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Methods for treating cancer resistant to cdk4/6 inhibitors

A technology of drug resistance and inhibitors, applied in pharmaceutical formulations, biochemical equipment and methods, drug combinations, etc., can solve the problems of patients with relapsed drug-resistant breast cancer

Pending Publication Date: 2021-07-23
RADIUS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although initial treatment with these agents may be successful, many patients eventually relapse with drug-resistant breast cancer

Method used

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  • Methods for treating cancer resistant to cdk4/6 inhibitors
  • Methods for treating cancer resistant to cdk4/6 inhibitors
  • Methods for treating cancer resistant to cdk4/6 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0130] Materials and methods

[0131] test compound

[0132] Erastran used in the following examples is (6R)-6-(2-(N-(4-(2-(ethylamino)ethyl)benzyl)-N-ethylamino)-4- Methoxyphenyl)-5,6,7,8-tetralin-2-ol dihydrochloride ((6R)-6-(2-(N-(4-(2-(ethylamino)ethyl) benzyl)-N-ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol dihydrochloride), for example manufactured by IRIX Pharmaceuticals Ltd. (Florence, SC). Erastrant is stored in the form of dry powder, prepared into a homogeneous suspension with deionized water containing 0.5% (w / v) methylcellulose, and administered orally to animal models. Tamoxifen, raloxifene, and estradiol (E2) were obtained from Sigma-Aldrich (St. Louis, MO) and administered by subcutaneous injection. Fulvestrant was obtained from Tocris Biosciences (Minneapolis, MN) and administered by subcutaneous injection. Other laboratory reagents were purchased from Sigma-Aldrich unless otherwise stated.

[0133] Development of resistance to CDK4 / 6...

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Abstract

Disclosed herein are methods of treating a CDK4 / 6 inhibitor resistant estrogen receptor alpha-positive cancer in a subject having either a wild-type estrogen receptor alpha and / or a mutant estrogen receptor alpha, the method comprising administering to the subject a therapeutically effective amount of elacestrant, or a pharmaceutically acceptable salt or solvate thereof, wherein the mutant estrogen receptor alpha comprises one or more mutations selected from the group consisting of D538G, Y537X1, L536X2, P535H, V534E, S463P, V392I, E380Q and combinations thereof, wherein: X1 is S, N, or C; and X2 is R or Q. In some embodiments, the CDK4 / 6 inhibitor resistant estrogen receptor alpha-positive cancer is selected from the group consisting of breast cancer, uterine cancer, ovarian cancer, and pituitary cancer.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application 62 / 776,323, filed December 6, 2018. The entire content of the above application, including the drawings, is hereby incorporated by reference in its entirety. technical field [0003] The present invention provides methods of using elacestrant to provide antitumor activity in ESR1 mutated cancer models that are resistant to CDK4 / 6 inhibitors. The present invention also relates to a method of treating estrogen positive (ER+) cancers with ESR1 mutations leading to resistance to CDK4 / 6 inhibitors, wherein said cancer is treated with elastrant. Background technique [0004] Breast cancers are classified into three subtypes based on the expression of three receptors: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (Her2). Overexpression of ER is found in many breast cancer patien...

Claims

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Application Information

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IPC IPC(8): A61P35/00A61K31/015A61K31/137A61K31/138A61K45/06
CPCA61K45/06A61K31/137A61K31/138A61K31/015A61P35/00A61K2300/00A61K31/565A61K31/566A61K31/4196C12Q1/6886C12Q2600/106C12Q2600/158
Inventor H·帕特尔T·比哈尼H·阿尔特N·陶
Owner RADIUS PHARMA INC