WO/2003/097049) ANTI-ESTROGEN RECEPTOR AGENTS FOR CHEMOTHERAPY AND PREVENTION
- From: J <nswex@nalid'anon>
- Date: Wed, 24 Oct 2007 12:35:35 -0400
WO/2003/097049) ANTI-ESTROGEN RECEPTOR AGENTS FOR CHEMOTHERAPY AND
PREVENTION
http://www.wipo.int/pctdb/en/wo.jsp?IA=WO2003097049&DIS ...too long
World Intellectual Property Organization
see http://tinyurl.com/33p5u7
[Excerpt]
ANTI-ESTROGEN RECEPTOR AGENTS FOR CHEMOTHERAPY AND PREVENTION FIELD OF
THE INVENTION [0001] The present invention is directed to the field of
tumor biology. Specifically, the present invention is directed to the
prevention and/or treatment of cancer. More specifically, the present
invention is directed to methods and compositions regarding tyrosine
kinase inhibitors for the prevention, treatment, or prevention and
treatment of cancer.
BACKGROUND OF THE INVENTION [0002] Aberrancies in expression of estrogen
receptor (ER) has been associated with a variety of cancers, including
breast cancer, endometrial cancer, cervical cancer and ovarian cancer. In
ER positive breast cancer, positive receptor status is associated with
favorable prognostic attributes including a lower rate of cell
proliferation and histologic evidence of tumor differentiation. During the
first several years following diagnosis, patients having ER- positive
tumors tend to have a lower recurrence rate, but this is balanced by a
higher recurrence rate in subsequent years, which results in an overall
modest prognostic significance. A useful aspect to having ER positive
cancer is in predicting response to hormonal therapy, both in the adjuvant
setting and for advanced disease. Several therapies, including prevention
and treatment, are available for ER positive cancers, although tamoxifen,
a triphenyl derivative, is currently the most prevalent. Tamoxifen reduces
proliferation of ER positive cancer cells through an estradiol antagonist
mechanism, although the drug increases the risk for endometrial cancer,
and, moreover, some patients develop resistance to it (for review, see
Jordan, 1994).
[0003] The complexities attributed to cancer biology are in large part a
result of the multitude of molecular and cellular phenotypes associated
with it, even within a given tissue or organ. For example, there are many
categories of breast cancer, such as those associated with ER status,
progesterone receptor status, tyrosine kinase amplification, and so forth.
In breast cancer having tyrosine kinase amplification, inhibitors of
tyrosine kinases, such as emodin, are currently known to be useful in
reducing proliferation of cells in vitro.
[0004] Emodin is a naturally occurring anthraquinone present in the roots
and bark of numerous plants of the genus Rhamnus. Emodin has been reported
to be a tyrosine kinase inhibitor that restricts the activity of p56 kick
kinase by preventing the binding of ATP in vitro (Jayasuriya et al.,
1992). Emodin also can inhibit the growth of cancer cells, including
lymphocytic leukemia (Kupchan et al., 1976), HL-60 human leukemia cells
(Yeh et al., 1988), and ras-transformed human bronchial epithelial cells
(Chan et al., 1993), by an unknown mechanism.
[0005] Emodin is particularly suited to treatment of HER-2/neu positive
cancers. The neu gene (also known as HER-2/neu or c-erbB-2) encodes a
185-kDa transmembrane tyrosine kinase (pl85neU) with homology to epidermal
growth factor receptor (Hung et al., 1986; Coussens et al., 1985;
Schechter et al., 1984; Sanba et al., 1985; Yamamoto et al., 1986).
Enhanced expression of neu is known to be involved in many human cancers,
including non- small cell lung cancer (NSCLC) and has been shown to
correlate with poor patient survival in NSCLC (Kern et al., 1990;
Schneider et al., 1989; Weiner et al., 1990), and the gene is amplified in
approximately 30% of primary breast cancers. Cellular and animal studies
have shown that an increase in neu tyrosine kinase activity increases the
expression of malignant phenotypes (Muller et al., 1988; Hudziak et al.,
1987; Muthuswamy et al., 1994; Yu et al., 1991; Yu et al., 1993; Hung et
al., 1989; Sistonen et al., 1989; Yu et al., 1994).
[0006] In U. S. Patent No. 6,172, 212, incorporated by reference herein in
its entirety, emodin is shown to inhibit neu tyrosine kinase activity and
preferentially represses the transformation ability and growth rate of
neu-overexpressing breast cancer cells.
[0007] The delivery of emodin-like tyrosine kinase inhibitors to cancer
cells is described for example, by Hung et al. in PCT/US97/01686,
incorporated by reference herein in its entirety. Hung et al. have
demonstrated that emodin and emodin-like compounds suppress the tyrosine
kinase activity of human breast cancer cells, suppress their transforming
ability, and induce their differentiation. Further, Hung et al. have found
that emodin also suppresses tyrosine phosphorylation of neu in lung cancer
cells and preferentially inhibits growth of these cells. Further, it
appears that emodin is able to sensitize lung cancer cells that
overexpress neu to the chemotherapeutic agents cisplatin, doxorubicin, and
VP16 (See, e. g., PCT/US97/01686).
[0008] Although several references (see, for example, Reddy et al., 1992;
Monti and Sinha, 1994; Di Domenico et al., 1996; Tesarik et al., 1999;
Nakagawa et al., 2000) describe tyrosine kinase inhibitors such as
genistein or RG-13022 for inhibiting cell proliferation in estrogen
receptor (ER) -positive human breast carcinoma cell lines, there is no
specific demonstration of their use for chemoprevention nor is the
HER-2/neu phenotype in these cell lines defined. Furthermore, emodin and
its derivatives are known for the suppression of growth of
HER-2/neu-overexpressing breast cancer cell lines (see, for example, Zhang
et al., 1995; Zhang et al., 1998; Zhang et al., 1999). Emodin has also
been shown to sensitize HER- 2/neu overexpressing chemoresistant non-small
cell lung cancer (NSCLC) cells (Zhang and Hung, 1996) or breast cancer
cells (Zhang et al., 1999) to chemotherapeutic drugs.
[0009] Bagatell et al. (2001) describe geldanamycin and radicicol
administration for therapy of breast cancer, although emodin is not taught
for therapy of breast cancer.
Furthermore, there is no teaching for tyrosine kinase inhibitors as
preventive for breast cancer.
[0010] In contrast to these references, the methods and compositions of
the present invention satisfy a need in the art for chemotherapeutic and
chemopreventive measures against ER-positive HER-2/neu negative breast
cancers, in particular embodiments using emodin.
[0011] Although some tyrosine kinase inhibitors are known to treat ER
positive cancers (Reddy et al., 1992; Monti and Sinha, 1994; Di Domenico
et al., 1996; Tesarik et al., 1999; Nakagawa et al., 2000), they are not
known to be useful for chemoprevention of ER positive cancers. Given that
the risk factors for developing breast cancer are known and there is a
beneficial utility of preventing a recurrence of breast cancer, the
present invention fulfills a need in the art to provide a prophylaxis for
ER positive cancers. That is, additional therapies against breast cancer
are needed, particularly given that some breast cancers become resistant
to tamoxifen over time (for review, see Jordan, 1994).
[0012] Tyrosine kinase inhibitors, such as emodin, have been well suited
for the treatment of HER-2/neu positive cancers, unrelated to the ER
nature of the cancer, especially given the tyrosine kinase nature of
HER-2/neu; however, they have not been utilized for the treatment of ER
positive HER-2/neu negative cancers, nor have they been realized as useful
for breast cancer prevention. The present invention satisfies a deficiency
in the art related to a dual approach to combat cancers which are both
HER-2/neu negative and ER positive through tyrosine kinase inhibitor
compounds, such as emodin.
SUMMARY OF THE INVENTION [0013] The present invention regards methods and
compositions directed to estrogen receptor positive (ER positive) cancers,
and, in some preferred embodiments, to ER positive breast cancers. Such
cancers include, for example: ovarian, endometrial, cervical, lung
cancers, head and neck cancers, melanoma, meningiomas, thymomoas and
lymphomas. In some specific embodiments, the invention relates to the
prevention, treatment, or prevention and treatment of ER positive breast
cancers.
[0014] In a preferred embodiment, the present invention regards prevention
of the development or proliferation of an ER positive cancer cell, such as
an ER positive breast cancer cell in an individual. The prevention
utilizes a composition having anti-estrogen receptor activity, and in some
particular embodiments such compositions also have tyrosine kinase
inhibitor activity. The anti-estrogen receptor activity is associated with
the same composition as the tyrosine kinase inhibitor activity and can
comprise any means to affect the estrogen receptor such that it prevents
transduction of the hormone estrogen signal and/or prevents an increase in
estrogen in the cell or tissue, particularly in a cell or tissue in which
the increase in estrogen would result in harmful effects. Thus, the
anti-estrogen receptor activity includes a decrease in levels of estrogen
receptor in the cell, an increase in its degradation, a downregulation of
expression of the polynucleotide which encodes it, or a decrease in the
halflife of a mRNA generated from a polynucleotide which encodes it.
[0015] In particular embodiments, the composition also comprises tyrosine
kinase inhibitor activity, wherein the activity comprises reducing,
impeding, obstructing, or otherwise interfering with, preferably in a
deleterious manner, the activity of a tyrosine kinase. Such interference
includes affecting any domain within the tyrosine kinase, such as a
catalytic domain, a regulatory domain, an extracellular domain, and so
forth. The inhibition can be, for example, the result of the tyrosine
kinase inhibitor affecting the protein structure, including removal or
modification of amino acid residues, increasing the degradation of the
polypeptide, blocking access to a particular domain, such as the catalytic
domain, affecting expression levels of the polynucleotide which encodes
it, or decreasing the half-life of the mRNA which is expressed from the
polynucleotide which encodes it. Specific examples of tyrosine kinase
inhibitors are well known in the art, including emodin, genistein, and
RG13022.
[0016] In other embodiments, the present invention addresses treatment of
an ER positive HER-2/neu negative breast cancer cell in an individual. The
treatment comprises contacting the cell with a composition having both
tyrosine kinase inhibitor activity and anti- estrogen receptor activity.
[0017] In a preferred embodiment, the prevention of the development or
proliferation of an ER positive cell with a composition having anti-ER
activity or the treatment of the ER positive HER-2/neu negative cell with
a composition having both tyrosine kinase inhibitor activity and
anti-estrogen receptor activity occurs in an individual having a risk of
developing breast cancer or an individual which has already received
treatment for the breast cancer.
The previous breast cancer therapy could comprise surgery, chemotherapy,
radiation, or a combination thereof. In a specific embodiment, the
individual having already received treatment for the ER positive breast
cancer has the cancer in remission. A skilled artisan recognizes that
breast cancer which recurs is not necessarily of the same type as was seen
with the original occurrence, and therefore, in a specific embodiment all
individuals having had breast cancer, regardless of the original etiology,
are candidates for prevention and treatment with the compositions and
methods described herein.
[0018] Furthermore, an individual who is at risk for developing breast
cancer or having a recurrence of breast cancer is particularly well-suited
to receive therapy with the methods and compositions described herein. A
skilled artisan recognizes the multiple risk factors for an individual to
develop breast cancer, including lifestyle and environmental factors,
genetic factors, and so forth. Moreover, one skilled in the art recognizes
histopathologies and specific mutations which are indicative of an
increased risk for developing breast cancer, particularly with
premalignant lesions.
.
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