Area:
Pharmacy, Pharmacology, Cell Biology, Oncology
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High-probability grants
According to our matching algorithm, Debra A. Tonetti is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2002 — 2003 |
Tonetti, Debra |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Pkc as a Marker in Tamoxifen Resistant Brest Cancer @ University of Illinois At Chicago
DESCRIPTION (provided by applicant): Resistance to tamoxifen (TAM), the most often prescribed endocrine treatment for breast cancer, represents a significant problem in the management of the disease. Identification of the key factors involved in the molecular mechanism of TAM resistance will undoubtedly lead to the development of logical therapeutic targets. We have previously reported that stable transfection of protein kinase C alpha (PKCa) into T47D human breast cancer cells results in a hormone-independent phenotype and TAM-resistant tumor growth. Tumors formed from these cells grow in the presence of TAM and regress in the presence of 17Beta-estradiol (E2). Our finding that a pure antiestrogen can inhibit these TAM-resistant tumors may have important implications for the treatment of TAM-resistant breast cancer. This information may now allow us to predict the efficacy of endocrine therapy. For example, tumors overexpressing PKCa may be stimulated to grow if the patient is given TAM therapy, therefore a more appropriate therapy may be an estrogen-like compound or a pure antiestrogen. However our T47D/PKCalpha tumor model cannot determine whether PKCalpha overexpression occurs in patients prior to TAM exposure, or is a result of long-term TAM treatment. The following Specific Aims provide the framework to substantiate the role of PKCalpha as a predictor or as a marker of TAM treatment failure as well as elucidate the downstream genes that may participate in TAM-resistant breast cancer. 1. To determine whether PKCalpha expression is predictive of TAM-treatment failure. We will perform immunohistochemical analysis to determine PKCalpha expression in paraffin-embedded breast cancer specimens obtained from the National Cancer Institute's Cooperative Breast Cancer Tissue Resource (NCI CBCTR). 2. To determine whether PKCa expression increases in recurrent (TAM-resistant) tumors relative to the primary tumor. We propose to study paired biopsies from patients from the Lynn Sage database at NMH where both primary and recurrent paraffin-embedded tumors are available to identify changes, if any, in the intensity and/or frequency of PKCalpha expression by immunohistochemistry. 3. Identify specific genes that are differentially expressed downstream of PKCa that mediate the hormone-independent phenotype in T47D:A18/PKCalpha cells and tumors. To examine the PKCa-mediated signaling pathway we will utilize our T47D:A18/PKCalpha cell culture and tumor model to investigate differential gene expression as determined by Atlas Gene Array technology.
|
0.915 |
2007 — 2011 |
Tonetti, Debra |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Pkc Alpha as a Marker For Logical Therapeutic Approaches to Breast Cancer @ University of Illinois At Chicago
[unreadable] DESCRIPTION (provided by applicant): For the past 30 years, tamoxifen (TAM) has been the most often prescribed endocrine treatment for breast cancer. In the past few years it was demonstrated that aromatase inhibitors are superior to TAM as adjuvant therapy in the postmenopausal patient population. Furthermore, aromatase inhibitors are effective as a second-line treatment following the emergence of TAM resistance and are being tested in the chemoprevention setting. This will bring a paradigm shift in the standard endocrine therapy for breast cancer in the near future. Identification of the key factors involved in the molecular mechanism of resistance to both TAM and aromatase inhibitors will undoubtedly lead to the development of logical therapeutic targets. We have developed and characterized a preclinical model of TAM resistance in the hormone-dependent T47D:A18 cell line that was engineered to overexpress protein kinase C alpha (PKCa). Tumors derived from these cells grow in athymic mice in an estrogen (E2)-independent and TAM-resistant fashion. Based on this model we examined clinical specimens and discovered that overexpression of PKCa is frequently associated with TAM resistance in human breast cancers. More recent preliminary data indicate that the T47D:A18/PKCa cells and tumors express high levels of Notch-4, a known breast oncogene and putative marker of breast cancer stem cells. Most interesting is our finding that T47D:A18/PKCa TAM-resistant tumors regress in the presence of E2 or raloxifene (RAL). It is our hypothesis that PKCa overexpressing, TAM-resistant tumors in patients may respond to treatment with RAL, E2 or Notch inhibitors. The T47D:A18/PKCa breast cancer tumor model will be used to investigate three therapeutic treatment strategies: (1) the opposing actions of TAM and RAL and the potential therapeutic application of RAL and other SERMS, (2) the role of Notch4 and effect of Notch inhibitors in TAM-resistance; and (3) the efficacy of estrogen as compared to aromatase inhibitor therapy. Relevance: The emergence of tamoxifen-resistant breast cancer is a critical problem in the management of advanced disease. Since essentially all patients with metastatic disease will relapse during tamoxifen treatment, alternative therapeutic strategies are needed. This proposal will address three potential approaches to treatment based on protein kinase C alpha (PKCa) as a biomarker to guide therapeutic choice. [unreadable] [unreadable] [unreadable]
|
0.915 |