Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-10-14
2001-10-23
Fredman, Jeffrey (Department: 1655)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S002600, C435S007100, C530S300000, C530S350000, C530S367000, C424S085100
Reexamination Certificate
active
06306832
ABSTRACT:
BACKGROUND OF THE INVENTION
The present application is a continuing application based on U.S. Provisional Application Ser. No. 60/043,545, filed Apr. 14, 1997, the entire contents of which is specifically incorporated herein by reference in its entirety.
1.1 Field of the Invention
The present invention relates generally to the field of molecular biology. More particularly, certain embodiments concern methods and compositions comprising native, site-specifically mutagenized, and synthetic peptides comprising portions of the human estrogen receptor, or estrogen receptor co-activator proteins. The invention further provides nucleic acid compositions encoding these peptide and protein compositions. Also provided are methods for synthesizing phosphotyrosyl and malonyltyrosyl peptide derivatives of these peptides and their use as antiestrogen compositions in the treatment of breast cancers, the preparation of pharmaceutical compositions, diagnostic kits, and the development of related assays for use in antitumor therapies.
1.2 Description of the Related Art
1.2.1 Breast Cancer
Breast cancer is the most common form of cancer among women, affecting about one in eight women. Approximately 185,700 new cases are diagnosed in the U.S. annually, and breast cancer is responsible for about 44,560 deaths in the U.S. per year. While predominantly observed in women, 1,400 cases of breast cancer are diagnosed annually in men, and 260 men die of breast cancer per year. Breast cancer first manifests itself as a painless lump, detectable by self-examination and clinical breast exams including mammograms. Commonly, growth initiates in the lining of the ducts or in the lobules of the breast. Current clinical treatments include mastectomy (removal of the entire breast) or lumpectomy (removal of the tumor and surrounding tissue) for localized tumors. Chemotherapy, radiotherapy, or hormone-blocking therapy may be further used to control cancerous cells. Breast cancer cells can metastasize to the lymph nodes, skin, lungs, liver, brain, or bones. Metastasis may occur early or late in the disease progression, although typically metastasis occurs once the cancerous growth reaches a size of about 20 mm. Metastasis is achieved by cells breaking away from the parental mass and entering either the bloodstream or the lymphatic system.
Genetic inheritance appears to play a role in about 5-10% of breast cancer patients. Mutations in the BRCA1, BRCA2, and p53 tumor suppressor genes have been observed to confer high risks of breast and ovarian cancers. BRCAI mutations are present at between 1 in 300 to 1 in 800 females. In the BRCA1 gene, over 200 different mutations have been discovered to date. The mutations observed are not localized to a single region, further complicating genetic analysis. Greater than 80% of the observed mutations result in a truncated form of the BRCA1 protein. Individuals with familial hereditary BRCA1 possess one normal and one mutant form of the gene, and are therefore much more likely to develop breast cancer. It is estimated that women with a hereditary BRCA1 mutation are about 76% likely to develop breast cancer by 70 years of age.
BRCA2 has been identified on chromosome 13q through linkage analysis of 15 breast cancer families that did not demonstrate BRCAI linked breast cancer. Unlike BRCA1 mutations, BRCA2 does not substantially elevate the risk of ovarian cancers. The BRCA2 gene encodes a protein of 3,418 amino acids, many of which are acidic or basic. Most mutations observed involve base deletions that alter the reading frame, and result in a premature truncation of the protein. BRCA1 and BRCA2 account for about 45% of familial inherited breast cancers each, leaving 10% for one or more additional genes. Interestingly, all male breast cancers appear to be due to mutations in the BRCA2 gene. Mutations found in breast tumor p53 genes are commonly single base pair changes which result in variants with increased cellular half lives. Altered p53 proteins have been observed in 20-25% of breast cancers.
1.2.2 Steroid Hormone Receptors
The steroid/thyroid hormone receptors are ligand-dependent transcription factors that function by binding to hormone response elements on target genes and regulating transcription (Evans, 1988). Although receptor-associated coactivators have been identified, the processes controlling steroid-specific gene transcription are poorly understood (LeDouarin et al., 1995). Most steroid/thyroid hormone receptors, including the human estrogen receptor (hER), bind to their hormone response elements as hetero- or homodimers (Kumar and Chambon, 1988; Kliewer et al., 1992), and it has been suggested that the dimerization of the steroid/thyroid hormone receptors is mediated, in part, through a leucine zipper motif in the carboxyl termini of the receptors (Forman et al., 1989; Fawell et al., 1990).
Antiestrogen therapy has had a significant impact on survival in patients with breast cancer (Jaiyesimi et al., 1995). The presence of estrogen receptor in breast tumors identifies those patients with a lower risk for disease recurrence and a better response to endocrine intervention. However, as breast cancer progresses, it usually becomes resistant to estrogens, and most patients no longer respond to treatment with tamoxifen or other antiestrogens. Results of new studies suggest that disruption of phosphotyrosine-dependent pathways may offer an alternate approach to antiestrogen treatment (Reddy et al., 1992). Modulation of the biologic activity of ER by estrogen and by tyrosine kinase signaling pathways appears to be functionally related to phosphorylation of specific conserved tyrosine residues in ER (Migliaccio et al., 1989; Castoria et al., 1993; Arnold et al., 1995; Pietras et al., 1995).
The ER is a phosphoprotein found in more than two-thirds of human breast tumors (Arnold and Notides, 1995; Weis et al., 1996; White et al., 1997). Estrogen binding to ER is thought to induce conformational changes in the receptor leading to formation of homodimers and association of the hormone-ER complexes with defmed palindromic DNA sequences termed estrogen responsive elements. EREs are usually located upstream of estrogen-responsive genes and act to regulate gene transcription and cell growth (Green and Chambon, 1988; Kato et al., 1995). Transcription is induced by two separate activation functions of the ER, an amino-terminal AF-1 region and a carboxy-terminal AF-2 region located in the hormone-binding domain of ER.
Phosphorylation of tyrosine in ER may be central to the regulation of receptor dimerization and the subsequent interaction with ERE in DNA (Castoria et al., 1993; Arnold et al., 1995; Pietras et al., 1995; Arnold and Notides, 1995; Arnold et al., 1995). New data suggest that Tyr537 may be required to maintain ER in a transcriptionally inactive state. Inactive ER is a monomer and upon estrogen-induced phosphorylation at Tyr537 and serine residues, it forms an active dimer that can bind ERE (Arnold et al., 1995; Pietras et al., 1995; Arnold and Notides, 1995; Arnold et al., 1995). Phosphotyrosine and neighboring amino acid residues on one ER monomer may provide a specific binding site for association with complementary domains on other ER monomers.
While the dimerization of most steroid hormone receptors is required for binding to DNA, accessory proteins and post-translational phosphorylation have also been implicated in DNA binding (Onate et al., 1994; Shuai et al., 1994; Hou et al., 1994). Arnold et al., (1995) demonstrated the phosphorylation of steroid/thyroid hormone receptors modulated their DNA binding affinity. The phosphorylation of the retinoic acid and progesterone receptors increases, while the phosphorylationof thyroid hormone receptor-&agr;
2
and nerve growth factor-I-B decreases their affinity for their respective response elements (Rochette-Egly et al., 1995; Denner et al., 1989; Katz et al., 1995; Hirataetal, 1993).
Human ER (hER), like other members of the steroid/thyroid hormone receptor superfamily, undergoes a hyperphosphorylation at serine residues f
Fredman Jeffrey
Howrey Simon Arnold & White , LLP
University of California
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