Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1997-12-05
2001-01-23
Chambers, Jasemine (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S320100
Reexamination Certificate
active
06177410
ABSTRACT:
UTILITY STATEMENT
Both BRCA1 and BRCA2 proteins have been identified as inhibitors of the growth of mammalian prostate cancer cells. Thus, a nucleic acid segment encoding the BRCA1 protein and a nucleic acid segment encoding the BRCA2 protein can be used in gene therapy methods for the treatment of prostate cancer.
The discovery and purification of the BRCA1 and BRCA2 proteins has broad utility. The purified BRCA1 and BRCA2 proteins can be used in treating prostate cancer.
ACTIVITY STATEMENT
The BRCA1 gene product is an inhibitor of the growth and proliferation of mammalian prostate cancer cells. The BRCA1 gene product is a secreted protein, thus indicating that it acts on a receptor to produce this activity.
The BRCA2 gene product is an inhibitor of the growth and proliferation of mammalian prostate cancer cells. The BRCA2 protein is a secreted protein, thus indicating that it acts on a receptor to produce this activity.
TECHNICAL FIELD
The present invention relates to a therapy for prostate cancer; and more particularly to a gene therapy method for prostate cancer using the BRCA gene family, and still more particularly, using the BRCA1 gene.
The publications and other materials used herein to illuminate the background of the invention, and in particular cases, to provide additional details respecting the practice, are incorporated herein by reference, and for convenience, are referenced by author and date in the following text, and respectively group in the appended list of references.
Table of Abbreviations
PPC-1
A prostate cancer cell line from primary tumor
DU145
A prostate cancer cell line from brain metastasis
LNCaP
A prostate cancer cell line from lymph node metastasis
PC3
A prostate cancer cell line from primary tumor
TSU
A prostate cancer cell line of unknown origin
D17S855
A prostate cancer cell genotype, indicating
number of alleles at markers flanking BRCA1
D17S1322
A prostate cancer cell genotype, indicating
number of alleles at markers flanking BRCA1
D17S1327
A prostate cancer cell genotype, indicating
number of alleles at markers flanking BRCA1
D17S1326
A prostate cancer cell genotype, indicating
number of alleles at markers flanking BRCA1
D17S1325
A prostate cancer cell genotype, indicating
number of alleles at markers flanking BRCA1
LXSN
A retroviral vector derived from a mouse retrovirus
Cys61Gly
A mutation in the BRCA1 protein at amino acid 61
wherein a cysteine is substituted for a glycine
340stop
A mutant BRCA1 protein wherein a stop codon is
inserted in place of the codon coding for amino acid 340
del(343-1081)
A BRCA1 mutant protein wherein amino acids
343-1081 have been deleted
1835stop
A mutant BRCA1 protein wherein a stop codon has
been inserted in place of the codon encoding the
amino at position 1835
AIM V
An animal serum free growth media for retroviral vectors
PSA
Prostate specific antigen
LTR regulated
gene expression controlled by the LXSN retroviral
promoter
BACKGROUND ART
A staggering estimated 317,000 new cases of prostate cancer will be diagnosed and over 45,000 prostate cancer deaths will occur this year in the United States making prostate cancer the most frequently diagnosed and second leading cause of cancer mortality in men in the United States. Deaths from prostate cancer in the United States are increasing every year by 2%-3% because fewer men are dying from cardiovascular disease. (Walsh, 1994) Unfortunately, the age-specific mortality rate for prostate cancer continues to rise in spite of earlier detection by serum PSA or current prostate cancer treatment modalities. Moreover, at the time of diagnosis the majority of men will have prostate cancer at a stage for which there is no cure and the prognosis is dismal.
African-American men have the highest prostate cancer mortality rates of any population in the world, twice that of white men 65 years or older. Furthermore, survival rates in the United States for all stages of prostate cancer diagnosed between 1983 and 1990 was 81.3% for Whites, but only 66.4% for Blacks. Of all prostate cancer deaths in 1991, Blacks accounted for 15.8%, Hispanics for 2.5%, and American Indians, Chinese, and Japanese for less than 1%. The general United States population is 75% White, 12% African-American, 8% Hispanic, and 3% Asian.
The standard method of treatment for the past 50 years has been castration, surgical or chemical, but the prostate cancer has eventually become androgen-independent, resumed growth, and killed the patient. Clearly, better androgen blockade is not the answer for treating prostate cancer. Rather, treatment efforts should focus on modifying the mutations that lead to prostate oncogenesis. Although some genetic markers can at least partially predict patients who are likely to develop metastatic disease, it is still impossible to predict absolutely patient prognosis and response to therapy. (Walsh, 1994; Carter et al., 1990) Thus, even well implemented early detection programs may not completely eradicate the eventual development of metastasis in some patients.
The molecular biology of prostate cancer is poorly understood. Attempts to develop animal models of prostate cancer with transgenic mice have been less successful than for animal models of other cancers such as breast cancer. (Mulders et al., 1990; Oesterling, 1991; Jurincic et al., 1990; Hamdy et al., 1992; Pang et al., 1995; Matuo et al., 1989; Dodd et al., 1983; Greenberg et al., 1994; Greenberg et al, 1995; Tutrone et al., 1993; Matsui et al., 1990; Halter et al., 1992; Cato et al., 1989; Choi et al., 1987; Tutrone et al., 1993; Matsui et al., 1990; Halter et al., 1992; Muller et al., 1990) This has presumably happened because little is known about prostate-specific promoters and because study of oncogenes and tumor suppressor genes have yielded few clear-cut candidate genes for prostate cancer.
Inherited mutations in BRCA1, (Hall et al., 1990; Miki et al., 1994) confer lifetime risk of breast cancer greater than 80% and increased risk of ovarian cancer. (Newman et al., 1988; Ford et al., 1994). Multiple lines of evidence suggest that BRCA1 is a tumor suppressor for the following six reasons:
(1) Most (87%) inherited mutations truncate the BRCA1 protein, leading to loss of BRCA1 function. (Breast Cancer Information Core, 1996)
(2) The wild-type allele is lost from >90% of breast and ovarian tumors from patients with inherited BRCA1 mutations. (Friedman et al., 1994; Neuhausen et al., 1994; Smith et al., 1992)
(3) BRCA1 expression is reduced in breast and ovarian tumors from patients not selected for family history. (Thompson et al., 1995) In such tumors, somatic inactivation of BRCA1 may occur through mechanisms such as large deletions or epigenetic silencing of BRCA1 expression, rather than point mutation. (Futreal et al., 1994; Cropp et al., 1993; Saito et al., 1993; Cliby et al., 1993; Russell et al., 1990; Takahashi et al., 1995; Yang-Feng et al., 1993)
(4) Inhibition of BRCA1 expression with antisense oligonucleotides leads to accelerated growth of normal and malignant mammary epithelial cells. (Thompson et al., 1995)
(5) Overexpression of BRCA1 inhibits growth of breast and ovarian cancer cell lines derived from patients not selected for family history. (Holt et al., 1996)
(6) Transfection or infection of MCF-7 breast cancer cells with the wild type BRCA1 gene inhibits tumor development and suppresses growth of established tumors in nude mice. (Holt et al., 1996) The biochemical mechanism responsible for growth inhibition and tumor suppression by BRCA1 involves secretion, since BRCA1 has sequence homology and functional analogy to the granin protein family. Wild type BRCA1 is localized to the Golgi; (Jensen et al., 1996) and wild-type BRCA1 is also present in the nucleus, although reports differ in the relative amounts of nuclear versus cytoplasmic protein. (Chen et al., 1995)
There has been no affirmative suggestion of a treatment of prostatic cancer comprising a therapeutic application of the BRCA gene family, and particularly comprising a therapeutic application involving BRCA1. This is true despite certain
Holt Jeffrey T.
Jensen Roy A.
King Mary-Claire
Robinson-Benion Cheryl L.
Steiner Mitchell S.
Beckerleg AnneMarie S.
Chambers Jasemine
Jenkins & Wilson, P.A.
Vanderbilt University
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