor gene expression, and control of signal transduction, apoptosis, and DNA repair; 2) Use of animals to understand the biology of breast cancer and to provide models for preclinical therapeutic and preventive studies; 3) Novel preventive strategies for breast cancer; 4) Population-based studies on breast cancer; 5) Molecular diagnostic/prognostic factors for breast cancer; and 6) The basic biology of breast cancer. In addition to laboratory pursuits each trainee has participated in departmental group meetings, journal clubs, and retreats. The goal of the training program is to further the successful training of fellows who will develop research programs of their own which continue to tackle problems of breast cancer
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