Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-05-17
2004-10-12
Kunz, Gary (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S004000, C435S091100, C435S091200, C435S091210, C436S063000, C436S064000, C536S023500, C536S024300, C536S024310, C536S024330
Reexamination Certificate
active
06803189
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to methods and compositions for the detection of cervical cancer. More specifically, the present invention relates to cervical cancer-associated proteins which act as cellular markers useful (i) in detecting cervical cancer, and (ii) as molecular targets for cervical cancer therapy.
BACKGROUND OF THE INVENTION
Cancer of the uterine cervix is one of the most common malignancies in women and remains a significant public health problem throughout the world. In the united States alone, invasive cervical cancer accounts for approximately 19% of all gynecological cancers (Miller et al. (1993) in “
Surveillance Epidemiology, and End Results Program cancer Statistics Review:
1973-1990”, NIH Pub. No. 93-2789, Bethesda, Md.: National Cancer Institute). In 1996, it is estimated that there will be 14,700 newly diagnosed cases and 4900 deaths attributed to this disease (American Cancer Society, Cancer Facts & Figures 1996, Atlanta, Ga.: American Cancer Society, 1996). In many developing countries, where mass screening programs are not widely available, the clinical problem is more serious. Worldwide, the number of new cases is estimated to be 471,000 with a 4 year survival rate of 40% (Munoz et al. (1989) “
Epidemiology of Cervical Cancer
” in “
Human Papillomavirus”
, New York, Oxford Press, pp 9-39; and National Institutes of Health, Consensus Development Conference Statement on Cervical Cancer, Apr. 1-3, 1996).
The precursor to cervical cancer is dysplasia, also known in the art as cervical intraepithelial neoplasia (CIN) or squamous intraepithelial lesions (SIL) (Brinton et al. (1992) “
Epidemiology of cervical Cancer: Overview
” in “
The Epidemiology of Cervical Cancer and Human Papillomavirus
”, Lyon, France: International Agency for Research on Cancer; and Tabbara et al. (1992) “
The Bethesda classification for squamous intraepithelial lesions: histologic, cytologic and viral correlates”, Obstet. Gynecol
79: 338-346). While it is not understood how normal cells become transformed, the concept of a continuous spectrum of histopathological change from normal, stratified epithelium through CIN to invasive cancer has been widely accepted for many years (see, for example, Mitchell et al. (1994) “
The natural history of cervical intraepithelial neoplasia: an argument of intermediate endpoint biomarkers”, Cancer Epidmiol. Biomark. Prev.
3: 619-626). A large body of epidemiological and molecular biological evidence has been gathered that establishes human papillomavirus (HPV) infection as a causative factor in cervical cancer (Munoz et al. (1992) in “
The Epidemiology of Human Papillomavirus and Cervical Cancer
”, IRAC publication no. 119, Lyon France: Int. Agency for Research on Cancer, pp 251-261). HPV is found in 85% or more of squamous cell invasive lesions, which represent the most common histologic type seen in cervical carcinoma (Cox et al. (1995)
Baillierre's Clin. Obstet Gynaecol.
91-37). Additional cofactors include, for example, oncogenes activated by point mutations, and chromosomal translocations of deletions (Spandidos et al. (1989)
J. Pathol.
157: 1-10).
Cytological examination of Papanicolaou-stained cervical smears (also referred to as Pap smears) currently is the method of choice for detecting cervical cancer. Despite the historical success of this test, concerns have arisen regarding its ability to predict reliably the behavior of same preinvasive lesions (Ostor et al. (1993)
Int. J. Gynecol. Pathol.
12: 186-192; and Genest et al. (1993)
Human Pathol
24: 730-736). The identification of a cervical cancer-associated tumor marker for reliably detecting early onset of cervical cancer and/or providing early prognostic information will greatly aid the management of cervical cancer.
All eukaryotic cells have a nucleus containing DNA, or chromatin, which is organized by an internal protein scaffolding known as the nuclear matrix (NM). The nuclear matrix was first described in 1974 by Berezney et al. (Berezney et al. (1974)
Biochem. Biophys. Res. Commun.,
60: 1410-1417). Penman et al. describe a method for selectively extracting insoluble interior nuclear matrix proteins and their associated nucleic acids from cells and determining the particular cell type by analyzing the proteins by two dimensional gel electrophoresis (see for example, U.S. Pat. No. 4,882,268, issued Nov. 21, 1989, and U.S. Pat. No. 4,885,236, issued Dec. 5, 1989, the disclosures of which are incorporated herein by reference).
The nuclear matrix is believed to be involved in a wide variety of nuclear functions fundamental to the control of gene expression. For a general review see, for example, Fey et al. (1991)
Crit. Rev. Euk. Gene Express.
1: 127-143. Tissue-specific nuclear matrix proteins have been identified in the rat, mouse and human. Fey et al. (1986)
Proc. Natl. Acad. Sci. USA
85: 121-125; Stuurman et al. (1990)
J. Biol. Chem.
265: 5460-5465; and Getzenberg et al. (1990)
Mol. Endocrinol.
4: 1336-1342. Changes in the presence or absence of specific nuclear matrix proteins have been associated with cellular transformation and differentiation (Bidwell et al. (1993)
Proc. Natl. Acad. Sci. USA
90: 3162-3166; Brancolini et al. (1991)
Proc. Natl. Acad. Sci. USA
88: 6936-6940; and Greenfield et al. (1991)
Proc. Nat. Acad. Sci. USA
88: 11217-11221).
Several recent studies using similar methodology have identified tumor-specific nuclear a matrix proteins in cancers of the prostate (Partin et al. (1993)
Cancer Res.
53: 744-746), breast (Khanuja et al. (1993)
Cancer Res.
53: 3394-3398), colon cancer (Keesee et al. (1994)
Proc. Natl. Acad. Sci. USA
91: 1913-1916), bone (Bidwell et al. (1994)
Cancer Res.
54: 28-32), bladder (Getzenberg et al. (1996)
Cancer Res.
56: 690-694) and the larynx (Donat et al. (1996)
Otolaryngol. Head Neck Surg.
114: 387-393). Molecular characterization of the specific nuclear matrix proteins, however, remains poorly defined, due to the low abundance of these proteins in the cell and their generally insoluble character.
There is, however, a need in the art for specific, reliable markers that are expressed differentially in normal and cancerous cervical tissue and that may be useful in the detecting cervical cancer or in the prediction of its onset. Accordingly, it is an object of this invention to provide cervical cancer-associated molecules which are useful as markers for the early and/or rapid detection of cervical cancers in an individual. It is another object of this invention to provide methods for detecting cervical cancers in an individual. It is another object of the invention to provide methods and compositions for treating cervical cancers in an individual and for monitoring the efficacy of such a treatment in the individual.
SUMMARY OF THE INVENTION
The invention provides a variety of methods and compositions for detecting and/or prognosing cervical cancer in a tissue or body fluid sample of an individual. The invention is based, in part, upon the discovery of cervical cancer-associated proteins which are present at detectable levels in cervical cancer cells, but which are not detectable in normal cervical cells, as determined by two-dimensional gel electrophoresis.
In one aspect, the invention provides a method for detecting cervical cancer in a human. The method comprises the step of detecting the presence of a cervical cancer-associated protein in a tissue or body fluid sample of the human thereby to indicate the presence of a cervical cancer or a precursor of a cervical cancer. The cervical cancer-associated protein is characterized as having a molecular weight of from about 44,900 Daltons to about 69,400 Daltons, as determined by standard polyacrylamide gel electrophoresis techniques and an isoelectric point of from about 5.1 to about 6.6 as determined by standard isoelectric focusing techniques. In addition, the cervical cancer-associated protein is further characterized as being a non-chromatin protein which is detectable at a higher level in a human cervical cancer c
Keesee Susan K.
Obar Robert
Wu Ying-Jye
Holleran Anne L.
Kunz Gary
Matritech, Inc.
Testa, Hurwitz and Thibeault, LLP
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