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Treatment of metastatic prostate cancer

a prostate cancer and metastatic technology, applied in the field of treatment of metastatic prostate cancer, can solve the problems of ineffective crpc, drug resistance to enzalutamide and abiraterone, and inability to cure crpc, so as to enhance the therapeutic effect of a compound

Inactive Publication Date: 2017-11-02
THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE DEPT OF VETERANS AFFAIRS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes a composition that includes an AR-V7 inhibitor and a compound selected from the group consisting of enzalutamide, abiraterone, docetaxel, bicalutamide, and combinations thereof. The composition can be a pharmaceutical composition that is suitable for oral administration to patients with prostate cancer. The invention also provides methods of treating prostate cancer by administering the composition to a patient in need of treatment. The invention also provides methods of reversing or reducing resistance to anti-androgen drugs or docetaxel in prostate cancer cells. The technical effects of the invention include enhancing the therapeutic effect of anti-androgen drugs and reversing or reducing resistance to docetaxel in prostate cancer cells.

Problems solved by technology

While these methods may be initially effective, they often become ineffective once a patient develops castration-resistant prostate cancer (CRPC).
To date, CRPC is not curable.
However, drug resistance to enzalutamide and abiraterone often develops in patients that have prostate cancer.
The serum levels of IL-6 are elevated in many men with advanced, hormone-refractory prostate cancer and are associated with progression and poor prognosis.

Method used

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  • Treatment of metastatic prostate cancer
  • Treatment of metastatic prostate cancer
  • Treatment of metastatic prostate cancer

Examples

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example 1

ivity in Prostate Cancer Cells, Enzalutamide Resistance, and Compositions and Methods for Treatment of Prostate Cancer Cells

[0261]a. Introduction

[0262]The deletion of LBD results in constitutive activation of the AR in prostate cancer cells. AR-V7 mRNA expression in different cell lines was detected as shown in FIG. 1A. CWR22rv1 and VCaP cells expressed significantly higher AR-V7 than LNCaP and C4-2 cells; the expression level of AR-V7 in CWR22rv1 cells was 25 times higher than in LNCaP and C4-2 cells, whereas VCaP cells exhibited a 15 fold increase in comparison. The results were also confirmed by Western blot, as shown in FIG. 1B, in which CWR22rv1 and VCaP cells expressed higher protein expression levels of AR variants, especially AR-V7, than LNCaP and C4-2 cells. AR-V7 has been shown constitutively active in prostate cancer cells. To confirm these results, EGFP-AR-V7 was transiently transfected into C4-2 cells, and 48 hours later, as shown in FIG. 1C, AR-V7 was only expressed in...

example 2

de Effects on Enzalutamide-Resistant Cells

[0343]CWR22Rv1 cells (4 million) were mixed with matrigel (1:1) and injected subcutaneously into the flanks of male SCID mice, tumor-bearing mice (tumor volume around 50-75 mm3) were treated 5 days per week as follows: Control: (5% PGE8000 in H2O p.o B.I.D.), niclosamide (200 mg / kg p.o B.I.D.). Tumors were measured using calipers twice a week and tumor volumes were calculated using length×width2 / 2. Tumor tissues were harvested after 3 weeks of treatment. The results are depicted in FIGS. 40A-40D. As shown in FIGS. 40A-40C, niclosamide significantly inhibited Rv1 xenograft tumor growth when administered orally. As shown in FIG. 40D, the dosage of niclosamide was well-tolerated as illustrated by maintenance of body weight in comparison to control mice that did not receive niclosamide.

[0344]The effects of niclosamide in combination with bicalutamide were examined in vitro and in vivo. As shown in FIGS. 41A and 41B, niclosamide significantly enh...

example 3

tivation and Intracrine Androgens Confer Resistance to Enzalutamide

a. Introduction

[0346]Targeting androgen signaling via androgen deprivation therapy has been the mainstay of clinical interventions in prostate cancer (PCa). While initially effective, the majority of men experience only transient benefit and relapse with castrate-resistant prostate cancer (CRPC), which is currently incurable. Enzalutamide, a second-generation antiandrogen, was recently approved for the treatment of castration resistant prostate cancer (CRPC) in patients. Despite these advances that provide temporary respite, resistance to enzalutamide occurs frequently. Several potential mechanisms of resistance have been revealed such as AR variants expression (Antonarakis et al., 2014; Li et al., 2013; Liu et al., 2014a), IL6-STAT3-AR axis activation (Liu et al., 2014b), AR F876L mutation (Joseph et al., 2013; Korpal et al., 2013) and glucocorticoid receptor (GR) overexpression (Arora et al., 2013; Isikbay et al., ...

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Abstract

The present invention provides new compositions and methods for treating prostate cancer, e.g., drug-resistant prostate cancer, such as anti-androgen drug (e.g., enzalutamide) resistant and / or castration resistant prostate cancer (CRPC). These new compositions include, but are not limited to, pharmaceutical compositions that include an AR-V7 inhibitor, such as niclosamide. Alternatively, these new compositions can include, but are not limited to, pharmaceutical compositions that include an AKR1C3 inhibitor, such as indomethacin. These new methods include, but are not limited to, methods of administering an AR-V7 inhibitor, such as niclosamide, and / or an AKR1C3 inhibitor, such as indomethacin, to treat patients having prostate cancer. The present invention also provides methods of inhibiting androgen receptor variant expression, e.g. AR-V7, and methods of killing cells expressing AR-V7. The present invention further provides methods of inhibiting AKR1C3 expression or activity, and methods of killing cells that express AKR1C3.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of PCT / US2014 / 062455, filed Oct. 27, 2014, which application claims the benefit of and priority to U.S. Provisional Patent Application Nos. 61 / 896,250, filed Oct. 28, 2013; and 61 / 914,389, filed on Dec. 11, 2013, the contents of all of which are incorporated herein by reference in their entireties for all purposes.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT[0002]This invention was made with Government support under Grant No. CA140468, awarded by the National Institutes of Health. The Government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Current methods for treating prostate cancer include targeting androgen signaling and also androgen deprivation therapy by administering anti-androgen drugs and androgen antagonists to patients having prostate cancer. While these methods may be initially effective, they often become ineffective onc...

Claims

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Application Information

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IPC IPC(8): G01N33/574A61K47/68C12Q1/68
CPCG01N33/57434A61K47/6869C12Q2600/178G01N2800/52C12Q1/6886A61K38/00A61K45/06A61K31/277A61K31/337A61K31/405A61K31/4166A61K31/58A61K31/609A61P13/08A61P15/00A61P35/00A61P35/04A61P43/00A61K2300/00
Inventor GAO, ALLEN C.LIU, CHENGFEILOUPAN, CHONG-XIAN
Owner THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE DEPT OF VETERANS AFFAIRS
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