This proposal is the Laboratory Program of a Breast Cancer Treatment Group, which is applying for funding through a COOPERATIVE AGREEMENT with the National Cancer Institute (RFA CA094-004). We have produced monoclonal antibodies (MAbs) against the EGF receptor which block its function in signal transduction and can prevent growth of tumors expressing the receptor, both in culture and in xenografts. Anti-HER2 MAbs from Genetech also have antitumor activity. We have demonstrated the capacity of combination treatment with antireceptor MAb plus chemotherapy to eliminate well-established human tumor xenografts. Our approach is novel in that it simultaneously attacks the breast cancer cell at two sites which appear to be critical to cell growth and survival: signal transduction pathways activated by essential growth factors, and DNA or cellular architectural elements (tubulin) that are susceptible to damage by the drugs most active against breast cancer. We anticipate that this 'double hit' approach will be a paradigm for other combination therapies, which can take advantage of the relative inability of malignant cells to handle insults that require regulation of growth at 'checkpoints' during repair of damage. We plan preclinical laboratory experiments to determine the optimal protocols for treating breast cancer patients with antireceptor MAbs plus chemotherapy. Both non-malignant 184 mammary epithelial cells and three breast cancer cell lines (MCF7, BT474, and MDA468) will be investigated, to obtain data on efficacy against low and high receptor expressors, and to explore possible selectivity in the toxicity of therapy. Scheduling and dosing of drug and antireceptor MAb will be major targets of studies in a series of experiments with cultures of breast cells, and against well- established nude mouse xenografts of breast cancer cells. The chemotherapeutic agents to be evaluated include those with strongest activity against human breast cancer. Initial studies have included doxorubicin, Taxol, and cisplatinum, cyclophosphamide and 5-fluorouracil will be added. The results of these preclinical experiments with anti EGF receptor MAbs will be translated directly into clinical trials in the paired Clinical Program of the COOPERATIVE AGREEMENT proposal. Results with anti-HER2 MAb will be incorporated into clinical trials by Genentech, Inc.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA065746-04
Application #
6103013
Study Section
Project Start
1998-01-08
Project End
1999-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Rayala, Suresh K; Kumar, Rakesh (2007) Sliding p21-activated kinase 1 to nucleus impacts tamoxifen sensitivity. Biomed Pharmacother 61:408-11
Manavathi, Bramanandam; Singh, Kamini; Kumar, Rakesh (2007) MTA family of coregulators in nuclear receptor biology and pathology. Nucl Recept Signal 5:e010
Ohshiro, Kazufumi; Rayala, Suresh K; Kondo, Seiji et al. (2007) Identifying the estrogen receptor coactivator PELP1 in autophagosomes. Cancer Res 67:8164-71
Singh, Rajesh R; Kumar, Rakesh (2007) MTA family of transcriptional metaregulators in mammary gland morphogenesis and breast cancer. J Mammary Gland Biol Neoplasia 12:115-25
Barnes, Christopher J; Ohshiro, Kazufumi; Rayala, Suresh K et al. (2007) Insulin-like growth factor receptor as a therapeutic target in head and neck cancer. Clin Cancer Res 13:4291-9
Rayala, Suresh K; Martin, Emil; Sharina, Iraida G et al. (2007) Dynamic interplay between nitration and phosphorylation of tubulin cofactor B in the control of microtubule dynamics. Proc Natl Acad Sci U S A 104:19470-5
Manavathi, Bramanandam; Rayala, Suresh K; Kumar, Rakesh (2007) Phosphorylation-dependent regulation of stability and transforming potential of ETS transcriptional factor ESE-1 by p21-activated kinase 1. J Biol Chem 282:19820-30
Rayala, Suresh K; Mascarenhas, Joseph; Vadlamudi, Ratna K et al. (2006) Altered localization of a coactivator sensitizes breast cancer cells to tumor necrosis factor-induced apoptosis. Mol Cancer Ther 5:230-7
Acconcia, Filippo; Manavathi, Bramanandam; Mascarenhas, Joseph et al. (2006) An inherent role of integrin-linked kinase-estrogen receptor alpha interaction in cell migration. Cancer Res 66:11030-8
Holm, Caroline; Rayala, Suresh; Jirstrom, Karin et al. (2006) Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients. J Natl Cancer Inst 98:671-80

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