US20230149350A1 - Lasofoxifene treatment of aromatase-resistant er+ cancer - Google Patents

Lasofoxifene treatment of aromatase-resistant er+ cancer Download PDF

Info

Publication number
US20230149350A1
US20230149350A1 US17/989,382 US202217989382A US2023149350A1 US 20230149350 A1 US20230149350 A1 US 20230149350A1 US 202217989382 A US202217989382 A US 202217989382A US 2023149350 A1 US2023149350 A1 US 2023149350A1
Authority
US
United States
Prior art keywords
lasofoxifene
cancer
patient
inhibitor
administered
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US17/989,382
Other languages
English (en)
Inventor
Barry Samuel Komm
Geoffrey L. Greene
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sermonix Pharmaceuticals Inc
Original Assignee
Sermonix Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sermonix Pharmaceuticals Inc filed Critical Sermonix Pharmaceuticals Inc
Priority to US17/989,382 priority Critical patent/US20230149350A1/en
Assigned to SERMONIX PHARMACEUTICALS, INC. reassignment SERMONIX PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GREENE, GEOFFREY L., KOMM, BARRY SAMUEL
Publication of US20230149350A1 publication Critical patent/US20230149350A1/en
Priority to US18/325,883 priority patent/US12023321B2/en
Priority to US18/764,277 priority patent/US12433866B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Estrogen receptor positive (ER + ) breast cancers are those that express estrogen receptor ⁇ (ER ⁇ ), which is encoded by the ESR1 gene. Approximately 70% of breast cancers are ER + and are, therefore, treated with agents that deplete circulating estrogen levels or that block estrogen signaling in the cancer cell (collectively, endocrine therapy).
  • SERMs selective estrogen receptor modulators
  • SESDs selective estrogen receptor degraders
  • AIs aromatase inhibitors
  • ER + tumors evolve various escape mechanisms. Among these is acquisition of gain-of-function mutations in the ESR1 gene that alter the ligand binding domain of the ER ⁇ receptor, rendering the receptor constitutively active at low levels, or in the absence, of estrogen. Despite the benefits of endocrine therapy, the majority of patients with ER + will eventually acquire resistance and progress.
  • Lasofoxifene a selective estrogen receptor modulator (SERM) was shown to reduce the risk of ER + breast cancer in women with wild estrogen receptors, post-menopausal women with no history of breast cancer being treated with osteoporosis.
  • SERM selective estrogen receptor modulator
  • ER + estrogen receptor positive
  • ESR1 Estrogen Receptor 1
  • the ER + cancer is locally advanced or metastatic breast cancer, optionally wherein the cancer is HER2 ⁇ .
  • the aromatase inhibitor is exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®).
  • the method further comprises the earlier step of: determining that the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene.
  • LBD ligand binding domain
  • ESR1 Estrogen Receptor 1
  • lasofoxifene is administered as lasofoxifene tartrate.
  • lasofoxifene is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration.
  • lasofoxifene is administered by oral administration. In certain of these embodiments, lasofoxifene is administered orally in a dose of 5 mg/day to about 10 mg/day.
  • the method further comprises treating said patient with at least one additional endocrine therapy.
  • the method further comprises administering an effective amount of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor.
  • CDK4/6 inhibitor is palbociclib, abemaciclib, or ribociclib. In some embodiments, the CDK4/6 inhibitor is abemaciclib.
  • the method further comprises administering an effective amount of an AKT inhibitor.
  • the AKT inhibitor is afuresertib.
  • the method further comprises administering an effective amount of an mTor inhibitor.
  • FIG. 1 shows a comparison of variant counts in the AI resistant breast tumor model MCF-7 LTLT cells versus two publicly available reference genomes of MCF7 “WT” from the literature.
  • FIG. 2 presents data showing that lasofoxifene inhibits primary tumor growth of MCF7 LTLT (AI-resistant, ER + , cells lacking ESR1 gain-of-function mutations) tumors.
  • the data are from in vivo imaging showing the total photon flux quantified with the live image software over time for each group. Mice were treated with vehicle, palbociclib, lasofoxifene, fulvestrant (ICI), lasofoxifene+palbociclib, or fulvestrant (ICI)+Palbociclib.
  • FIG. 3 is a histogram summarizing data showing that lasofoxifene inhibits primary tumor growth in AI-resistant ER + cells lacking ESR1 gain-of-function mutations.
  • the histogram shows the total photon flux of the mammary glands at day 104.
  • N 6-12 glands+/ ⁇ SEM.
  • P values are: * p ⁇ 0.05, ** p ⁇ 0.005, *** p ⁇ 0.0005, **** p ⁇ 0.0001.
  • FIG. 4 presents data showing that lasofoxifene inhibits increases in primary tumor weight in AI-resistant, ER + cells lacking ESR1 gain-of-function mutations.
  • FIGS. 6 A- 6 C present data showing that lasofoxifene reduces Ki67 proliferation index as a single agent and in combination with palbociclib in the Let+ cohort.
  • FIG. 6 A shows % Ki67 in a comparison of vehicle versus the Let ⁇ versus Let + cohorts.
  • FIG. 6 B and FIG. 6 C show the % Ki67 for the Let ⁇ and Let + cohorts, respectively.
  • N 3-6 glands+/ ⁇ SEM.
  • P values are: * p ⁇ 0.05, ** p ⁇ 0.005, *** p ⁇ 0.0005, **** p ⁇ 0.0001.
  • FIGS. 8 A- 8 B present ex vivo radiance measurements in bone.
  • FIG. 8 B shows representative images.
  • FIGS. 9 A- 9 D present data showing that ER ⁇ and glucocorticoid receptor (GR) protein expression is lower in MCF7aro and LTLT compared to MCF7 and T47D.
  • FIG. 9 A western blot showing ER ⁇ and actin.
  • FIG. 9 B normalization of ER ⁇ levels to actin.
  • FIG. 9 C western blot showing GR and actin.
  • FIG. 9 D normalization of GR protein band to actin.
  • FIGS. 10 A- 10 E present data comparing AR, HER2 and PR protein levels in MCF7aro and MCF7 LTLT compared to MCF7 and T47D.
  • FIG. 10 A western blot showing AR and actin.
  • FIG. 10 B normalization of AR levels to actin.
  • FIG. 10 C western blot showing Her2 expression in MCF7 LTLT.
  • FIG. 10 D normalization of Her 2 to actin for T47D and MCF7 LTLT.
  • FIG. 10 E western blot showing PR. For AR and Her2, one gel was run. For PR, showing one of two representative experiments.
  • Postmenopausal patients with estrogen receptor positive (ER ⁇ + ) primary invasive breast cancer are typically treated with aromatase inhibitors (AIs) as first line adjuvant therapy.
  • AIs aromatase inhibitors
  • Patients who become resistant to AIs are currently treated with the SERD, fulvestrant, and/or with CDK4/6 inhibitors, such as palbociclib, as second line therapy.
  • Lasofoxifene has previously been demonstrated to retain its ability to inhibit progression of ER + tumors that have become AI-resistant through acquisition of gain-of-function (activating) mutations in the ligand binding domain of the ER ⁇ receptor. Lasofoxifene's ability to prevent progression of AI-resistant ER + cancers that escape endocrine therapy by other mechanisms is unknown.
  • CDK4/6 cyclin-dependent kinase 4/6
  • ER + estrogen receptor positive
  • ESR1 Estrogen Receptor 1
  • the method further comprises the earlier step of determining that the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene.
  • LBD ligand binding domain
  • ESR1 Estrogen Receptor 1
  • the methods may comprise administering to the patient an effective amount of lasofoxifene or a pharmaceutically acceptable salt, a prodrug, or functional derivative thereof in combination with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, such as palbociclib, abemaciclib or ribociclib, and/or in combination with an aromatase inhibitor, such as exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®).
  • CDK4/6 cyclin-dependent kinase 4/6
  • an aromatase inhibitor such as exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®).
  • the patient has been diagnosed with ER + cancer.
  • the ER status has been determined by immunohistochemistry (IHC) performed on a sample of the patient's cancer, by RT-PCR, by massive parallel next generation sequencing (NGS), or by other conventional techniques.
  • the sample is tumor tissue from a biopsy.
  • the sample is a liquid biopsy (e.g., serum, circulating DNA of a tumor biomarker) from a blood draw, saliva, or other bodily fluids.
  • the patient has been diagnosed with ER + breast cancer.
  • the cancer is ER + /HER2 ⁇ breast cancer.
  • the patient has been diagnosed with ER + primary breast cancer.
  • the cancer is locally advanced or metastatic ER + breast cancer.
  • the patient has previously been treated with an aromatase inhibitor selected from exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®).
  • the patient is premenopausal, perimenopausal or post menopausal. In some embodiments, the patient is premenopausal and has primary ER + breast cancer. In some embodiments, the patient is premenopausal and has locally advanced or metastatic ER + breast cancer. In some embodiments, the patient is perimenopausal and has primary ER + breast cancer. In some embodiments, the patient is perimenopausal and has locally advanced or metastatic ER + breast cancer. In some embodiments, the patient is postmenopausal and has primary ER + breast cancer. In some embodiments, the patient is postmenopausal and has locally advanced or metastatic ER + breast cancer.
  • the patient is premenopausal and has primary, or has locally advanced or metastatic ER + breast cancer, and has previously been treated with an aromatase inhibitor in combination with a second therapy.
  • the patient may have been treated with letrozole in combination with a second therapy such as goserelin (Zeladex®) or leuprolide (Lupron®).
  • the patient has been diagnosed with an ER + cancer other than breast cancer. In some of these embodiments, the patient has been diagnosed with ER + ovarian cancer. In some of these embodiments, the patient has been diagnosed with ER + lung cancer.
  • the cancer is a gynecological cancer selected from uterine cancer, cervical cancer, peritoneal cancer, vulva cancer, and vaginal cancer.
  • the patient has been diagnosed with ER + primary uterine cancer.
  • the uterine cancer is selected from endometrioid, clear-cell carcinoma, papillary serous, carcinosarcoma, leiomyosarcoma, and endometrial stromal sarcoma (ESS).
  • the uterine cancer is uterine endometrial stromal sarcoma uterine endometrial adenosarcoma, uterine adenosquamous carcinoma, uterine leiomyosarcoma or uterine corpus carcinoma.
  • the patient has been diagnosed with ER + cervical cancer.
  • the cervical cancer is cervical clear-cell carcinoma.
  • the patient has been diagnosed with ER + vulvar/vaginal cancer.
  • the vulva or vaginal cancer is a squamous cell carcinoma (SCC) or an adenocarcinoma.
  • the patient has been diagnosed with ER + lung cancer.
  • the lung cancer is lung adenosarcoma, squamous cell lung carcinoma, or small cell lung carcinoma.
  • the cancer is a gastrointestinal cancer selected from esophageal cancer, gastric cancer, small intestine cancer, colon cancer, rectal cancer, and colorectal cancer.
  • the patient has been diagnosed with ER + primary esophageal cancer.
  • the esophageal cancer is adenocarcinoma or squamous cell carcinoma.
  • the patient has been diagnosed with ER + primary gastric cancer.
  • the gastric cancer is gastric adenocarcinoma.
  • the patient has been diagnosed with ER + primary small intestine cancer.
  • the small intestine cancer is an adenocarcinoma, carcinoid tumor, lymphoma, or sarcoma such as leiomyosarcoma.
  • the small intestine cancer is malignant small intestinal neoplasm.
  • the patient has been diagnosed with ER + primary colon cancer.
  • the colon cancer is colon adenocarcinoma.
  • the patient has been diagnosed with ER + primary rectal cancer.
  • the rectal cancer is rectal adenocarcinoma.
  • the patient has been diagnosed with ER + primary colorectal cancer.
  • the colorectal cancer is colorectal adenocarcinoma and colorectal mucinous adenocarcinoma.
  • the cancer is selected from bladder cancer, e.g., bladder urothelial carcinoma; glioblastoma, e.g., conventional glioblastoma multiforme; skin cancer, e.g., skin squamous cell carcinoma; melanoma, e.g., cutaneous melanoma; infiltrating renal pelvic cancer; pancreatic cancer, e.g., pancreatic adenocarcinoma and cancer of unknown primary origin.
  • bladder cancer e.g., bladder urothelial carcinoma
  • glioblastoma e.g., conventional glioblastoma multiforme
  • skin cancer e.g., skin squamous cell carcinoma
  • melanoma e.g., cutaneous melanoma
  • infiltrating renal pelvic cancer pancreatic cancer, e.g., pancreatic adenocarcinoma and cancer of unknown primary origin.
  • the ER + cancer is a primary cancer. In some embodiments, the ER + cancer is a localized cancer. In some embodiments, the cancer is locally advanced. In some embodiments, the cancer is a metastatic ER + cancer.
  • the patient's cancer has relapsed or progressed after tamoxifen treatment. In some embodiments, the patient's cancer has relapsed or progressed after fulvestrant treatment. In some embodiments, the patient's cancer has relapsed or progressed after aromatase inhibitor treatment. In some of these embodiments, the patient's cancer has relapsed or progressed after multiple lines of endocrine therapy treatment.
  • the patient has been previously determined not to have a mutation in the LBD of the ESR1 gene.
  • Some embodiments of the methods described herein further include the step of detecting the mutations in ESR1 gene.
  • massively parallel next generation sequencing is used for detecting the estrogen receptor mutations in the patient's cancer.
  • the entire genome is sequenced.
  • selected gene panels of cancer-related genes are sequenced.
  • all coding exons within a given set of genes are sequenced.
  • known “hotspot” regions within a given set of genes are sequenced.
  • the inherent error rate of current next generation sequencing techniques is up to 1%, limiting the sensitivity and specificity of detection.
  • targeted sequencing is used for detecting the presence of the ESR1 mutations. Although targeted sequencing allows deeper sequencing, it is also currently limited by the 1% error rate. In some embodiments, methods with reduced sequencing error rate are used.
  • Safe-Sequencing System (Safe-SeqS) is used, which tags each template molecule to allow for confident identification of rare variants. See kinde et al., Proceedings of the National Academy of Sciences 108(23): 9530-9535 (2011).
  • ultrasensitive Duplex sequencing is used, which independently tags and sequences each of the two strands of a DNA duplex. See Schmitt et al., Proceedings of the National Academy of Sciences 109(36): 14508-14513 (2012).
  • digital droplet PCR is used, which emulsifies DNA in thousands to millions of droplets to encapsulate single DNA molecules, designed with mutant specific primers. See Vogelstein and Kinzler, Proceedings of the National Academy of Sciences 96(16): 2322-2326 (1999) and Huggett et al., Clinical Chemistry 61(1): 79-88 (2014).
  • the detection of the ESR1 mutations takes place at the initial diagnosis. In some embodiments, the detection of the mutations takes place at the time of disease progression, relapse, or recurrence. In some embodiments, the detection of the mutations takes place at the time of disease progression. In some embodiments, the detection of the mutations takes place at the time when the disease is stable.
  • one or more tissue specimens are obtained for detection of the mutations.
  • the tissue specimen is a tumor biopsy.
  • the tissue specimen is a biopsy of metastases.
  • liquid biopsies are obtained for detection of the mutations.
  • the liquid biopsy is circulating tumor cells (CTCs).
  • the liquid biopsy is cell-free DNA from blood samples.
  • the ESR1 mutations are monitored by circulating tumor DNA (ctDNA) analysis.
  • the ctDNA analysis is performed throughout the course of treatment.
  • the ctDNA is extracted from patient blood samples.
  • the ctDNA is evaluated by digital PCR analysis of the ESR1 mutations.
  • lasofoxifene is administered to the patient as adjuvant treatment. In certain embodiments, lasofoxifene is administered to the patient as adjuvant treatment alone. In certain other embodiments, lasofoxifene is administered to the patient as adjuvant treatment in combination with other endocrine therapies. In some embodiments, lasofoxifene is administered to the patient after the primary treatment. In some of these embodiments, lasofoxifene is administered to the patient after surgical removal or debulking of the cancer.
  • lasofoxifene is administered to the patient as adjuvant therapy in combination with an aromatase inhibitor (AI).
  • AI aromatase inhibitor
  • the aromatase inhibitor is exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®).
  • the aromatase inhibitor predisposes the patient to bone-related toxic effects. In some embodiments, the aromatase inhibitor predisposes the patient to osteoporosis. In some embodiments, the aromatase inhibitor predisposes the patient to bone loss. In some embodiments, the aromatase inhibitor predisposes the patient to bone fractures. In some embodiments, the aromatase inhibitor predisposes the patient to bone pain.
  • the aromatase inhibitor predisposes the patient to vulvovaginal atrophy (VVA).
  • lasofoxifene is administered continuously during the administration of the aromatase inhibitor. In some other embodiments, lasofoxifene is administered cyclically during the administration of the aromatase inhibitor. In some embodiments, lasofoxifene and the aromatase inhibitor are administered together (simultaneously). In some other embodiments, lasofoxifene and the aromatase inhibitor are administered separately (sequentially).
  • the dosing regimen of lasofoxifene is different from the dosing regimen of the aromatase inhibitor.
  • the dosing quantity of lasofoxifene is different from the dosing quantity of the aromatase inhibitor.
  • the dosing schedule of lasofoxifene is different from the dosing schedule of the aromatase inhibitor.
  • the route of administration of lasofoxifene is different from the route of administration of the aromatase inhibitor.
  • the dosing regimen of lasofoxifene is the same as the dosing regimen of the aromatase inhibitor.
  • the dosing quantity of lasofoxifene is the same as the dosing quantity of the aromatase inhibitor.
  • the dosing schedule of lasofoxifene is the same as the dosing schedule of the aromatase inhibitor.
  • the route of administration of lasofoxifene is the same as the route of administration of the aromatase inhibitor.
  • lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for one year. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for two years. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for three years. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for four years. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for five years.
  • lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for six years. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for seven years. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for eight years. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for nine years. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for ten years.
  • lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for more than ten years. In certain embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor until the patient's cancer progresses on therapy.
  • lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to increase the disease-free survival of the cancer patient. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to decrease the incidence of contralateral breast cancer. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to prevent the recurrence or progression of the cancer.
  • the selected patient is treated with an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, a prodrug or functional derivative thereof.
  • Lasofoxifene has the following structure:
  • lasofoxifene is administered to the selected patient as lasofoxifene tartrate.
  • pharmaceutically acceptable salt refers to non-toxic pharmaceutically acceptable salts. See Gould, International Journal of Pharmaceutics 33: 201-217 (1986) and Berge et al., Journal of Pharmaceutical Sciences 66(1): 1-19 (1977). Other salts well known to those in the art may, however, be used.
  • organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid.
  • Organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • Embodiments also include prodrugs of the compounds disclosed herein.
  • prodrugs include functional derivatives of the compounds described herein which are readily convertible in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “ Design of Prodrugs ”, H. Bundgaard, Elsevier, 1985.
  • a functional derivative of lasofoxifene encompasses a proteolysis targeting chimera (PROTAC) comprising lasofoxifene.
  • PROTACS proteolysis targeting chimera
  • PROTACS are heterobifunctional small molecules with three chemical elements: lasofoxifene, a ubiquitin ligand binding moiety or ULM group, and a linker for conjugating these two elements.
  • lasofoxifene is covalently conjugated to a ubiquitin ligand binding moiety or ULM group via a linker.
  • Non-limiting examples of such linkers include ester linkers, amide linkers, maleimide or maleimide-based linkers; valine-citrulline linkers; hydrazone linkers; N-succinimidyl-1-(2-pyridyldithio)butyrate (SPDB) linkers; Succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) linkers; vinylsulfone-based linkers; linkers that include polyethylene glycol (PEG), such as, but not limited to tetraethylene glycol; linkers that include propanols acid; linkers that include caproleic acid, and linkers including any combination thereof.
  • PEG polyethylene glycol
  • the linker is a chemically-labile linker, such as an acid-cleavable linker that is stable at neutral pH (bloodstream pH 7.3-7.5) but undergoes hydrolysis upon internalization into the mildly acidic endosomes (pH 5.0-6.5) and lysosomes (pH 4.5-5.0) of a target cell (e.g., a cancer cell),
  • Chemically-labile linkers include, but are not limited to, hydrazone-based linkers, oxime-based linkers, carbonate-based linkers, ester-based linkers, etc.
  • the linker is an enzyme-labile linker, such as an enzyme-labile linker that is stable in the bloodstream but undergoes enzymatic cleavage upon internalization into a target cell, e.g., by a lysosomal protease (such as cathepsin or plasmin) in a lysosome of the target cell (e.g., a cancer cell).
  • a lysosomal protease such as cathepsin or plasmin
  • Enzyme-labile linkers include, but are not limited to, linkers that include peptidic bonds, e.g., dipeptide-based linkers such as valine-citrulline linkers, such as a maleimidocaproyl-valine-citruline-p-aminobenzyl (MC-vc-PAB) linker, a valyl-alanyl-para-aminobenzyloxy (Val-Ala-PAB) linker, and the like.
  • MC-vc-PAB maleimidocaproyl-valine-citruline-p-aminobenzyl
  • Val-Ala-PAB valyl-alanyl-para-aminobenzyloxy
  • ULM group is covalently bonded to the linker to which is attached lasofoxifene, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph or prodrug thereof.
  • Some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are intended to be encompassed by some embodiments.
  • the processes for the preparation of the compounds as disclosed herein give rise to mixtures of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form or as individual enantiomers or diastereomers by either stereospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers or diastereomers by standard techniques, such as the formation of stereoisomeric pairs by salt formation with an optically active base, followed by fractional crystallization and regeneration of the free acid.
  • the compounds may also be resolved by formation of stereoisomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. It is to be understood that all stereoisomers, racemic mixtures, diastereomers, cis-trans isomers, and enantiomers thereof are encompassed by some embodiments.
  • Methods for treatment of estrogen receptor positive (ER + ) cancers include administering a therapeutically effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, a prodrug, or functional derivative thereof.
  • the lasofoxifene, the pharmaceutically acceptable salt, or the prodrug of the invention can be formulated in pharmaceutical compositions.
  • the composition further comprises a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material can depend on the route of administration, e.g., oral, intravenous, transdermal, vaginal topical, or vaginal ring.
  • compositions for oral administration can be in tablet, capsule, powder or liquid form.
  • a tablet can include a solid carrier such as gelatin or an adjuvant.
  • Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal oil, vegetable oil, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can also be included.
  • the lasofoxifene will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilizers, buffers, antioxidants and/or other additives can be included, as required.
  • compositions for vaginal topical administration can be in the form of ointment, cream, gel or lotion.
  • the pharmaceutical compositions for vaginal topical administration often include water, alcohol, animal oil, vegetable oil, mineral oil or synthetic oil. Hydrocarbon (paraffin), wool fat, beeswax, macrogols, emulsifying wax or cetrimide can also be included.
  • a composition can be administered alone or in combination with other treatments, either simultaneously or sequentially, dependent upon the condition to be treated.
  • treatment In the methods of administering an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, a prodrug, or functional derivative thereof, in the form of a pharmaceutical composition as described above for treatment of ER + cancer, the terms “treatment”, “treating”, and the like are used herein to generally mean obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic, in terms of completely or partially preventing a disease, condition, or symptoms thereof, and/or may be therapeutic in terms of a partial or complete cure for a disease or condition and/or adverse effect, such as a symptom, attributable to the disease or condition.
  • Treatment covers any treatment of a disease or condition of a mammal, particularly a human, and includes: (a) preventing the disease or condition from occurring in a subject which may be predisposed to the disease or condition but has not yet been diagnosed as having it; (b) inhibiting the disease or condition (e.g., arresting its development); or (c) relieving the disease or condition (e.g., causing regression of the disease or condition, providing improvement in one or more symptoms). Improvements in any conditions can be readily assessed according to standard methods and techniques known in the art.
  • the population of subjects treated by the method of the disease includes subjects suffering from the undesirable condition or disease, as well as subjects at risk for development of the condition or disease.
  • the term “effective amount” means a dose that produces the desired effect for which it is administered. The exact dose will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques. See Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999).
  • lasofoxifene a pharmaceutically acceptable salt thereof, a prodrug, or functional derivative thereof, is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration.
  • lasofoxifene is administered to the patient by oral administration. In certain embodiments, lasofoxifene is administered at about 5 mg/day per os to about 10 mg/day per os, for example, in some embodiments, lasofoxifene is administered at about 5 mg/day per os. In some embodiments, lasofoxifene is administered at about 6 mg/day per os. In some embodiments, lasofoxifene is administered at about 7 mg/day per os. In some embodiments, lasofoxifene is administered at about 8 mg/day per os. In some embodiments, lasofoxifene is administered at about 9 mg/day per os.
  • lasofoxifene is administered at about 10 mg/day per os.
  • lasofoxifene is administered to the patient by oral administration (per os) at a dosage of about 0.5 mg/day per os to about 10 mg/day per os, such as about 0.5 mg/day per os to about 5 mg/day per os, about 1 mg/day per os to about 5 mg/day per os, about 2 mg/day per os to about 5 mg/day per os, about 3 mg/day per os to about 5 mg/day per os, about 4 mg/day per os to about 5 mg/day per os, about 0.5 mg/day per os to about 4 mg/day per os, about 1 mg/day per os to about 4 mg/day per os, about 2 mg/day per os to about 4 mg/day per os, about 3 mg/day per os to about 4 mg/
  • lasofoxifene is administered at about 0.5 mg/day per os. In some embodiments, lasofoxifene is administered at about 1 mg/day per os. In some embodiments, lasofoxifene is administered at about 1.5 mg/day per os. In some embodiments, lasofoxifene is administered at about 2 mg/day per os. In some embodiments, lasofoxifene is administered at about 2.5 mg/day per os. In some embodiments, lasofoxifene is administered at about 3 mg/day per os. In some embodiments, lasofoxifene is administered at about 3.5 mg/day per os.
  • lasofoxifene is administered at about 4 mg/day per os. In some embodiments, lasofoxifene is administered at about 4.5 mg/day per os. In some embodiments, lasofoxifene is administered at about 5 mg/day per os. In some embodiments, lasofoxifene is administered at about 6 mg/day per os. In some embodiments, lasofoxifene is administered at about 7 mg/day per os. In some embodiments, lasofoxifene is administered at about 8 mg/day per os. In some embodiments, lasofoxifene is administered at about 9 mg/day per os.
  • lasofoxifene is administered at about 10 mg/day per os. In some other embodiments, lasofoxifene is administered at more than 10 mg/day per os. In some embodiments, lasofoxifene is administered at about 0.5 mg/day to about 10 mg/day.
  • lasofoxifene is administered at about 0.5 mg/day, about 1 mg/day, about 1.5 mg/day, about 2 mg/day, about 2.5 mg/day, about 3 mg/day, about 3.5 mg/day, about 4 mg/day, about 5 mg/day, about 5.5 mg/day, about 6 mg/day, about 6.5 mg/day, about 7 mg/day, about 7.5 mg/day, about 8 mg/day, about 8.5 mg/day, about 9 mg/day, about 9.5 mg/day, or about 10 mg/day. In some embodiments, lasofoxifene is administered orally at about 5 mg/day.
  • lasofoxifene is administered once every day. In certain embodiments, lasofoxifene is administered once every two days. In certain embodiments, lasofoxifene is administered once every three days. In certain embodiments, lasofoxifene is administered once every four days. In certain embodiments, lasofoxifene is administered once every five days. In certain embodiments, lasofoxifene is administered once every six days. In certain embodiments, lasofoxifene is administered once every week. In certain embodiments, lasofoxifene is administered once every two weeks. In certain embodiments, lasofoxifene is administered once every three weeks. In certain embodiments, lasofoxifene is administered once every month.
  • lasofoxifene is administered to the patient by vaginal ring administration. In some of these embodiments, lasofoxifene is administered once every two weeks. In some of these embodiments, lasofoxifene is administered once every three weeks. In some of these embodiments, lasofoxifene is administered once every month. In some of these embodiments, lasofoxifene is administered once every two months. In some of these embodiments, lasofoxifene is administered once every three months. In some of these embodiments, lasofoxifene is administered once every four months.
  • lasofoxifene is administered to the ER + breast cancer patient until the patient's cancer progresses on therapy, is in full remission or until the side effects are intolerable.
  • lasofoxifene, a pharmaceutically acceptable salt thereof, a prodrug, or functional derivative thereof is administered either alone or in combination with other therapies.
  • lasofoxifene is administered in combination with at least one other therapy.
  • lasofoxifene and other therapies are administered together (simultaneously).
  • lasofoxifene and other therapies are administered at different times (sequentially).
  • the additional therapy that the patient is treated with is endocrine therapy.
  • the patient is treated with at least one line of additional endocrine therapy.
  • the patient is treated with one line of additional endocrine therapy.
  • the patient is treated with multiple lines of additional endocrine therapy.
  • the patient's cancer has relapsed or progressed after the previous therapy.
  • the patient is treated with the additional endocrine therapy at the original doses. In some other embodiments, the patient is treated with the additional endocrine therapy at doses higher than original doses. In certain embodiments, the patient is treated with the additional endocrine therapy at doses lower than original doses.
  • the additional endocrine therapy is treatment with a selective ER modulator (SERM) other than lasofoxifene.
  • SERM selective ER modulator
  • the selective ER modulator is selected from tamoxifen, raloxifene, apeledoxifene, toremifene, and ospermifene, broparestrol, ormeloxifene, OP-1074, and GDC-0945.
  • the selective ER modulator is tamoxifen.
  • the additional endocrine therapy is treatment with a selective ER degrader (SERD).
  • SESD selective ER degrader
  • the selective ER degrader binds to the estrogen receptor and leads to the proteasomal degradation of the receptor.
  • the selective ER degrader is selected from fulvestrant, RAD1901 (elacestrant), ARN-810 (GDC-0810), giredestrant (GDC-9545), amcenestrant (SAR439859), rintodestrant (G1T48), LSZ102, LY3484356, zN-c5, D-0502, SHR9549, camizestrant (AZD9833), and AZD9496.
  • the endocrine therapy is fulvestrant.
  • the additional endocrine therapy is treatment with an aromatase inhibitor (AI).
  • AI aromatase inhibitor
  • the aromatase inhibitor is selected from exemestane (Aromasin®), letrozole (Femara®), and anastrozole (Arimidex®).
  • the endocrine therapy is ovarian suppression.
  • the ovarian suppression is achieved by oophorectomy or treatment with a GnRH antagonist.
  • the ovarian suppression is achieved by treatment with goserelin (Zeladex®) or leuprolide (Lupron®).
  • the additional therapy is administration to the patient of an effective amount of a cell cycle inhibitor. In certain embodiments, the additional therapy is administration of an effective amount of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. In some embodiments, the additional therapy is a CDK4/6 inhibitor selected from the group of palbociclib, abemaciclib, and ribociclib.
  • the additional therapy is administration to the patient of an effective amount of a cell cycle inhibitor. In certain embodiments, the additional therapy is administration of an effective amount of AKT kinase inhibitor. In some embodiments, the additional therapy is a AKT inhibitor selected from the group of afuresertib, capivasertib and ipatasertib.
  • the additional therapy is administration to the patient of an inhibitor of a pathway that cross-talks with and activates the ER transcriptional activity.
  • the additional therapy is a mammalian target of rapamycin (mTOR) inhibitor.
  • the mTOR inhibitor is Everolimus.
  • lasofoxifene in combination with Everolimus is administered to a postmenopausal woman with locally advanced or metastatic cancer who has progressed on a non-steroidal A1 and/or fulvestrant either as monotherapy or in combination with a CDK4/6 inhibitor.
  • the additional therapy is a phosphoinositide 3-kinase (PI3K) inhibitor or a heat shock protein 90 (HSP90) inhibitor.
  • PI3K phosphoinositide 3-kinase
  • HSP90 heat shock protein 90
  • the additional therapy is administration to the patient of an effective amount of a growth factor inhibitor.
  • the additional therapy is a human epidermal growth factor receptor 2 (HER2) inhibitor.
  • the HER2 inhibitor is trastuzumab (Herceptin®).
  • the HER2 inhibitor is ado-trastuzumab emtansine (Kadcyla®).
  • the additional therapy is administering to the patient an effective amount of a histone deacetylase (HDAC) inhibitor.
  • HDAC histone deacetylase
  • the HDAC inhibitor is vorinostat (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (Farydak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), kevetrin, CUDC-101, AR-42, tefinostat (CHR-2835), CHR-3996,
  • the HDAC inhibitor is entinostat (MS-275) with the proviso that the patient is not treated with a HER2 inhibitor.
  • the HDAC inhibitor is vorinostat (Zolinza®).
  • the HDAC inhibitor is romidepsin (Istodax®).
  • the additional therapy is administering to the patient an effective amount of a checkpoint inhibitor.
  • the checkpoint inhibitor is an antibody.
  • the checkpoint inhibitor is an antibody specific for programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
  • PD-1 programmed cell death protein 1
  • PD-L1 programmed death-ligand 1
  • CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • the PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®).
  • the CTLA-4 antibody is ipilimumab (Yervoy®).
  • the additional therapy is administering to the patient an effective amount of cancer vaccine.
  • the additional therapy is administering to the patient an effective amount of denosumab.
  • the additional therapy is administering to the patient an effective amount of a serotonin-norepinephrine reuptake inhibitor (SNRI), a selective serotonin reuptake inhibitor (SSRI), or gabapentin.
  • SNRI serotonin-norepinephrine reuptake inhibitor
  • SSRI selective serotonin reuptake inhibitor
  • gabapentin gabapentin.
  • the SNRI is venlafaxine (Effexor®).
  • the additional therapies described in the preceding paragraphs can be used in combination.
  • Lasofoxifene, a pharmaceutically acceptable salt thereof, a prodrug, or functional derivative thereof can be administered in combination with two therapies, for example an endocrine therapy such as aromatase inhibitor (e.g. letrizole) and a cell cycle inhibitor such as a CDK4/6 inhibitor (e.g. palbociclib, abemaciclib, and ribociclib).
  • an endocrine therapy such as aromatase inhibitor (e.g. letrizole)
  • a cell cycle inhibitor such as a CDK4/6 inhibitor (e.g. palbociclib, abemaciclib, and ribociclib).
  • the method comprises administering an amount of lasofoxifene, a pharmaceutically acceptable salt thereof, a prodrug, or functional derivative thereof, effective to increase the disease-free survival of the ER + cancer patient. In some embodiments, the method comprises administering lasofoxifene in an amount effective to reduce recurrence of ER + cancer. In some embodiments, the method comprises administering lasofoxifene in an amount effective to increase time to recurrence of ER + cancer. In some embodiments, the method comprises administering lasofoxifene in an amount effective to reduce metastasis of ER + cancer. In some embodiments, the method comprises administering lasofoxifene in an amount effective to increase duration of progression-free survival of the ER + cancer patient.
  • the method increases the disease-free survival of the ER + cancer patient. In certain embodiments, the method reduces recurrence of ER + cancer. In certain embodiments, the method increases time to recurrence of ER + cancer. In certain embodiments, the method reduces metastasis of ER + cancer to bone. In certain embodiments, the method reduces metastasis of ER + cancer to tissues other than bone. In certain embodiments, the method reduces metastasis of ER + cancer to the brain. In certain embodiments, the method reduces metastasis of ER + cancer to the lung. In certain embodiments, the method reduces metastasis of ER + cancer to the liver. In certain embodiments, the method increases duration of progression-free survival of the ER + cancer patient. The methods may comprise administering lasofoxifene in combination with one or more additional therapeutic agents, as described herein.
  • the method increases the disease-free survival in ER + cancer patient with AI resistance. In some embodiments, the method reduces recurrence of cancer in patient with AI resistance. In some embodiments, the method increases time to recurrence of cancer in patient with AI resistance. In some embodiments, the method reduces metastasis of cancer in patient with AI resistance. In some embodiments, the method increases duration of progression-free survival in ER + cancer patient with AI resistance.
  • the method increases disease-free survival, reduces recurrence, increases time to recurrence, reduces metastasis, and/or increases duration of progression-free survival in patients with ER + locally advanced or metastatic cancer that has developed A1 resistance.
  • the cancer has developed AI resistance by acquiring one or more mutations other than a gain of function mutation in LBD of the ESR1 discussed herein.
  • the method reduces the selective pressure and prevents the expansion of the AI resistant clones in ER + locally advanced or metastatic cancer during treatment.
  • the method is effective to prevent fracture and bone loss in women who are concurrently being treated with one or more drugs causing or predisposing to osteoporosis.
  • the method is effective to decrease vaginal pH, increase vaginal lubrication, and/or improve vaginal cell maturation index in women who are concurrently being treated with one or more drugs causing or predisposing to vulvovaginal atrophy (VVA).
  • VVA vulvovaginal atrophy
  • the method reduces one or more symptoms of sexual dysfunction in women who are concurrently being treated with one or more drugs causing or predisposing to sexual dysfunction.
  • the method treats hot flashes in women who are concurrently being treated with one or more drugs causing or predisposing to hot flashes.
  • the method increases one or more quality of life measures selected from joint ache, urogenital symptoms, bone loss, and bone fractures.
  • A1a Lasofoxifene or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, for use in a method of reducing the progression of estrogen receptor positive (ER + ) cancer in a patient who has progressed on an aromatase inhibitor, wherein the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene, the method comprising: administering to the patient an effective amount of lasofoxifene or a pharmaceutically acceptable salt, prodrug or functional derivative thereof.
  • LBD ligand binding domain
  • ESR1 Estrogen Receptor 1
  • A1b Lasofoxifene or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, for use in a method of reducing metastasis of ER + cancer in a patient who has progressed on an aromatase inhibitor, wherein the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene, optionally wherein the method reduces metastasis of ER + cancer to bone or to the brain, preferably wherein the method reduces metastasis of ER + cancer to the brain.
  • LBD ligand binding domain
  • ESR1 Estrogen Receptor 1
  • a combination comprising Lasofoxifene or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, and a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for separate, simultaneous or sequential use in a method of reducing the progression of estrogen receptor positive (ER + ) cancer in a patient who has progressed on an aromatase inhibitor, wherein the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene, optionally wherein the combination further comprises an aromatase inhibitor such as letrozole.
  • CDK4/6 cyclin-dependent kinase 4/6
  • a combination comprising Lasofoxifene or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, and a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for separate, simultaneous or sequential use in a method of reducing metastasis of ER + cancer in a patient who has progressed on an aromatase inhibitor, wherein the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene, optionally wherein the combination further comprises an aromatase inhibitor such as letrozole.
  • CDK4/6 cyclin-dependent kinase 4/6
  • Lasofoxifene or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, for use according to any one of embodiments Ala to Ale, wherein the ER + cancer is locally advanced or metastatic breast cancer, optionally wherein the cancer is HER2 ⁇ .
  • Lasofoxifene or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, for use according to any previous embodiment, wherein the aromatase inhibitor is exemestane, letrozole, or anastrozole.
  • Lasofoxifene or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, for use according to any previous embodiment, wherein the method comprises:
  • Lasofoxifene or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, for use according to any previous embodiment, wherein lasofoxifene is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration.
  • Lasofoxifene or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, for use according to any previous embodiment, wherein lasofoxifene is administered by oral administration.
  • Lasofoxifene or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, for use according to any previous embodiment, wherein the cancer has a mutation in a gene listed in Table 1.
  • Lasofoxifene or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, for use according to any previous embodiment, wherein the method further comprises treating said patient with at least one additional endocrine therapy.
  • Lasofoxifene or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, for use according to any previous embodiment, wherein the method further comprises administering to said patient an effective amount of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, optionally wherein the CDK4/6 inhibitor is administered orally, e.g. in a dose of 70 mg/kg.
  • CDK4/6 cyclin-dependent kinase 4/6
  • Lasofoxifene, or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, and a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for simultaneous, separate or sequential use in a method of reducing the progression of estrogen receptor positive (ER + ) cancer in a patient who has progressed on an aromatase inhibitor, wherein the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene.
  • LBD ligand binding domain
  • ESR1 Estrogen Receptor 1
  • Embodiment A11 or A12 wherein said CDK4/6 inhibitor is palbociclib, abemaciclib, or ribociclib, optionally wherein the CDK4/6 inhibitor is palbociclib, preferably wherein the CDK4/6 inhibitor is abemaciclib.
  • Lasofoxifene or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, for use according to any one of embodiments A1-A10, wherein the method further comprises administering to said patient an effective amount of an AKT inhibitor.
  • A15 Lasofoxifene, or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, and an AKT inhibitor for simultaneous, separate or sequential use in a method of reducing the progression of estrogen receptor positive (ER + ) cancer in a patient who has progressed on an aromatase inhibitor, wherein the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene.
  • LBD ligand binding domain
  • ESR1 Estrogen Receptor 1
  • Lasofoxifene or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, for use according to any one of embodiments A1-A10, further comprising administering to said patient an effect amount of an mTor inhibitor.
  • Lasofoxifene, or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof, and an mTor inhibitor for simultaneous, separate or sequential use in a method of reducing the progression of estrogen receptor positive (ER + ) cancer in a patient who has progressed on an aromatase inhibitor, wherein the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene.
  • LBD ligand binding domain
  • ESR1 Estrogen Receptor 1
  • Postmenopausal patients with estrogen receptor positive (ER ⁇ + ) primary invasive breast cancer are typically treated with aromatase inhibitors (AIs) as first line adjuvant therapy.
  • AIs aromatase inhibitors
  • Patients who become resistant to AIs are treated with fulvestrant and/or CDK4/6 inhibitors, such as palbociclib, as second line therapy.
  • Lasofoxifene a selective estrogen receptor modulator (SERM) was developed for the treatment of vaginal atrophy and osteoporosis.
  • Luciferase-GFP tagged LTLT cells were injected into the mammary ducts of NSG mice (MIND model) and tumor progression was monitored by live luminescence imaging of primary tumors, as well as ex vivo imaging and histochemical analysis of metastatic sites at study endpoint. Primary tumor area was also measured at study endpoint. Lasofoxifene alone and in combination with palbociclib was significantly more effective than fulvestrant, both alone and in combination with palbociclib, in terms of inhibiting primary tumor growth. In addition, all treatments except fulvestrant alone inhibited bone metastasis versus vehicle. These data show that lasofoxifene is more effective than fulvestrant in this tumor model and demonstrate that lasofoxifene is an effective therapy for AI-resistant breast cancers that do not express ER ⁇ activating mutations.
  • MCF 7 LTLT cells also known as LTLT-Ca cells (Sabnis, G., et al. Cancer Res. 69, 1416-1428 (2009)), are derivatives of the hormone receptor positive (ER + , PR + , GR + ) human breast cancer cell line, MCF7 which bears WT and mutant ER ⁇ .
  • MCF 7 LTLT cells have an acquired resistance to aromatase inhibitors. They were originally derived in the Brodie lab by long term treatment of MCF7aro cells with the aromatase inhibitor, letrozole (Sabnis et al., 2009). MCF-7aro cells are stably transfected with the aromatase gene (Sun, X. Z., et al.
  • MCF7 LTLT cells were a kind gift of Ganesh Raj from UT Southwestern. MCF7aro cells were kindly provided by Shiuan Chen at City of Hope.
  • L2G lentivirus vector pFU-Luc2-eGFP
  • a ubiquitin promotor Liu, H., et al. Proc. Natl Acad. Sci.
  • the MCF 7 LTLT cells (LT-LT cells in FIG. 1 ) were determined to lack ESR1 mutations, and to have 18,687 novel variants, among which were 1508 exonic, nonsynonymous, variants. Notable genes having variants (63 genes, 85 variants) are listed in Table 1.
  • MCF7aro and MCF 7 LTLT cell lines To characterize the MCF7aro and MCF 7 LTLT cell lines, we performed western blots and probed for ER ⁇ , progesterone receptor (PR), androgen receptor (AR) and glucocorticoid receptor (GR).
  • PR progesterone receptor
  • AR androgen receptor
  • GR glucocorticoid receptor
  • FIGS. 9 A- 9 D show the relative protein levels of ER ⁇ and GR protein in MCF7aro and MCF7 LTLT cells, compared to ER ⁇ in normal MCF7 and T47D cells.
  • the expression of actin was used as an internal control for each cell line.
  • MCF7 LTLT cells express less ER ⁇ protein than normal MCF7 cells and also less than T47D cells ( FIG. 9 A ), also shown by the ratio of ER to actin expression ( FIG. 9 B ).
  • GR protein levels are lower in MCF7 LTLT and MCF7aro cells, but similar to T47D cells ( FIGS. 9 C- 9 D ). In both assays, the expression of actin is consistent across cell lines ( FIGS. 9 A and 9 C ).
  • FIGS. 10 A- 10 B show that AR levels are lower in MCF7aro and MCF7 LTLT compared to MCF7 and T47D.
  • FIG. 10 C and FIG. 10 D show the presence of HER2, which has previously been reported to be upregulated in the MCF7 LTLT cell line. PR was not detected in any of the MCF7, MCF7aro, or MCF7 LTLT cells ( FIG. 10 E ).
  • cells were plated at 2500-3000 cells/well in a 96 well plate either in RPMI or CS RPMI (SRPMI) and treated with various concentrations of letrozole, from 0.1 nM up to 10 ⁇ M.
  • SRPMI CS RPMI
  • cells were cultured in CS serum for 48 hours prior to treatment.
  • Treatments with estradiol and SERMs (lasofoxifene) were performed in SRPMI.
  • 96 well plates were scanned every 6 hours in an IncuCyte S3 (Essen Bioscience) for up to 1 week. Analyses was performed by counting GFP tagged nuclei via the IncuCyte software.
  • mice were purchased from The Jackson Laboratories. Prior to injection, mice were anesthetized via inhalation with 2-3% isoflurane in oxygen. Injections of single-cell suspensions of 250,000 MCF7 cells in the mammary ducts of inguinal glands 4 and 9 were performed as described (Behbod, F., et al. Breast Cancer Res. 11, R66 (2009); Sflomos, G., et al. Cancer Cell 29, 407-422 (2016); Laine, M., et al. Breast Cancer Res. 23, 54 (2021)).
  • mice were injected with 100 ⁇ l of a 0.1 M luciferin solution in PBS (Perkin Elmer XenoLight #122799).
  • mice were separated into 2 equal groups; one group received 10 ⁇ g/day of letrozole in 15% PEG400 in PBS via subcutaneous injection, “LTLT-Let”; the other group wasn't administered letrozole (“LTLT”).
  • LTLT letrozole
  • mice in each group were randomized and treated 5 days/week with lasofoxifene (10 mg/kg, in 100 ⁇ l of PBS containing 15% PEG400), palbociclib (70 mg/kg, Med Chem Express #HY-50567, in 50 mM sodium lactate buffer pH4), or vehicle. Lasofoxifene and vehicle were administered subcutaneously.
  • Palbociclib was administered via oral gavage 5 times/week.
  • Fulvestrant (Med Chem Express #HY-13636) (“ICI”) (5 mg/mouse) was administered once per week via subcutaneous injection in 100 ⁇ l of mineral oil. Mice were also treated with combinations of lasofoxifene+palbociclib, fulvestrant+palbociclib, lasofoxifene+letrozole and palbociclib or fulvestrant+palbociclib, or letrozole.
  • mice were sacrificed, and mammary gland tumors were excised and weighed. Liver, bone brain and lungs were removed and imaged ex vivo in the IVIS 200, following an in vivo injection of luciferin 8 min prior to sacrifice, to measure luciferase activity.
  • H&E and IHC slides were scanned on a Nikon eclipse Ti2 microscope with a 10 ⁇ objective for high resolution images. Ki67 score was determined using standardized manual counting.
  • MCF7 LTLT cells labeled with GFP luciferase were injected into the mammary ducts of NSG mice to establish tumors that represent an AI resistant, non-ESR1-mutated, breast cancer model.
  • Treatment with lasofoxifene, palbociclib and combinations of lasofoxifene and palbociclib were carried out in the presence (Let + ) or absence (Let ⁇ ) of letrozole, to account for the potential loss of letrozole resistance (“reversion”) in the Let cohort.
  • Mice were imaged every other week in a Xenogen IVIS scanner to estimate tumor growth. At the end of the study, mammary glands were removed and weighed.
  • ICI fulvestrant
  • fulvestrant appeared to increase tumor photon flux in the presence of letrozole (data not shown) rather than inhibiting it as expected. This result is currently an unexplained anomaly.
  • FIG. 5 shows tumor area as a percentage (%) of total tissue in the mammary gland, based on H&E staining of a representative section, in the Let ⁇ cohorts. H&E slides were scanned on a Nikon microscope and analyzed with the NSI element software. H&E staining shows that the % tumor area in the Let ⁇ cohort is significantly lower for lasofoxifene alone, compared to vehicle, and that lasofoxifene+palbociclib is significantly lower than vehicle. Palbociclib+fulvestrant (ICI) is also significantly lower than vehicle in the Let ⁇ cohort. Although lasofoxifene+palbociclib appears to be lower than fulvestrant (ICI)+palbociclib, this difference does not reach statistical significance.
  • ICI fulvestrant
  • lasofoxifene or lasofoxifene+palbociclib combination is effective in inhibiting primary tumor growth in cancer cells that have developed resistance to letrozole, a commonly prescribed aromatase inhibitor (AI) to treat ER+ breast cancer, through mechanisms other than acquisition of gain-of-function mutations in the ligand binding domain of the ER ⁇ receptor (encoded by the ESR1 gene).
  • AI aromatase inhibitor
  • Immunohistochemistry with anti-Ki67 antibody was performed on fixed mammary glands to determine the proliferation index for MCF7 LTLT primary tumors.
  • FIGS. 7 A- 7 C and FIG. 8 A show box plots of the average radiance for liver ( FIG. 7 A ), lung (FIG. 7 B 3 ), brain ( FIG. 7 C ) and bone ( FIG. 8 A ) in Let ⁇ treatment group. Data for Let + group were evaluated but are not shown. The average radiance for all organs is low, indicating that minimal metastasis was observed. No statistically significant pattern for liver, lung and brain was observed, although the lasofoxifene+palbociclib signal is visually lower in brain than any other treatment versus vehicle for both Let ⁇ and Let + cohorts.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US17/989,382 2021-11-18 2022-11-17 Lasofoxifene treatment of aromatase-resistant er+ cancer Abandoned US20230149350A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US17/989,382 US20230149350A1 (en) 2021-11-18 2022-11-17 Lasofoxifene treatment of aromatase-resistant er+ cancer
US18/325,883 US12023321B2 (en) 2021-11-18 2023-05-30 Lasofoxifene treatment of aromatase-resistant ER+cancer
US18/764,277 US12433866B2 (en) 2021-11-18 2024-07-04 Lasofoxifene treatment of aromatase-resistant ER+ cancer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163280769P 2021-11-18 2021-11-18
US17/989,382 US20230149350A1 (en) 2021-11-18 2022-11-17 Lasofoxifene treatment of aromatase-resistant er+ cancer

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US18/325,883 Continuation US12023321B2 (en) 2021-11-18 2023-05-30 Lasofoxifene treatment of aromatase-resistant ER+cancer

Publications (1)

Publication Number Publication Date
US20230149350A1 true US20230149350A1 (en) 2023-05-18

Family

ID=79163840

Family Applications (3)

Application Number Title Priority Date Filing Date
US17/989,382 Abandoned US20230149350A1 (en) 2021-11-18 2022-11-17 Lasofoxifene treatment of aromatase-resistant er+ cancer
US18/325,883 Active US12023321B2 (en) 2021-11-18 2023-05-30 Lasofoxifene treatment of aromatase-resistant ER+cancer
US18/764,277 Active US12433866B2 (en) 2021-11-18 2024-07-04 Lasofoxifene treatment of aromatase-resistant ER+ cancer

Family Applications After (2)

Application Number Title Priority Date Filing Date
US18/325,883 Active US12023321B2 (en) 2021-11-18 2023-05-30 Lasofoxifene treatment of aromatase-resistant ER+cancer
US18/764,277 Active US12433866B2 (en) 2021-11-18 2024-07-04 Lasofoxifene treatment of aromatase-resistant ER+ cancer

Country Status (12)

Country Link
US (3) US20230149350A1 (enExample)
EP (1) EP4433048A1 (enExample)
JP (1) JP2024538402A (enExample)
KR (1) KR20240132447A (enExample)
CN (1) CN118574612A (enExample)
AU (2) AU2022389457B2 (enExample)
CA (1) CA3238899A1 (enExample)
GB (1) GB202116903D0 (enExample)
IL (1) IL312895A (enExample)
MX (1) MX2024005959A (enExample)
TW (1) TW202333666A (enExample)
WO (1) WO2023091553A1 (enExample)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12023321B2 (en) 2021-11-18 2024-07-02 Sermonix Pharmaceuticals, Inc. Lasofoxifene treatment of aromatase-resistant ER+cancer
WO2025043004A1 (en) * 2023-08-21 2025-02-27 Duke University Treatment of solid cancer with lasofoxifene
WO2025075631A1 (en) * 2023-10-06 2025-04-10 Sermonix Pharmaceuticals, Inc. Lasofoxifene treatment of endocrine therapy resistant er+ cancer
US12414924B2 (en) 2016-10-11 2025-09-16 Duke University Lasofoxifene treatment of breast cancer

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025165887A1 (en) * 2024-01-30 2025-08-07 Sermonix Pharmaceuticals, Inc. Lasofoxifene treatment of er+ cancers with constitutively active esr1 mutations

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010088331A1 (en) * 2009-01-30 2010-08-05 Glaxosmithkline Llc Crystalline n-{(1-s)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1h-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride
WO2019119891A1 (zh) * 2017-12-21 2019-06-27 惠科股份有限公司 显示装置及其背光模组

Family Cites Families (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6060503A (en) 1991-12-02 2000-05-09 Endorecherche, Inc. Benzopyran-containing compounds and method for their use
US5552412A (en) 1995-01-09 1996-09-03 Pfizer Inc 5-substitued-6-cyclic-5,6,7,8-tetrahydronaphthalen2-ol compounds which are useful for treating osteoporosis
UA51676C2 (uk) 1995-11-02 2002-12-16 Пфайзер Інк. (-)цис-6(s)-феніл-5(r)[4-(2-піролідин-1-ілетокси)феніл]-5,6,7,8-тетрагідронафталін-2-ол d-тартрат, спосіб його одержання, спосіб лікування захворювань, що піддаються лікуванню агоністами естрогену, та фармацевтична композиція
IL120266A (en) 1996-02-28 2005-05-17 Pfizer Use of estrogen antagonists and estrogen agonists in the preparation of medicaments for inhibiting pathological conditions
HN1996000101A (es) 1996-02-28 1997-06-26 Inc Pfizer Terapia combinada para la osteoporosis
US20040044080A1 (en) 1997-10-28 2004-03-04 Place Virgil A. Treatment of dyspareunia with topically administered nitroglycerin formulations
YU26700A (sh) 1999-05-24 2002-06-19 Pfizer Products Inc. Postupak za cis-1-(2-(4-(6-metoksi-2-fenil-1,2,3,4- tetrahidronaftalen-1-il)fenoksi)etil)pirolidin
EP1086692A3 (en) 1999-07-28 2003-07-09 Pfizer Products Inc. Estrogen agonists and antagonists for multiple indications
US6436977B1 (en) 1999-09-29 2002-08-20 Pfizer Inc. Dosing regimens for lasofoxifene
CO5271697A1 (es) 2000-01-12 2003-04-30 Pfizer Prod Inc Composiciones y procedimientos para el tratamiento de afecciones que responden a un aumento de testosterona
BR0108107A (pt) 2000-01-28 2003-03-11 Endorech Inc Moduladores seletivos dos receptores de estrogênio em combinação com estrogênios; kits e composições farmacêuticas para praticar tal combinação; bem como a administração da referida combinação
DE10039199A1 (de) 2000-08-10 2002-02-21 Schering Ag Kombinationspräparate aus einem ERß selektiven Estrogen und einem SERM oder Antiestrogen
JP2004507465A (ja) 2000-08-11 2004-03-11 ワイス エストロゲン受容体陽性癌腫の治療方法
WO2002056903A2 (en) 2001-01-17 2002-07-25 Praecis Pharmaceuticals Inc. Methods for treating hormone associated conditions using a combination of lhrh antagonists and specific estrogen receptor modulators
AU781168B2 (en) 2001-01-26 2005-05-12 Pfizer Products Inc. Method of treating certain cancers using an estrogen agonist/antagonist
RU2278861C2 (ru) 2002-03-28 2006-06-27 Пфайзер Продактс Инк. Очищенный лазофоксифен и способ очистки рацемического лазофоксифена рекристаллизацией
PA8576201A1 (es) 2002-07-10 2004-05-26 Pfizer Prod Inc Composicion farmaceutica que tiene una distribucion y potencia uniforme de farmaco
US8835413B2 (en) 2004-10-20 2014-09-16 Endorecherche, Inc. Sex steroid precursors alone or in combination with a selective estrogen receptor modulator and/or with estrogens and/or a type 5 cGMP phosphodiesterase inhibitor for the prevention and treatment of vaginal dryness and sexual dysfunction in postmenopausal women
US20090012052A1 (en) 2006-11-09 2009-01-08 Ore Pharmaceuticals Inc. Method for treating er+ breast cancer
US20110015134A1 (en) 2007-04-16 2011-01-20 Retsky Michael W Method of treatment for early stage cancer
CZ2007373A3 (cs) 2007-05-29 2008-12-10 Zentiva, A. S Zpusob prípravy lasofoxifenu
CA2725390C (en) 2008-04-08 2014-09-23 Syndax Pharmaceuticals, Inc. Use of a hdac inhibitor and a her-2 inhibitor in the treatment of breast cancer
WO2009137543A2 (en) 2008-05-06 2009-11-12 Ore Pharmaceuticals Inc. Methods for breast cancer screening and treatment
EP2239570A1 (en) 2009-04-10 2010-10-13 PamGene B.V. Method for determining the estrogen receptor status of breast cancer
MX373926B (es) 2009-05-27 2020-07-10 Ptc Therapeutics Inc Metodos para tratar cancer y estados no neoplasicos.
US20130253035A1 (en) 2010-08-16 2013-09-26 Duke University Camkk-beta as a target for treating cancer
US20120052508A1 (en) 2010-08-27 2012-03-01 Rutgers, The State University Of New Jersey Genetic markers and diagnostic methods for resistance of breast cancer to hormonal therapies
US20140134170A1 (en) 2011-03-11 2014-05-15 Merrimack Pharmaceuticals, Inc. Use of inhibitors of egfr-family receptors in the treatment of hormone refractory breast cancers
AU2012255920A1 (en) 2011-05-18 2013-11-07 Merck Sharp & Dohme Corp. Therapeutic anti-IGF1R combinations
WO2013056178A2 (en) 2011-10-14 2013-04-18 Foundation Medicine, Inc. Novel estrogen receptor mutations and uses thereof
EP2791128A4 (en) 2011-12-16 2015-04-22 Olema Pharmaceuticals Inc NOVEL BENZOPYRAN COMPOUNDS, COMPOSITIONS AND USES THEREOF
US20160038506A1 (en) 2012-02-14 2016-02-11 Repros Therapeutics Inc. Selective Estrogen Receptor Modulators With Short Half-Lives and Uses Thereof
US9969683B2 (en) 2012-07-13 2018-05-15 Gtx, Inc. Method of treating estrogen receptor (ER)-positive breast cancers with selective androgen receptor modulator (SARMS)
US20160030389A1 (en) 2013-03-13 2016-02-04 Alevere Medical Corporation Use of indole compounds for fat reduction and skin and soft tissue tightening
US9204286B1 (en) 2013-03-15 2015-12-01 Sprint Communications Company L.P. System and method of branding and labeling a mobile device
WO2015136016A2 (en) 2014-03-13 2015-09-17 F. Hoffmann-La Roche Ag Therapeutic combinations with estrogen receptor modulators
SG11201607339VA (en) 2014-03-13 2016-10-28 Hoffmann La Roche Methods and compositions for modulating estrogen receptor mutants
US9421264B2 (en) 2014-03-28 2016-08-23 Duke University Method of treating cancer using selective estrogen receptor modulators
ES3055185T3 (en) 2014-03-28 2026-02-10 Univ Duke Treatment of an estrogen receptor positive breast cancer using a selective estrogen receptor modulator
CN113101292B (zh) 2014-05-08 2023-07-11 上海市生物医药技术研究院 双炔失碳酯组合物和疾病治疗方法
KR20170078811A (ko) 2014-11-07 2017-07-07 리폭센 테크놀로지즈 리미티드 원발성 호르몬 저항성 자궁내막암 및 유방암 치료 방법
AU2016247674A1 (en) 2015-04-14 2017-10-19 Atossa Genetics Inc. Compositions and methods of treatment of breast disorders and estrogen-related disorders
KR20250152679A (ko) 2015-04-29 2025-10-23 래디어스 파마슈티컬스, 인코포레이티드 암을 치료하는 방법
ES2909576T3 (es) 2016-10-11 2022-05-09 Univ Duke Tratamiento con lasofoxifeno del cáncer de mama ER+
WO2018071437A1 (en) 2016-10-11 2018-04-19 Sermonix Pharmaceuticals, Llc Lasofoxifene treatment of vva and osteoporosis in survivors of breast cancer and other malignancies
CN115737637A (zh) 2017-01-10 2023-03-07 王巍 拉索昔芬调节膜结合雌激素信号的应用及治疗癌症的方法
US11497730B2 (en) 2018-04-10 2022-11-15 Duke University Lasofoxifene treatment of breast cancer
JP7571006B2 (ja) 2018-08-17 2024-10-22 ジェネンテック， インコーポレイテッド 乳がんの処置のための診断的および治療的方法
EP4412649A4 (en) 2021-10-05 2025-11-05 Univ Duke Compositions containing small molecule tumor immunity regulators and their methods of use
GB202116903D0 (en) 2021-11-18 2022-01-05 Sermonix Pharmaceuticals Inc Lasofoxifene treatment of aromatase-resistant er+ cancer
JP2025517483A (ja) 2022-05-25 2025-06-05 サーモニックス ファーマシューティカルズ， インコーポレイテッド Ｃｄｋ４／６阻害剤で進行したｅｒ＋乳がんのラソフォキシフェン併用処置

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010088331A1 (en) * 2009-01-30 2010-08-05 Glaxosmithkline Llc Crystalline n-{(1-s)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1h-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride
WO2019119891A1 (zh) * 2017-12-21 2019-06-27 惠科股份有限公司 显示装置及其背光模组

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Smyth (Clinical Cancer Research Vol. 26 pages 3947-3957 published 2020) (Year: 2020) *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12414924B2 (en) 2016-10-11 2025-09-16 Duke University Lasofoxifene treatment of breast cancer
US12023321B2 (en) 2021-11-18 2024-07-02 Sermonix Pharmaceuticals, Inc. Lasofoxifene treatment of aromatase-resistant ER+cancer
US12433866B2 (en) 2021-11-18 2025-10-07 Sermonix Pharmaceuticals, Inc. Lasofoxifene treatment of aromatase-resistant ER+ cancer
WO2025043004A1 (en) * 2023-08-21 2025-02-27 Duke University Treatment of solid cancer with lasofoxifene
WO2025075631A1 (en) * 2023-10-06 2025-04-10 Sermonix Pharmaceuticals, Inc. Lasofoxifene treatment of endocrine therapy resistant er+ cancer

Also Published As

Publication number Publication date
US20230321035A1 (en) 2023-10-12
WO2023091553A1 (en) 2023-05-25
CN118574612A (zh) 2024-08-30
IL312895A (en) 2024-07-01
US12023321B2 (en) 2024-07-02
CA3238899A1 (en) 2023-05-25
US12433866B2 (en) 2025-10-07
JP2024538402A (ja) 2024-10-18
AU2022389457B2 (en) 2024-12-19
AU2022389457A1 (en) 2024-07-04
US20240358677A1 (en) 2024-10-31
MX2024005959A (es) 2024-08-14
TW202333666A (zh) 2023-09-01
GB202116903D0 (en) 2022-01-05
KR20240132447A (ko) 2024-09-03
AU2025201821A1 (en) 2025-04-03
EP4433048A1 (en) 2024-09-25
AU2025201821B2 (en) 2026-03-26

Similar Documents

Publication Publication Date Title
US12433866B2 (en) Lasofoxifene treatment of aromatase-resistant ER+ cancer
US12414924B2 (en) Lasofoxifene treatment of breast cancer
WO2025075631A1 (en) Lasofoxifene treatment of endocrine therapy resistant er+ cancer
HK40077706A (en) Lasofoxifene treatment of er+ breast cancer
WO2025165887A1 (en) Lasofoxifene treatment of er+ cancers with constitutively active esr1 mutations
HK40005311A (en) Lasofoxifene treatment of er+ breast cancer
HK40005311B (en) Lasofoxifene treatment of er+ breast cancer

Legal Events

Date Code Title Description
AS Assignment

Owner name: SERMONIX PHARMACEUTICALS, INC., OHIO

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KOMM, BARRY SAMUEL;GREENE, GEOFFREY L.;REEL/FRAME:062572/0270

Effective date: 20230201

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: EXPRESSLY ABANDONED -- DURING EXAMINATION