Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-07-16
2004-08-24
Ungar, Susan (Department: 1642)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C435S320100, C435S252100, C435S069100
Reexamination Certificate
active
06780984
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to particular marker proteins that can be used in the prognosis of prostate cancer. The present invention further relates to novel transcription factors that can effect apoptosis in cancerous cells. Methods of treating cancer cells, and prostate cancer cells are also provided. The nucleic acid and amino acid sequences of the novel transcription factors are provided along with probes, including nucleotide probes and antibodies, which can be used to determine the presence or absence of the novel transcription factor.
BACKGROUND OF THE INVENTION
It is generally acknowledged in the medical community that all men will eventually develop prostate cancer, provided that they live long enough for the condition to develop. For example, 50% of all men over 50, and essentially all men over 70 suffer from some form of prostate hyperplasia. Indeed, prostate cancer is the most frequently diagnosed cancer in the United States, with over a quarter of a million new cases being diagnosed each year. Despite the roughly $4 billion dollars per year spent treating this disease, forty thousand men die every year due to prostate cancer, which makes prostate cancer the second leading cause of cancer death in men.
Although the pathogenesis of prostate cancer has not been completely delineated, androgen is believed to play an important role in the development and progression of prostate cancer. It is well established that androgen-dependent growth of the normal prostate stops once the gland reaches the normal size. Indeed, androgen controls the homeostasis of the normal prostate through the androgen action pathway, a cascade of molecular and cellular events triggered by androgen leading to cell growth, differentiation, and/or death. In addition, programmed cell death (i.e., apoptosis) is triggered in the prostate when testosterone levels are completely depleted, and the prostate undergoes regression. Thus, castrated mammals have been employed as an experimental animal model for studying prostate cancer and cDNA collections enriched in genes regulated in prostate homeostasis, and prostrate regression have been disclosed [U.S. Pat. No. 5,821,352, Issued Oct. 13, 1998; and U.S. Pat. No. 5,928,871, Issued Jul. 27, 1999, the contents of which are hereby incorporated by reference in their entireties].
As alluded to above, one characteristic of prostate cancer is that it generally arises relatively late in life and then progresses slowly. If this were always true, the optimal medical response would be to simply monitor the progression of the cancer rather than aggressively treating it, since by the time the cancer progressed to a life threatening stage, the patient would have likely expired due to other more rapidly progressing factors. However, prostate cancers are highly heterogeneous in their progression. Some cancers grow very rapidly and need to be treated aggressively, whereas others are very slow growing and not life-threatening. Thus, one of the most important considerations in the present day treatment of prostate cancer is distinguishing aggressive prostate cancers, which need aggressive treatment, from less aggressive ones, which only require monitoring.
Unfortunately, there are no prognostic tests that can distinguish aggressive prostate cancers from less aggressive forms of the disease. Currently, there is no effective way to distinguish aggressive prostate cancers from slow-growing prostate cancers. Indeed, the present technology relies on monitoring the protein PSA, which not only results in a high percentage of false positives, but also cannot be used as a predictor of the future progression of the disease.
Considering the severe side-effects and expense associated with treating cancer, and prostate cancer treatment in particular, better prognosis tools are desperately needed. Therefore, there is a need to identify other factors that are diagnostic of cancer, and prostate cancer in particular. Furthermore, there is a need to identify means that can be used to accurately predict the progression of cancer, such as prostate cancer. In addition, there is a need to identify means that can be used to identify individual stages of the progression of prostate regression. Furthermore, there is a need to identify factors that can be used in the treatment of cancer, and in particular, prostate cancer.
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.
SUMMARY OF THE INVENTION
The present invention therefore provides methods that allow aggressive forms of cancer to be identified. In one such embodiment, an aggressive form of prostate cancer is identified. Importantly, a specific protein, TID-1 (otherwise known as TRAITS) is shown to be down-regulated in aggressive forms of cancer. Such cancers include epithelium-derived carcinomas, kidney cancers, lymphomas, leukemias and particularly, prostate cancer.
A particular aspect of the present invention provides the identity of two proteins that are down-regulated in aggressive prostate cancer, but not in slowly progressing prostate cancers. As provided herein, the two prostate proteins, calreticulin and TID-1, are shown to play important roles in the part of the androgen action pathway that suppresses cell proliferation and/or prevents prostate cancer. Therefore the expression of calreticulin (e.g., human calreticulin having the amino acid sequence of SEQ ID NO:36, encoded by the nucleic acid sequence of SEQ ID NO:35) and TID-1 (e.g., human TID-1 having the amino acid sequence of SEQ ID NO:18, encoded by the nucleic acid sequence of SEQ ID NO:17) in prostate cancer cells can be used as markers to distinguish aggressive forms of prostate cancer, which require immediate treatment, from slow growing forms that need only to be monitored.
Although the present invention is not dependent on any particular model, as disclosed below, the present invention is consistent with the unexpected finding that part of the androgen action pathway acts to suppress cell proliferation. This growth suppression is essential for prostate homeostasis and furthermore, limits the cell number in a healthy prostate. In contrast, the inactivation of the part of the androgen action pathway that acts to suppress cell proliferation results in uncontrolled growth leading to prostate cancer.
Therefore, the present invention provides methods of identifying an animal subject, preferably a human subject that is likely to have an aggressive form of prostate cancer. In one embodiment the likelihood determined is between 50 to 100%. In another embodiment the likelihood determined is greater than 70%. In a preferred embodiment, the method identifies an individual that has an 80% or more likelihood of having an aggressive form of prostate cancer. One such method comprises determining the level of calreticulin in a prostate sample from the animal subject. In one embodiment, the sample is obtained by radical prostatectomy. In another embodiment, the sample is obtained by needle biopsy.
When the level of calreticulin determined is 75% or more down-regulated in tumor cells relative to that determined in benign prostatic epithelial cells of the same specimen, the animal subject is identified as being likely to have an aggressive form of prostate cancer. In one embodiment the determination of the level of calreticulin is performed in situ. In another embodiment the determination of the level of calreticulin is performed in vitro. In still another embodiment, the determination of the level of calreticulin is performed in vivo. In a preferred embodiment, the determination of the level of calreticulin is performed by Laser Capture Microscopy coupled with a Western blot.
In a particular embodiment the determination of the level of calreticulin is performed with an antibody specific for calreticulin. In another such embodiment the determination of the level of calreticulin is performed by PCR with a primer specific for an mRNA encoding calreticulin. In s
Wang Zhou
Xiao Wuhan
Klauber & Jackson
Northwestern University
Ungar Susan
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