Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-07-30
2004-01-06
Marschel, Ardin H. (Department: 1631)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S007100, C435S287200, C536S023100
Reexamination Certificate
active
06673545
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a composition comprising a plurality of cDNAs which are differentially expressed in prostate cancer and which may be used entirely or in part to diagnose, to stage, to treat, or to monitor the progression or treatment of prostate cancer.
BACKGROUND OF THE INVENTION
Array technology can provide a simple way to explore the expression of a single polymorphic gene or the expression profile of a large number of related or unrelated genes. When the expression of a single gene is examined, arrays are employed to detect the expression of a specific gene or its variants. When an expression profile is examined, arrays provide a platform for examining which genes are tissue specific, carrying out housekeeping functions, parts of a signaling cascade, or specifically related to a particular genetic predisposition, condition, disease, or disorder.
The potential application of gene expression profiling is particularly relevant to improving diagnosis, prognosis, and treatment of disease. For example, both the levels and sequences expressed in tissues from subjects with prostate cancer may be compared with the levels and sequences expressed in normal tissue.
Prostate cancer is a common malignancy in men over the age of 50, and the incidence increases with age. In the U.S., there are approximately 132,000 newly diagnosed cases of prostate cancer and more than 33,000 deaths from the disorder each year.
Once cancer cells arise in the prostate, they are stimulated by testosterone to a more rapid growth. Thus, removal of the testes can indirectly reduce both rapid growth and metastasis of the cancer. Over 95 percent of prostatic cancers are adenocarcinomas which originate in the prostatic acini. The remaining 5 percent are divided between squamous cell and transitional cell carcinomas, both of which arise in the prostatic ducts or other parts of the prostate gland.
As with most cancers, prostate cancer develops through a multistage progression ultimately resulting in an aggressive, metastatic phenotype. The initial step in tumor progression involves the hyperproliferation of normal luminal and/or basal epithelial cells that become hyperplastic and evolve into early-stage tumors. The early-stage tumors are localized in the prostate but eventually may metastasize, particularly to the bone, brain or lung. About 80% of these tumors remain responsive to androgen treatment, an important hormone controlling the growth of prostate epithelial cells. However, in its most advanced state, cancer growth becomes androgen-independent and there is currently no known treatment for this condition.
A primary diagnostic marker for prostate cancer is prostate specific antigen (PSA). PSA is a tissue-specific serine protease almost exclusively produced by prostatic epithelial cells. The quantity of PSA correlates with the number and volume of the prostatic epithelial cells, and consequently, the levels of PSA are an excellent indicator of abnormal prostate growth. Men with prostate cancer exhibit an early linear increase in PSA levels followed by an exponential increase prior to diagnosis. However, since PSA levels are also influenced by factors such as inflammation, androgen and other growth factors, some scientists maintain that changes in PSA levels are not useful in detecting individual cases of prostate cancer.
Current areas of cancer research provide additional prospects for markers as well as potential therapeutic targets for prostate cancer. Several growth factors have been shown to play a critical role in tumor development, growth, and progression. The growth factors Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), and Tumor Growth Factor alpha (TGF&agr;) are important in the growth of normal as well as hyperproliferative prostate epithelial cells, particularly at early stages of tumor development and progression, and affect signaling pathways in these cells in various ways (Lin J et al. (1999) Cancer Res. 59:2891-2897; Putz T et al. (1999) Cancer Res 59:227-233). The TGF-&bgr; family of growth factors are generally expressed at increased levels in human cancers and the high expression levels in many cases correlates with advanced stages of malignancy and poor survival (Gold L I (1999) Crit Rev Oncog 10:303-360). Finally, there are human cell lines representing both the androgen-dependent stage of prostate cancer (LNCap) as well as the androgen-independent, hormone refractory stage of the disease PC3 and DU-145) that have proved useful in studying gene expression patterns associated with the progression of prostate cancer, and the effects of cell treatments on these expressed genes (Chung T D (1999) Prostate 15:199-207).
The present invention provides for a composition comprising a plurality of cDNAs for use in detecting changes in expression of genes encoding proteins that are associated with prostate cancer. Such a composition can be employed for the diagnosis, prognosis or treatment of prostate cancer and related disorders correlated with differential gene expression. The present invention satisfies a need in the art in that it provides a set of differentially expressed genes which may be used entirely or in part to diagnose, to stage, to treat, or to monitor the progression or treatment of a subject with prostate cancer.
SUMMARY
The present invention provides a composition comprising a plurality of cDNAs and their complements which are differentially expressed in prostate adenocarcinomas and which are selected from SEQ ID NOs:1-1-3, 5, 6, 8, 10-15, 17-19, 21, 23-28, 30, 32, 34-36, 38, 40, 42-45, 47-50, 52, 53, 55, 56, 58-65, 67, 68, 70-73, 75, 76, 78-86, 88-90, 92-97, 99-101 as presented in the Sequence Listing. In one embodiment, each cDNA is differentially regulated in metastatic versus non-metastatic tissue samples, SEQ ID NOs:1-3, 5, 6, 8, 10-15, 17-19, 21, 23-28, 30, 32, 34-36, 38, 40, 42-45, 47-50, 52, 53, 55, 56, 58-65, 67, 68, 70-73, 75; in another embodiment, each cDNA is differentially regulated at all stages of the disease, SEQ ID NOs:76, 78-86, 88-90, 92-97, 99-101. In one aspect, the composition is immobilized on a substrate. In another aspect, the composition is used to diagnose the presence and stage of prostate cancer in a subject. The invention also provides proteins encoded by the cDNAs and which are selected from SEQ ID NOs:4, 7, 9, 16, 20, 22, 29, 31, 33, 37, 39, 41, 46, 51, 54, 57, 66, 69, 74, 77, 87, 91, 98 as presented in the Sequence Listing.
The invention also provides a high throughput method to detect differential expression of one or more of the cDNAs of the composition. The method comprises hybridizing the substrate comprising the composition with the nucleic acids of a sample, thereby forming one or more hybridization complexes, detecting the hybridization complexes, and comparing the hybridization complexes with those of a standard, wherein differences in the size and signal intensity of each hybridization complex indicates differential expression of nucleic acids in the sample. In one aspect, the sample is from a subject with prostate cancer and differential expression determines an early, mid, and late stage of the disorder.
The invention further provides a high throughput method of screening a library or a plurality of molecules or compounds to identify a ligand. The method comprises combining the substrate comprising the composition with a library or a plurality of molecules or compounds under conditions to allow specific binding and detecting specific binding, thereby identifying a ligand. The library or a plurality of molecules or compounds are selected from DNA molecules, RNA molecules, peptide nucleic acid molecules, mimetics, peptides, transcription factors, repressors, and other regulatory proteins.
The invention still further provides an isolated cDNA encoding the protein comprising the amino acid sequence of SEQ ID NO:37. The invention also provides an isolated cDNA comprising SEQ ID NO:36 as presented in the Sequence Listing. The invention also provides a vector comprising the cDNA, a host cell
Faris Mary
Turner Christopher M.
Incyte Corporation
Incyte Corporation
Marschel Ardin H.
Smith Carolyn L
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