Human tumor-associated gene

Details Human tumor-associated gene Human tumor-associated gene

1999-01-21

2004-01-06

Helms, Larry (Department: 1642)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S023100, C435S320100, C435S243000, C435S358000, C530S350000

Reexamination Certificate

active

06673914

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the field of cancer diagnostics. More particularly, it concerns markers for use in the diagnosis and prognosis of cancer. Also provided are related protein, DNA and antibody compositions and various methods of use thereof, including methods for cancer diagnosis and treatment.
2. Description of Related Art
Cancer is one of the leading causes of disease, being responsible for 526,000 deaths in the United States each year (Boring et al., 1993). For example, breast cancer is the most common form of malignant disease among women in Western countries and, in the United States, is the most common cause of death among women between 40 and 55 years of age (Forrest, 1990). The incidence of breast cancer is increasing, especially in older women, but the cause of this increase is unknown. Malignant melanoma is another form of cancer whose incidence is increasing at a frightening rate, at least sixfold in the United States since 1945, and is the single most deadly of all skin diseases (Fitzpatrick, 1986).
One of the most devastating aspects of cancer is the propensity of cells from malignant neoplasms to disseminate from their primary site to distant organs and develop into metastases. Despite advances in surgical treatment of primary neoplasms and aggressive therapies, most cancer patients die as a result of metastatic disease. Animal tests indicate that about 0.01% of circulating cancer cells from solid tumors establish successful metastatic colonies (Fidler, 1993).
Thus, the detection of occult cancer cells in circulation is important in assessing the level of tumor progression and metastasis. Because subclinical metastasis can remain dormant for many years, monitoring of patients' blood for circulating tumor cells may prove advantageous in detecting tumor progression before metastasis to other organs occurs. Assessment of circulating tumor cells also would provide a rapid monitoring system to determine if a specific therapy is effective.
The recognition or lack of recognition of cancer cells by a host organism is a complicated process. Understanding of the field presumes some understanding of both basic immunology and oncology. Early research on mouse tumors revealed that these cells displayed molecules which led to rejection of tumor cells when transplanted into syngeneic animals. These molecules are “recognized” by T-cells in the recipient animal, and provoke a cytolytic T-cell response with lysis of the transplanted cells. This evidence was obtained with tumors induced in vitro by chemical carcinogens (Prehn, et al., 1957; Klein et al., 1960; Gross, 1943, Basombrio, 1970), as well as on tumors induced in vitro via ultraviolet radiation. (Kripke, 1974). The antigens expressed by the tumors and which elicited the T-cell response were found to be different for each tumor. This class of antigens has come to be known as “tumor specific transplantation antigens” (TSTAs).
While T-cell mediated immune responses were observed for tumors induced through the application of carcinogens, spontaneous tumors were thought to be generally non-immunogenic. These were, therefore, believed not to present antigens which provoked a response to the tumor in the tumor carrying subject (Hewitt, et al., 1976).
Later research found that when spontaneous tumors were subjected to mutagenesis, immunogenic variants were produced which did generate a response. Indeed, these variants were able to elicit an immune protective response against the original tumor (Van Pel et al., 1983). Thus, it has been shown that it is possible to elicit presentation of a so-called “tumor rejection antigen” in a tumor which is a target for a syngeneic rejection response. Similar results have been obtained when foreign genes have been transfected into spontaneous tumors (Fearon et al., 1988) in this regard.
A class of antigens has been recognized which are presented on the surface of tumor cells and are recognized by cytolytic T cells, leading to lysis. This class of antigens will be referred to as “tumor rejection antigens” (TRAs). TRAs may or may not elicit antibody responses. These antigens have been studied by cytolytic T cell characterization studies, i.e., the in vitro study of the identification of the antigen by a particular cytolytic T cell (CTL) subset. The subset proliferates upon recognition of the presented tumor rejection antigen, and the cells presenting the antigen are lysed. Characterization studies have identified CTL clones which specifically lyse cells expressing the antigens. (Levy et al., 1977; Boon et al., 1980; Brunner et al., 1980; Maryanski et al., 1980; Maryanski et al., 1982; Palladino et al., 1987).
U.S. Pat. No. 5,342,774, incorporated herein by reference, described a family of human tumor rejection antigen precursor coding genes, referred to as the MAGE family (van der Bruggen et al., 1991; Traversari et al., 1992). It now is clear that the various genes of the MAGE family are expressed in tumor cells, and can serve as markers for the diagnosis of such tumors, as well as for other purposes discussed therein.
Although MAGE expression has been identified in different types of cell lines and tumor tissues, it is not ubiquitously expressed in tumors of all types. Similar molecules, such as PAGE, BAGE (Boel et al., 1995) and GAGE (van den Eynde, 1995) have been identified as tumor recognition antigens for a variety of cancers including melanoma, sarcomas, non-small cell lung cancers, head and neck tumors, bladder tumors and prostate tumors. However, there remains a significant scientific hurdle in identifying which MAGE gene will be expressed by a particular tumor type. Thus, while on one level one can say that MAGE, BAGE and PAGE genes are “markers” for tumors, on the level of specific tumor types, the correlation of marker and tumor type is not predictable, and must be determined empirically. Thus, there is a need to define tumor marker antigens that are expressed ubiquitously on all cancer types.
SUMMARY OF THE INVENTION
The present invention seeks to overcome these and other drawbacks inherent in the prior art by providing nucleic acid species and marker genes that are expressed in cancers cells, and methods of making and using such nucleic acids and related proteins and antibodies. Further provided are methods for the diagnosis, prognosis and treatment of cancers using one or more of the foregoing compositions.
Thus, in order to meet the objectives of the present invention, there is provided herein a DNA segment comprising an isolated gene that encodes a HOJ-1 polypeptide. In particular embodiments, there is provided a gene that encodes a human HOJ-1 polypeptide. In other preferred embodiments, there is provided a gene that encodes a HOJ-1 protein or peptide that includes a contiguous amino acid sequence from SEQ ID NO:2. In still other embodiments, the gene includes a contiguous nucleic acid sequence from SEQ ID NO:1. In certain embodiments, the present invention provides a nucleic acid segment that encodes a HOJ-1 peptide of from about 105 to 109 amino acids in length.
The DNA segment may comprise a gene that encodes the HOJ-1 protein of SEQ ID NO:2. In other embodiments, the present invention comprises a gene that has the nucleic acid sequence of SEQ ID NO:1. In particular aspects, the gene is positioned under the control of a promoter. In preferred aspects, the gene is positioned under the control of a recombinant promoter in an expression vector. In other specific embodiments, the gene is positioned in reverse orientation under the control of a promoter, the promoter expressing an antisense product. In particular embodiments, the DNA segment may be further defined as a recombinant vector.
Other aspects of the present invention provide a recombinant host cell comprising a DNA segment that comprises an isolated gene that encodes a HOJ-1 protein. In preferred embodiments the recombinant host cell of the present invention further may be defined as a prokaryotic host cell. In other embodiments, the reco

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