Method of treating cancer using selective estrogen receptor modulators
Inventors
Wardell, Suzanne E. • Nelson, Erik R. • McDonnell, Donald P.
Assignees
Publication Number
US-12263142-B2
Publication Date
2025-04-01
Expiration Date
2034-10-10
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Abstract
Disclosed herein are methods of treating subjects suffering from estrogen receptor positive cancer of the brain by administering a selective estrogen receptor degrader (SERM). Also disclosed are methods of treating a cancer that is resistant to an estrogen receptor modulator by administering a SERM.
Core Innovation
The invention provides methods for treating estrogen receptor positive cancers of the brain, and cancers that are resistant to estrogen receptor modulators, by administering a selective estrogen receptor modulator (SERM), particularly (R)-6-{2-{ethyl[4-(2-ethylaminoethyl)benzyl]amino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-ol (also known as RAD1901). This compound exhibits both SERM and selective estrogen receptor degrader (SERD) activities in a dose-dependent manner, offering tissue-selective therapeutic effects.
The problem addressed is the lack of effective treatments for estrogen receptor positive cancers of the brain, such as breast cancer brain metastases (BCBM), due to limited penetration of existing SERMs and SERDs across the blood brain barrier. Additionally, current therapies for estrogen receptor modulator-resistant cancers, including those with acquired or de novo resistance to drugs like tamoxifen, are insufficient, particularly for advanced or metastatic disease.
This invention leverages the brain-penetrant properties and unique pharmacology of RAD1901, which can induce estrogen receptor degradation at higher doses and act as a partial agonist at lower doses, to inhibit tumor growth and overcome resistance. The method also encompasses combination treatments with other therapeutic agents for enhanced efficacy in targeting both brain and peripheral tumors.
Claims Coverage
There are two independent claims in the patent, each focusing on inventive features regarding the method of treating estrogen receptor positive breast cancer brain metastasis resistant to an aromatase inhibitor using a specific SERM compound.
Method of treating estrogen receptor positive breast cancer brain metastasis resistant to an aromatase inhibitor using (R)-6-{2-{ethyl[4-(2-ethylaminoethyl)benzyl]amino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-ol
The main inventive feature includes: - Administering (R)-6-{2-{ethyl[4-(2-ethylaminoethyl)benzyl]amino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-ol to subjects diagnosed with estrogen receptor positive breast cancer brain metastasis that is resistant to an aromatase inhibitor. - The method encompasses administration of the compound at a dosage range of about 10 mg/day to about 500 mg/day. - Administration can be as a single dose or a multi-dose regimen, and the delivery routes include oral, intravenous, intradermal, intramuscular, or subcutaneous injections.
Method of treating estrogen receptor positive breast cancer brain metastasis resistant to an aromatase inhibitor using a composition comprising the specified compound
The main inventive feature includes: - Administering a composition comprising (R)-6-{2-{ethyl[4-(2-ethylaminoethyl)benzyl]amino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-ol to a subject with estrogen receptor positive breast cancer brain metastasis resistant to an aromatase inhibitor. - The composition may contain the compound at a dose of about 10 mg to about 500 mg. - Administration options include single or multi-dose regimens and multiple delivery routes, such as oral, intravenous, intradermal, intramuscular, or subcutaneous. - The method may further include co-administering an effective amount of at least one agent selected from a CDK4/6 inhibitor, antiestrogen, ligand of retinoic acid or retinoxic X receptor, antiprogestin, antiandrogen, vitamin D or its metabolite, farnesyl transferase inhibitor, PPARα or gamma agonist, or MAP kinase inhibitor.
The inventive features define methods for treating estrogen receptor positive breast cancer brain metastasis resistant to aromatase inhibitors, particularly by administering a specified SERM/SERD compound alone or in combination, across a range of dosing strategies and administration routes, expanding therapeutic options for this challenging disease.
Stated Advantages
RAD1901 is able to penetrate the blood brain barrier, allowing for effective treatment of estrogen receptor positive cancers of the brain, including breast cancer brain metastases.
The compound provides therapeutic benefit in tumors that are resistant to traditional estrogen receptor modulators, including those resistant to tamoxifen or aromatase inhibitors.
RAD1901 induces dose-dependent degradation of the estrogen receptor, offering both SERM-like and SERD-like activity for tailored treatment based on dosage.
The method enables combination therapy with multiple types of cancer treatments or agents for broader efficacy against metastatic and resistant cancers.
Documented Applications
Treatment of estrogen receptor positive cancers of the brain, including breast cancer brain metastases (BCBM), astrocytoma, atypical teratoid rhabdoid tumor (ATRT), chondrosarcoma, choroid plexus carcinoma, craniopharyngioma, ependymoma, germ cell tumor, glioblastoma, glioma, hemangioma, juvenile pilocytic astrocytoma, medulloblastoma, meningioma, neurofibroma, neuronal and mixed neuronal-glial tumors, oligoastrocytoma, oligodendroglioma, pineal tumor, pituitary tumor, primitive neuroectodermal tumor (PNET), schwannoma, and leptomeningeal metastases.
Treatment of cancers resistant to estrogen receptor modulators, such as tamoxifen-resistant breast cancer, as well as resistant endometrial and ovarian cancers.
Use as a targeted therapy for breast cancer brain metastases, particularly in cases where resistance to aromatase inhibitors is present.
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