Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-11-09
2002-03-26
Horlick, Kenneth R. (Department: 1656)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S007100, C536S023500, C530S350000, C530S387100
Reexamination Certificate
active
06361948
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the field of prostate cancer detection. More specifically, novel compositions are provided which serve as prognostic indicators for late stage disease. Methods are also provided which facilitate the identification of those patients at risk for aggressive prostate cancer progression.
BACKGROUND OF THE INVENTION
Several publications are referenced in this application by numerals in parentheses in order to more fully describe the state of the art to which this invention pertains. Full citations for these references are found at the end of the specification. The disclosure of each of these publications is incorporated by reference herein.
This year prostate cancer is expected to be diagnosed in 200,000 men in the U.S. and to result in the loss of 38,000 lives. Such numbers make prostate cancer the most frequently diagnosed malignancy (other than that of the skin) in American males and the second leading cause of cancer-related death in that group. Physicians usually detect cancers by finding a lump in the prostate gland, which is a walnut shaped structure that helps to maintain the viability of sperm. Such lumps may be discovered during a routine checkup or an examination prompted by a patient's complaint of sudden urinary discomfort, or occasional impotence.
In some instances, prostate cancer is detected in the course of treatment for a disorder called benign prostatic hyperplasia. This condition, an aging-related enlargement of the prostate, affects more than half of all men older than 45 and gives rise (albeit more gradually) to the same urinary troubles caused by a prostate tumor. If the symptoms become too troublesome, a transurethral resection of the prostate, a process whereby parts of the gland are scraped away may be performed. Whenever resection is done, the excised tissue is analyzed under a microscope for evidence of malignancy, which is occasionally found.
A simple blood test for prostate specific antigen (PSA) constitutes a third means of detecting prostate cancer. Increased PSA levels can signal the presence of cancer in individuals who display no symptoms of prostate abnormalities.
Most prostate cancer (CaP) patients have no known risk factors for tumor development or rate of disease progression. The present inventors have appreciated the need for molecular markers for prostate cancer progression to identify patients who are at risk for aggressive disease and would benefit from early treatment.
SUMMARY OF THE INVENTION
This invention provides novel biological molecules useful for identification, detection and/or regulation of complex signaling events involved in prostate cancer progression. According to one aspect of the present invention, an isolated double stranded nucleic acid molecule, CLAR1, is provided which encodes a protein between about 250 and about 300 amino acids in length (preferably about 276 amino acids) that is a late stage specific marker for prostate cancer progression. The protein encoded by the CLAR1 nucleic acid molecule comprises a presently determined carboxy-terminal serine phosphorylation site and at least one or a multiplicity of SH3 binding domains. In a particularly preferred embodiment, the CLAR1 marker protein has an amino acid sequence of SEQ ID NO: 2. An exemplary nucleic acid molecule of the invention is set forth in SEQ ID NO: 1.
According to another aspect of the present invention, an isolated nucleic acid molecule is provided, which has a sequence selected from the group consisting of: (1) SEQ ID NO: 1; (2) a sequence which hybridizes with SEQ ID NO: 1; 3) a nucleic acid sequence encoding a polypeptide of SEQ ID NO: 2; 4) a nucleic acid sequence encoding a polypeptide of SEQ ID NO: 3; and 5) a natural allelic variant of a sequence of 1), 2), 3) or 4).
According to another aspect of the present invention, an isolated late stage-specific prostate cancer progression marker protein is provided which has a deduced molecular weight of between about 30 kDa and 50 kDa (preferably between about 30 kDa and 40 kDa and most preferably 33.8 kDa). In a preferred embodiment of the invention, the protein is of human origin, and has an amino acid sequence which is the same as or substantially the same as SEQ ID NO: 2. In yet another embodiment, the polypeptide may be derived from an alternatively spliced CLAR1 mRNA molecule and has a sequence the same as or substantially the same as SEQ ID NO: 3.
A further aspect of the present invention provides an oligonucleotide or polynucleotide fragment of the nucleotide sequence shown in SEQ ID NO: 1 or a complementary sequence thereof, in particular, for use in a method of obtaining and/or screening nucleic acid.
According to another aspect of the present invention, antibody binding domains or antibodies immunologically specific for the proteins described hereinabove are provided.
Various terms relating to the biological molecules of the present invention are used hereinabove and also throughout the specifications and claims. The terms “specifically hybridizing,” “percent similarity” and “percent identity (identical)” are defined in detail in the description set forth below.
With reference to nucleic acids of the invention, the term “isolated nucleic acid” is sometimes used. This term, when applied to DNA, refers to a DNA molecule that is separated from sequences with which it is immediately contiguous (in the 5′ and 3′ directions) in the naturally occurring genome of the organism in which it originated. For example, the “isolated nucleic acid” may comprise a DNA molecule inserted into a vector, such as a plasmid or virus vector, or integrated into the genomic DNA of a prokaryote or eukaryote. A nucleic acid molecule of the present invention may be single or double stranded.
With respect to RNA molecules of the invention, the term “isolated nucleic acid” primarily refers to an RNA molecule encoded by an isolated DNA molecule as defined above. Alternatively, the term may refer to an RNA molecule that has been sufficiently separated from RNA molecules with which it would be associated in its natural state (i.e., in cells or tissues), such that it exists in a “substantially pure” form (the term “substantially pure” is defined below).
With respect to protein, the term “isolated protein” or “isolated and purified protein” is sometimes used herein. This term refers primarily to a protein produced by expression of an isolated nucleic acid molecule of the invention. Alternatively, this term may refer to a protein which has been sufficiently separated from other proteins with which it would naturally be associated, so as to exist in “substantially pure” form.
The term “substantially pure” refers to a preparation comprising at least 50-60% by weight of a given compound (e.g., nucleic acid, oligonucleotide, protein, etc.). More preferably, the preparation comprises at least 75% by weight, and most preferably 90-99% by weight of the given compound. Purity is measured by methods appropriate for the given compound (e.g. chromatographic methods, agarose or polyacrylamide gel electrophoresis, HPLC analysis, and the like). “Isolated is not meant to exclude artificial or synthetic mixtures with other compounds, or the presence of impurities which do not interfere with biological activity, and which may be present, for example, due to incomplete purification, addition of stabilizers, or compounding into pharmaceutically acceptable preparations.
With respect to antibodies of the invention, the term “immunologically specific” refers to antibodies that bind to one or more epitopes of a protein of interest (e.g., CLAR1), but which do not substantially recognize and specifically bind other molecules in a sample containing a mixed population of antigenic biological molecules.
With respect to oligonucleotides, the term “specifically hybridizing” refers to the association between two single-stranded nucleotide molecules of sufficiently complementary sequence to permit such hybridization under pre-determined conditions generally used in the art (sometimes termed “subs
Rondinelli Rachel
Tricoli James V.
Dean Dorfman Herrell & Skillman
Horlick Kenneth R.
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