Method for Treatment of Primary Hormone Resistant Endometrial and Breast Cancers

a breast cancer and hormone-resistant technology, applied in the field of primary hormone-resistant endometrial and breast cancer treatment, can solve the problems of no treatment option for patients with recurrent or metastatic endometrial carcinoma, and the depletion of prs in the target tissue of progestin treatmen

Inactive Publication Date: 2017-07-20
LIPOXEN TECHNOLOGIES LTD
View PDF0 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]In one aspect, the invention provides a method of treatment of a primary progesterone receptor-negative (PR−) endometrial cancer in a subject in need thereof, said method comprising administering to the subject (i) an effective amount of cridanimod or a salt or an ester thereof, wherein said effective amount is sufficient to sensitize cancer cells of the subject to inhibitory action of a progesterone receptor (PR) agonist, and (ii) a therapeutically effective amount of a PR agonist (collectively (i) and (ii) constituting a therapeutic treatment). In one embodiment, the above method of treatment results in complete response (CR) or partial response (CR/PR) or stable disease (SD) as per RECIST criteria (e.g., RECIST 1.0 or RECIST 1.1). In one embodiment, the PR agonist is progesterone. In another embodiment, the PR agonist is selected from the group consisting of medroxyprogesterone acetate, megestrol acetate, hydroxyprogesterone caproate, levonorgestrel, mometasone furoate, and synthetic progestin R5020. In one embodiment, the effective amount of cridanimod or salt or ester thereof is sufficient to induce PR in cancer cells of the subject. In one specific embodiment, the effective amount of cridanimod or salt or ester thereof induces PR in cancer cells of the subject to the level of more than 10 fmol PR receptors per mg of cytosol protein or until the equal or more than 1% of cancer cells become PR positive as determined by immunohistochemistry staining. In another embodiment, the effective amount of cridanimod or salt or ester thereof is sufficient to activate inactive form of PR in cancer cells of the subject. In one embodiment, the effective amount of cridanimod or salt or ester thereof is within the range of 1-50 mg/kg/day. In one embodiment, cridanimod or salt or ester thereof is administered in a single daily dose, or on each alternate day, or twice a week. In one embodiment, (i) cridanimod or salt or ester thereof and (ii) the PR agonist are administered concurrently (e.g., in one composition or in two separate compositions). In another embodiment, (i) cridanimod or salt or ester thereof is administered prior to (ii) the PR agonist. In one embodiment, prior to the administration of (i) cridanimod or salt or ester thereof and (ii) the PR agonist, the expression level of PRs is determined in a cancer sample obtained from the subject (e.g., using a ligand binding assay).
[0010]In a related aspect, the invention provides a pharmaceutical composition comprising (i) cridanimod or a salt or an ester thereof and (ii) a PR agonist. The invention also provides a method of treatment of a primary progesterone receptor-negative (PR−) endometrial cancer in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of said pharmaceutical composition. In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient. In one embodiment, the PR agonist is progesterone. In another embodiment, the PR agonist is selected from the group consisting of medroxyprogesterone acetate, megestrol acetate, hydroxyprogesterone caproate, levonorgestrel, mometasone furoate, and synthetic progestin R5020.
[0011]In a separate

Problems solved by technology

Currently no therapy of recurrent or metastatic endometrial carcinoma is available to patients.
Unfortunately, proges

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Method for Treatment of Primary Hormone Resistant Endometrial and Breast Cancers

Examples

Experimental program
Comparison scheme
Effect test

example 1

tion of PR-Agonist and Sodium Cridanimod has Limited Efficacy in Secondary PR-Negative Endometrial Cancer with Acquired Resistance to PR-Agonist but is Highly Effective in Primary PR-Negative Endometrial Cancer

[0095]Eight patients with advanced and metastatic endometrial cancer (FIGO stage III-IV; Mutch. Gynecol Oncol. 2009, 115:325-328) were included to the study. All patients were not amenable for treatment for surgery, chemo- or radiotherapy. Tumor tissue samples from the patients were assessed for PR level. Primary progesterone receptor-negative (PR−) cancer was registered in 3 patients; secondary progesterone receptor-negative (PR−) cancer was registered in 5 patients. All patients were treated with oral PR agonist medroxyprogesterone acetate (MPA) at dose of 500 mg once a day and sodium cridanimod (SC) intramuscular injections at dose of 500 mg twice a week. The responses (complete response, partial response or stable disease) according to RECIST 1.0 (www.recistcom; Therasse e...

example 2

tion of PR-Agonist and Sodium Cridanimod has Significant Antitumor Effect in an Animal Model of Human Primary PR-Negative Endometrial Cancer and Limited Efficacy in an Animal Model of Human Secondary PR-Negative Endometrial Cancer

[0097]In order to confirm the above clinical findings, cridanimod / PR-agonist therapy was tested in animal models of human primary and secondary PR-negative cancers:

[0098]Mouse Model of Primary PR-Negative Endometrial Cancer:

[0099]40 female 8-week-old immunodeficient BNX nu / nu mice (Harlan Laboratories) were bilaterally s.c. injected with 5×106 of human primary PR-negative endometrial cancer cells HEC-1B in 0.1 ml of Matrigel forming two tumors per mouse. Treatment was started on the next day after the injection and discontinued after 5 weeks. Cohorts (10 mice / group) received either:

1) Vehicle control group: vehicle only, 0.9% sodium chloride for injection i.m each alternate day and i.p. for 5 days / week.

2) MA only control group: megestrol acetate (MA) (10 mg...

example 3

tion of Tamoxifen and Sodium Cridanimod is Highly Effective for Treatment of Primary ER-Negative Breast Cancer

[0107]Nine women (48-69 years old) with primary PR / ER-negative (diagnosed using LBA and ICH methods) and HER2 negative (as determined with IHC Dako DakoCytomation's HercepTest), i.e., triple negative breast cancer (TNBC) of stage III-IV not amenable for surgery, chemo- or radiotherapy were treated with tamoxifen (40 mg / day orally) in combination with sodium cridanimod solution injected intramuscularly (i.m.) twice a week at a dose of 500 mg during the first four weeks. After discontinuation of sodium cridanimod, patients continued to take tamoxifen only. The response was assessed each 8 weeks according to RECIST 1.0 criteria (www.recistcom; Therasse et al., J. Natl. Cancer Inst., 2000, 92(3):205-216). The interim results of the trial are shown in Table 4, below.

TABLE 4Patient PR / ER Tamoxifen dailyClinical Progression-free#statusdose, mgeffectperiod, months1Negative20PR82Nega...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
Fractionaaaaaaaaaa
Frequencyaaaaaaaaaa
Volumeaaaaaaaaaa
Login to view more

Abstract

The invention provides a method for treatment of primary progesterone receptor-negative (PR−) endometrial cancer comprising administering (i) cridanimod or a salt or an ester thereof and (ii) a progesterone receptor (PR) agonist. The invention further provides a method for treatment of a primary estrogen receptor-negative (ER−) breast cancer, comprising administering (i) cridanimod or a salt or an ester thereof and (ii) a selective estrogen receptor modulator (SERM) or a selective estrogen receptor down-regulator (SERD). Also provided are compositions related to the above methods.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 62 / 076,546, filed on Nov. 7, 2014, the disclosure of which is herein incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The invention provides a method for treatment of primary progesterone receptor-negative (PR−) endometrial cancer comprising administering (i) cridanimod or a salt or an ester thereof and (ii) a progesterone receptor (PR) agonist. The invention further provides a method for treatment of a primary estrogen receptor-negative (ER−) breast cancer, comprising administering (i) cridanimod or a salt or an ester thereof and (ii) a selective estrogen receptor modulator (SERM) or a selective estrogen receptor down-regulator (SERD). Also provided are compositions related to the above methods.BACKGROUND OF THE INVENTION[0003]Endometrial cancer is one of the most common invasive gynecologic cancers. Currently no therapy of recurrent or metastatic e...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): A61K31/57A61K31/473
CPCA61K31/473A61K31/57A61K31/135A61K31/138A61K31/40A61K31/565A61K31/58A61K2300/00A61P35/00A61P43/00
Inventor GENKIN, DMITRYSURKOV, KIRILL
Owner LIPOXEN TECHNOLOGIES LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap