Steroid hormone receptor interacting protein kinase

Details Steroid hormone receptor interacting protein kinase Steroid hormone receptor interacting protein kinase

2001-01-19

2004-01-06

Achutamurthy, Ponnathapu (Department: 1652)

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

Transferase other than ribonuclease

C435S189000, C435S193000, C424S094100, C424S094500, C530S300000

Reexamination Certificate

active

06673586

ABSTRACT:

BACKGROUND OF THE INVENTION
Prostate cancer now ranks as the most prevalent cancer in men. Approximately 160,000 new cases are diagnosed each year; of these new cases, 35,000 will die of metastatic disease. In women, breast cancer kills 45,000 women per year. Steroid hormone receptors and the factors that bind steroid hormone receptors are key players in the maintenance of healthy tissue. Similarly, disregulation of steroid hormone receptors and steroid hormone receptor interacting proteins are important to the development of a wide variety of sex steroid hormone dependent cancers and diseases. Current therapies for such afflictions include surgery (e.g., castration) and chemical treatment (e.g., chemotherapy and hormone ablation therapy).
Androgens in normal prostate epithelium appear to primarily drive differentiation. In contrast, prostate cancer growth is directly androgen stimulated. Thus, one common therapy for the treatment of prostate cancer is androgen ablation therapy, to which most patients respond. Unfortunately, virtually all prostate cancer relapse is clinically androgen independent. Significantly, most androgen independent tumors express high levels of androgen receptor as well as androgen receptor regulated genes, indicating that the androgen receptor is transcriptionally active (van der Kwastet et al.,
Int. J. Cancer
48, 189-193 (1991); Ruizeveld de Winter et al.,
Am. J. Pathol
. 144, 735-746 (1994); Taplin et al.,
N. Engl. J. Med
. 332, 1393-1398 (1995); Hobisch et al.,
Cancer Res
. 55, 3068-3072 (1995); Visakorpi et al.,
Nat. Genet
. 9, 401-406 (1995); and Koivisto et al.,
Cancer Res
. 57, 314-319 (1997)).
It has been demonstrated that structural changes in the androgen receptor contribute to altered androgen receptor function in primary or androgen independent prostate cancer. Most reports find that the androgen receptor is wild-type in primary androgen dependent prostate cancer, with a few exceptions (Tilley et al.,
Clin. Cancer Res
. 2, 277-285 (1996)). In contrast, androgen receptor mutations have been identified in androgen independent prostate cancer (Taplin et al., supra; Culig et al.,
Mol. Endocrinol
. 7, 1541-1550 (1993); Suzuki et al.,
J. Steroid Biochem. Mol. Biol
. 46, 759-765 (1993); Suzuki et al.,
Prostate
29, 153-158 (1996); and Taplin et al.,
Cancer Res
. 59, 2511-2515. (1999)). An analysis of androgen independent prostate cancer from a large number of bone marrow metastases recently showed that androgen receptor ligand binding domain mutations occur primarily in patients treated with the androgen receptor antagonist flutamide (Taplin et al., supra). Importantly, these mutations result in androgen receptors that are strongly stimulated by hydroxyflutamide. Fortunately, patients with these mutations respond to subsequent treatment with bicalutamide, an androgen receptor antagonist that remains active against these mutant androgen receptors (Taplin et al., supra; and Joyce et al.,
J. Urol
. 159, 149-153 (1998)).
The above results indicate that additional mechanisms must contribute to androgen independent androgen receptor activity in the majority of patients treated with androgen ablation. For example, androgen receptor function is modulated by a growing list of associated proteins, some of which likely contribute to prostate cancer development or progression. Some of these proteins function as transcriptional co-activators through intrinsic histone acetyltransferase activity, association with CBP/p300, and/or binding to components of the RNA polymerase II complex (Onate et al.,
Science
270, 1354-1357 (1995); Hong et al.,
Proc. Natl. Acad. Sci. U.S.A
. 93, 4948-4952 (1996); Voegel et al.,
EMBO J
. 15, 3667-3675 (1996); Anzick et al.,
Science
277, 965-968 (1997); Torchia et al.,
Curr. Opin. Cell Biol
. 10, 373-383 (1998); Kamei et al.,
Cell
85, 403-414 (1996); and Spencer et al.,
Nature
389, 194-198 (1997)), but their roles and the roles of other androgen receptor associated proteins in prostate cancer remain unclear.
There remains a need for additional therapies for steroid hormone related carcinomas and other steroid hormone-related diseases. A better understanding of androgen receptor-associated cellular communication could greatly facilitate the discovery of drugs and therapeutic methods for the treatment of a broad range of conditions with fewer of the serious and variable side effects prevalent with currently available chemotherapeutic reagents and surgical procedures. Novel agonists and antagonists of the androgen receptor pathway would be invaluable to the field of therapeutics for steroid hormone receptor-related ailments.
SUMMARY OF THE INVENTION
The present invention provides a substantially pure nucleic acid molecule encoding a steroid hormone-interacting p21-activated kinase (PAK
SI
) polypeptide. Preferably, the nucleic acid molecule has the nucleic acid sequence of SEQ ID NO: 1. The invention also provides a substantially pure PAK
SI
polypeptide. Preferably, the substantially pure PAK
SI
polypeptide has the amino acid sequence of SEQ ID NO: 2. In a related aspect, the present invention provides a therapeutic composition that includes a PAK
SI
polypeptide formulated in a physiologically acceptable carrier.
The present invention also provides a method of inhibiting a steroid hormone receptor by administering to an individual a compound that is capable of inhibiting PAK
SI
. The compound may be capable of inhibiting PAK
SI
expression or PAK
SI
activity. In a related aspect, the method further provides a method of inhibiting a prostate tumor or a breast tumor by contacting the tumor with a compound that is capable of inhibiting PAK
SI
.
Alternatively, the present invention provides a method of stimulating the beneficial effects of a steroid hormone receptor by administering to an individual a PAK
SI
agonist. PAK
SI
agonists can also be used to treat and prevent other steroid hormone-related diseases. In one preferred embodiment, a PAK
SI
agonist can be administered to an individual to stimulate the therapeutic effects of an estrogen. For example, a PAK
SI
agonist can be administered to a patient diagnosed with cardiovascular disease to promote vasodilation. Thus, the present invention provides a method of inhibiting cardiovascular disease by administering to an individual a PAK
SI
agonist.
A particularly valuable aspect of the invention is that it provides for the identification of PAK
SI
modulatory compounds that may serve as useful therapeutics. Accordingly, the present invention provides a method of determining whether a compound is a PAK
SI
modulatory compound. The method involves the steps of: (a) providing a cell expressing a PAK
SI
polypeptide; (b) contacting the cell with a compound; and (c) measuring the expression or enzymatic-activity of PAK
SI
by the cell. An alteration in the level of the expression or activity indicates that the compound is a PAK
SI
modulatory compound.
Alternatively, a PAK
SI
modulatory compound can be identified by the steps of: (a) providing a PAK
SI
polypeptide or a PAK
SI
polypeptide fragment having PAK
SI
enzymatic activity; (b) contacting the PAK
SI
polypeptide or a PAK
SI
polypeptide fragment with the compound; and (c) measuring the enzymatic-activity of PAK
SI
. An alteration in the level of the activity of PAK
SI
indicates that the compound is a PAK
SI
modulatory compound. The PAK
SI
polypeptide or a PAK
SI
polypeptide fragment can be a recombinant polypeptide or polypeptide fragment. This method for the identification of a PAK
SI
modulatory compound can be performed in vitro.
The present invention further provides a method of diagnosing a mammal, preferably a human, for the presence of prostate cancer. Alternatively, the present invention provides a method of determining whether a mammal has an increased likelihood of developing prostate cancer. The method involves measuring PAK
SI
gene expression in a sample (e.g., of prostate tissue) from a mammal to determine whether an alteration in PAK
SI
expression has occurred relative to the PAK
SI

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