WO2016094457A1 - Procédés de traitement de cancer du sein de type basal et pauvre en claudine et traitement combiné de celui-ci - Google Patents

Procédés de traitement de cancer du sein de type basal et pauvre en claudine et traitement combiné de celui-ci Download PDF

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WO2016094457A1
WO2016094457A1 PCT/US2015/064573 US2015064573W WO2016094457A1 WO 2016094457 A1 WO2016094457 A1 WO 2016094457A1 US 2015064573 W US2015064573 W US 2015064573W WO 2016094457 A1 WO2016094457 A1 WO 2016094457A1
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breast cancer
basal
cancer
foxc1
wnt
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Partha S. RAY
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Ray Partha S
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Priority to US15/617,333 priority Critical patent/US10570458B2/en
Priority to US16/798,140 priority patent/US20200325544A1/en

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    • 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
    • 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
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • 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
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57415—Specifically defined cancers of breast
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57496—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving intracellular compounds
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4703—Regulators; Modulating activity
    • G01N2333/4706—Regulators; Modulating activity stimulating, promoting or activating activity

Definitions

  • CSCs Cancer stem cells
  • Figure 1 illustrates the regulation of CSCs.
  • Figure 2 illustrates the parallel between mammary epithelium differentiation and breast cancer subtypes.
  • Figure 3 shows a proposed mechanism of FOXC1 regulation by Wnt/ ⁇ catenin signaling.
  • Figure 4 shows FOXC1 as a downstream mediator of Wnt-driven regulation of CSCs in basal-like breast cancer.
  • Figure 5 shows an analysis of beta-catenin (CTNNB1 ) expression level and survival using a breast cancer transcriptomic database (Curtis et al., 2012).
  • Figure 6 shows the correlation between FOXC1 expression and Wnt activity upon biological and pharmacologic inhibition and stimulation with a natural ligand.
  • Figure 6A shows FOXC1 expression upon biological inhibition with siRNA knockdown of LRP6, a canonical Wnt signaling cell surface receptor.
  • Figure 6B shows the relative FOXC1 mRNA expression with the siRNA knockdown of LRP6.
  • Figure 6C shows decreased FOXC1 expression upon pharmacological inhibition with iCRT-3.
  • Figure 6D shows an increase in FOXC1 expression with addition of Wnt3a, a canonical Wnt signaling ligand.
  • Figure 7 shows the relative survival of representative breast cancer cell lines upon inhibition of Wnt/ ⁇ catenin signaling with increasing doses of the inhibitor iCRT3.
  • Figure 7A shows the relative survival of the MCF-7 (luminal) breast cancer cell line (see line with diamonds); the SKBR3 breast cancer cell line (overexpresses HER2) (see line with triangles); and the BT-549 breast cancer cell line (basal-like) (see line with squares).
  • Figure 7B shows the relative survival of the BT-549 breast cancer cell line (high constitutive FOXC1 expression) (see line with squares); the HS578T breast cancer cell line (high constitutive FOXC1 expression) (see line with Xs); and the MDA- MB-231 breast cancer cell line (low constitutive FOXC1 expression) (see line with circles).
  • Figure 8 shows the relative survival of representative breast cancer cell lines upon proteasome inhibition with increasing doses of the inhibitor bortezomib.
  • Figure 8A shows the relative survival of the MCF-7 (luminal) breast cancer cell line (see line with diamonds); the HS578T breast cancer cell line (basal-like) (see line with squares); and the SKBR3 breast cancer cell line (overexpresses HER2) (see line with triangles).
  • Figure 8B shows the relative survival of the HS578T breast cancer cell line (basal-like) (bottom line); the BT-549 breast cancer cell line (basal-like) (see middle line); and the MDA-MB-231 breast cancer cell line (low constitutive FOXC1 expression) (see top line).
  • Figure 9 shows mammosphere formation upon inhibition of Wnt/ ⁇ catenin signaling by iCRT-3.
  • Figure 9A shows mammosphere formation with addition of DMSO and
  • Figure 9B shows mammosphere formation with the addition of iCRT-3.
  • Figure 10 is a bar graph showing the fold change of mRNA expression of the stem related genes BMI-1 , FOXC1 , KIT, NANOG, OCT4, and SOX2 upon inhibition of Wnt/ ⁇ catenin signaling by addition of iCRT-3 on day 4 (left hand bar) and day 7 (right hand bar).
  • Figure 1 1 shows mammosphere formation upon simultaneous inhibition of Wnt/ ⁇ catenin signaling by addition of iCRT-3 and inhibition of NF- ⁇ signaling.
  • Figure 1 1A shows mammosphere formation with addition of DMSO and
  • Figure 1 1 B shows mammosphere formation with the addition of iCRT-3 and bortezomib.
  • Figure 12 shows the Human FOXC1 Amino Acid Sequence (SEQ ID NO: 1 ).
  • the methods may comprise determining an expression level of FOXC1 in a population of tumor cells obtained from the subject and administering one or more proteasome inhibitors, and optionally, one or more Wnt inhibitors, to the subject to treat the cancer if the population of tumor cells expresses FOXC1 .
  • the proteasome inhibitor may be bortezomib.
  • the one or more Wnt inhibitors may be iCRT3.
  • the cancer may be a basal-like breast cancer. In certain embodiments, the basal-like breast cancer may be triple negative breast cancer.
  • the basal-like breast cancer may be ER positive breast cancer. In certain embodiments, the basal-like breast cancer may be HER2 positive breast cancer. In certain embodiments, the cancer may be claudin-low cancer. In certain embodiments, determining the expression level of FOXC1 in the population of tumor cells may be performed via quantitative RT-PCR (qRT-PCR).
  • combination therapies comprising one or more Wnt inhibitors and one or more proteasome inhibitors.
  • the one or more proteasome inhibitors may be bortezomib.
  • the one or more Wnt inhibitors may be iCRT3.
  • the one or more Wnt inhibitors may be a therapeutically effective amount.
  • the one or more proteasome inhibitors may be a therapeutically effective amount.
  • methods for treating cancer in a subject comprising administering one or more proteasome inhibitors, and optionally, one or more Wnt inhibitors, to the subject to treat the cancer.
  • the one or more proteasome inhibitors may be bortezomib. In certain embodiments, the one or more Wnt inhibitors may be iCRT3. In certain embodiments, the cancer may be a basal-like breast cancer. In certain embodiments, the basal-like breast cancer may be triple negative breast cancer. In certain embodiments, the basal-like breast cancer may be ER positive breast cancer. In certain embodiments, the basal-like breast cancer may be HER2 positive breast cancer. In certain embodiments, the cancer may be claudin- low cancer.
  • the Wnt/ ⁇ catenin signaling pathway is well known as a regulator of embryonic development and stem cell biology, and is prominently active in basal-like and claudin-low breast cancers. It was previously reported that transcription factor FOXC1 plays a role in mediating aggressive cell traits in basal-like/claudin low breast cancer (see Ray et al., 2010). As shown in Example 1 below, FOXC1 is a target of Wnt/ ⁇ catenin signaling and FOXC1 expression predicts response to Wnt inhibition. Further, Wnt mediated regulation of FOXC1 appears to be critical for cancer stem cells (CSCs) in basal-like/claudin low breast cancer.
  • CSCs cancer stem cells
  • Wnt inhibitors as a single agent may not work well in treating basal-like/claudin low breast cancer.
  • treatment cocktails targeting multiple pathways governing CSCs need to be considered for rational design of effective targeted therapy against basal-like/claudin low breast cancer.
  • bortezomib a proteasome inhibitor that inhibits nuclear factor kappa-light-chain- enhancer of activated B cells (NF- ⁇ ), effectively overcomes cancer stem cell escape triggered by Wnt inhibitor therapy in Forkhead box C1 (FOXC1 ) positive basal- like/claudin-low breast cancer.
  • bortezomib a candidate drug to treat all types of basal-like/claudin-low breast cancers.
  • Bortezomib has previously been used in a clinical trial to treat triple-negative patients; however, this trial yielded inconclusive results because it was not possible to accurately select basal- like patients.
  • the patients in the trial were composed of a mix of basal-like positive and basal-like negative patients.
  • FOXC1 is a marker for basal-like breast cancer, which affects ⁇ 70% of triple negative breast cancer.
  • basal-like breast cancer includes more than just triple-negative breast cancer as it is present in up to 30% ER+ type cancers and in >15% HER2+ type cancers. Screening of patients using FOXC1 as a marker will help to more efficiently select patients with basal-like positive cancers for treatment with bortezomib.
  • Forkhead box transcription factors including FOXC1 , also known as forkhead-like 7 (FKHL7)
  • FOXC1 also known as forkhead-like 7 (FKHL7)
  • FKHL7 forkhead-like 7
  • the FOXC1/FKHL7 gene and protein sequences are known, and can be found in GenBank (Accession Nos. AR140209 (complete sequence), AR140210 (coding sequence) and AAE63616 (amino acid sequence).
  • FOXC1 has emerged as the most indicative and the most characteristic biomarker of basal-like breast cancers, in its ability to diagnose, prognose, and treat basal-like breast cancers.
  • kits for treating a subject with breast cancer including first screening a population of breast cancer tumor cells of the subject to determine whether the breast cancer tumor cells express FOXC1 , and subsequently treating that subject having breast cancer tumor cells expressing FOXC1 with bortezomib.
  • the breast cancer tumor cells express FOXC1 if the level of FOXC1 is higher than a predetermined cutoff level.
  • the predetermined cutoff level may be determined by a 90th percentile level of FOXC1 expression levels for a dataset of breast cancer tumors, the dataset comprising all breast cancer subtypes.
  • Methods used to determine whether a population of tumor cells express FOXC1 may include any suitable method, including but not limited to, immunohistochemistry (or other immunoassay), PCR, RT-PCR, quantitative RT-PCR (qRT-PCR) (or any other PCR-based method), and/or the methods, assays and materials described in International Application Nos. PCT/US10/44817 entitled “Methods for Diagnosis, Prognosis, and Treatment of Primary and Metastatic Basal-Like Breast Cancer and Other Cancer Types;” and PCT/US12/23871 entitled “FOXC1 Antibodies and Methods of Their Use;” the subject matter of both of which are hereby incorporated by reference as if fully set forth herein.
  • detecting the presence or absence of FOXC1 may be accomplished by an in vitro immunoassay, such as immunocytochemistry (ICC), immunohistochemistry (IHC), Western blot or fluorescent in situ hybridization (FISH).
  • an in vivo imaging modality may be used, such as magnetic resonance imaging (MRI), positron emission tomography (PET) or microPET, computed tomography (CT), PET/CT combination imager, cooled charged coupled device (CCD), camera optical imaging, optical imaging and single photon emission computed tomography (SPECT).
  • MRI magnetic resonance imaging
  • PET positron emission tomography
  • CT computed tomography
  • CCD cooled charged coupled device
  • SPECT cooled charged coupled device
  • FOXC1 antibody or functional fragment thereof should be conjugated to an intracellular delivery agent to facilitate deliver of the antibody or functional fragment thereof to the cytoplasm of target cells.
  • an anti-FOXC1 monoclonal antibody may be used to detect expression level of FOXC1 in a cell.
  • the antibody may specifically bind a target antigenic peptide sequence of human FOXC1 ( Figure 12; SEQ ID NO: 1 ).
  • the target antigenic peptide sequence is 5' -AHAEQYPGGMARAYGPYTPQPQPKD-3' (SEQ ID NO:2), which corresponds to amino acids 51 to 75 of SEQ ID NO:1 (see Figure 12).
  • a cysteine residue may be added to the N-terminus (i.e., 5'-C- AHAEQYPGGMARAYGPYTPQPQPKD-3' (SEQ ID NO:3)) to assist in conjugation to the carrier protein as necessary.
  • the subject may be administered one or more proteasome inhibitors, and optionally one or more Wnt inhibitors, to treat the cancer.
  • the proteasome inhibitor may be bortezomib.
  • the Wnt inhibitor may be beta-Catenin/Tcf Inhibitor III (i.e., iCRT3 or 2-[[[2-(4-ethylphenyl)-5-methyl-4-oxazolyl]methyl]thio]-N-(2- phenylethyl)acetamide).
  • the cancer may be basal-like/claudin- low breast cancer.
  • the cancer may be basal-like breast cancer.
  • the basal-like breast cancer may be a triple negative breast cancer, an ER positive breast cancer, or a HER2 positive breast cancer.
  • the cancer may be claudin-low breast cancer.
  • the methods for treating a cancer in a subject include determining the expression level of FOXC1 in a population of tumor cells obtained from the subject; and administering one or more proteasome inhibitors, and optionally one or more Wnt inhibitors, to the subject to treat the cancer if the population of tumor cells expresses FOXC1 .
  • the proteasome inhibitor may be bortezomib.
  • the cancer may be basal-like/claudin-low breast cancer.
  • the cancer may be basal-like breast cancer.
  • the basal-like breast cancer may be triple negative breast cancer, ER positive breast cancer, or HER2 positive breast cancer.
  • the cancer may be claudin-low breast cancer.
  • combination therapies comprising one or more Wnt inhibitors and one or more proteasome inhibitors.
  • the proteasome inhibitor may be bortezomib.
  • the one or more Wnt inhibitors may be iCRT3.
  • the combination therapy may be used to treat a FOXC1 positive cancer.
  • the FOXC1 positive cancer may be a basal-like breast cancer.
  • the basal-like breast cancer may be a triple negative breast cancer, an ER positive breast cancer, or a HER2 positive breast cancer.
  • the cancer may be claudin-low breast cancer.
  • Optimal dosages of the combination therapy i.e., the one or more Wnt inhibitors and one or more proteasome inhibitors
  • the combination therapy i.e., the one or more Wnt inhibitors and one or more proteasome inhibitors
  • the pharmaceutical composition may be effected continuously or intermittently.
  • the pharmaceutical composition may be administered to a subject either singly or in a cocktail containing one or more Wnt inhibitors and one or more proteasome inhibitors, other therapeutic agents, compositions, or the like, including, but not limited to, tolerance-inducing agents, potentiators and side-effect relieving agents.
  • Treating” or “treatment” of a condition may refer to preventing the condition, slowing the onset or rate of development of the condition, reducing the risk of developing the condition, preventing or delaying the development of symptoms associated with the condition, reducing or ending symptoms associated with the condition, generating a complete or partial regression of the condition, or some combination thereof. Treatment may also mean a prophylactic or preventative treatment of a condition.
  • the use of a proteasome inhibitor (e.g., bortezomib) and optionally, one or more Wnt inhibitors, for treating a FOXC1 positive cancer is provided herein.
  • the FOXC1 positive cancer may be a basal-like breast cancer.
  • the basal-like breast cancer may be a triple negative breast cancer, an ER positive breast cancer, or a HER2 positive breast cancer.
  • the cancer may be claudin-low breast cancer. All of the embodiments described herein apply to such uses.
  • a "subject” refers to a mammal, such as a human. In some embodiments, the subject is a patient.
  • the one or more proteasome inhibitors, and optionally, one or more Wnt inhibitors may be administered in combination with a therapeutic agent, radiotherapy, surgery, or any combination thereof.
  • a “therapeutically effective amount,” “therapeutically effective concentration” or “therapeutically effective dose” is an amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • This amount will vary depending upon a variety of factors, including but not limited to the characteristics of the one or more Wnt inhibitors and one or more proteasome inhibitors or pharmaceutical compositions thereof (including activity, pharmacokinetics, pharmacodynamics, and bioavailability thereof), the physiological condition of the subject treated (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication) or cells, the nature of the pharmaceutically acceptable carrier or carriers in the formulation, and the route of administration.
  • an effective or therapeutically effective amount may vary depending on whether the one or more Wnt inhibitors and one or more proteasome inhibitors disclosed herein or the pharmaceutical composition thereof is administered alone or in combination with other drug(s), other therapy/therapies or other therapeutic method(s) or modality/modalities.
  • One skilled in the clinical and pharmacological arts will be able to determine an effective amount or therapeutically effective amount through routine experimentation, namely by monitoring a cell's or subject's response to administration of the one or more Wnt inhibitors and one or more proteasome inhibitors or the pharmaceutical composition thereof and adjusting the dosage accordingly.
  • Remington The Science and Practice of Pharmacy, 21 st Edition, Univ. of Sciences in Philadelphia (USIP), Lippincott Williams & Wilkins,
  • the one or more proteasome inhibitors, and optionally, one or more Wnt inhibitors, used in the methods and therapies herein may be administered as a combination of one or more therapeutic agents for the treatment of cancer.
  • a combination or “in combination with,” as used herein, means in the course of treating the same cancer in the same subject using two or more agents, drugs, treatment regimens, treatment modalities or a combination thereof, in any order. This includes simultaneous administration, as well as in a temporally spaced order of up to several days apart.
  • Such combination treatment may also include more than a single administration of any one or more of the agents, drugs, treatment regimens or treatment modalities. Further, the administration of the two or more agents, drugs, treatment regimens, treatment modalities or a combination thereof may be by the same or different routes of administration.
  • the treatment as described herein may be administered by any suitable route of administration, alone or as part of a pharmaceutical composition.
  • a route of administration may refer to any administration pathway known in the art, including but not limited to aerosol, enteral, nasal, ophthalmic, oral, parenteral, rectal, transdermal (e.g., topical cream or ointment, patch), or vaginal.
  • transdermal administration may be accomplished using a topical cream or ointment or by means of a transdermal patch.
  • Parenter refers to a route of administration that is generally associated with injection, including infraorbital, infusion, intraarterial, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal, or transtracheal.
  • therapeutic agents that may be administered as a treatment include, but are not limited to, chemotherapeutic agents, therapeutic antibodies and fragments thereof, toxins, radioisotopes, enzymes (e.g., enzymes to cleave prodrugs to a cytotoxic agent at the site of the tumor), nucleases, hormones, immunomodulators, antisense oligonucleotides, nucleic acid molecules (e.g., mRNA molecules, cDNA molecules or RNAi molecules such as siRNA or shRNA), chelators, boron compounds, photoactive agents and dyes.
  • the therapeutic agent may also include a metal, metal alloy, intermetallic or core-shell nanoparticle bound to a chelator that acts as a radiosensitizer to render the targeted cells more sensitive to radiation therapy as compared to healthy cells.
  • Chemotherapeutic agents that may be used in accordance with the embodiments described herein are often cytotoxic or cytostatic in nature and may include, but are not limited to, alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, mitotic inhibitors hormone therapy, targeted therapeutics and immunotherapeutics.
  • the chemotherapeutic agents that may be used as therapeutic agents in accordance with the embodiments of the disclosure include, but are not limited to, 13-cis-Retinoic Acid, 2-Chlorodeoxyadenosine, 5- Azacitidine, 5-Fluorouracil, 6-Mercaptopurine, 6-Thioguanine, actinomycin-D, adriamycin, aldesleukin, alemtuzumab, alitretinoin, all-transretinoic acid, alpha interferon, altretamine, amethopterin, amifostine, anagrelide, anastrozole, arabinosylcytosine, arsenic trioxide, amsacrine, aminocamptothecin, aminoglutethimide, asparaginase, azacytidine, bacillus calmette-guerin (BCG), bendamustine, bevacizumab, bexarotene, bicalut
  • Therapeutic antibodies and functional fragments thereof, that may be used as therapeutic agents in accordance with the embodiments of the disclosure include, but are not limited to, alemtuzumab, bevacizumab, cetuximab, edrecolomab, gemtuzumab, ibritumomab tiuxetan, panitumumab, rituximab, tositumomab, and trastuzumab and other antibodies associated with breast cancer.
  • Toxins that may be used as therapeutic agents in accordance with the embodiments of the disclosure include, but are not limited to, ricin, abrin, ribonuclease (RNase), DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, and Pseudomonas endotoxin.
  • Radioisotopes that may be used as therapeutic agents in accordance with the embodiments of the disclosure include, but are not limited to, 32 P, 89 Sr, 90 Y, 99m Tc, 99i Mo, 3 1, 153 Sm, 177 Lu, 186 Re, 213 Bi, 223 Ra and 225 Ac.
  • the treatment and administration steps described herein may include any suitable treatment used in accordance with standard practice for treatment of breast cancer.
  • the treatment is not limited to any particular treatment.
  • FDA United States Food and Drug Administration
  • the pharmaceutical composition may also include a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier may be a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body.
  • the carrier may be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or some combination thereof.
  • Each component of the carrier must be "pharmaceutically acceptable” in that it must be compatible with the other ingredients of the formulation. It also must be suitable for contact with any tissue, organ, or portion of the body that it may encounter, meaning that it must not carry a risk of toxicity, irritation, allergic response,
  • Example 1 Proteasome Inhibitor Bortezomib Inhibits NF- ⁇ and Effectively Overcomes Cancer Stem Cell Escape Triggered by Wnt Inhibitor Therapy in FOXC1 Positive Basal-Like/Claudin-Low Breast Cancer.
  • the Wnt/ ⁇ catenin signaling pathway is active in basal-like/claudin-low breast cancers (Scheel et al., 2001 ). It was previously shown that FOXC1 plays a critical role in mediating aggressive cell traits in such cancers (see Figure 1 and 2; Ray et al, 2010). As provided herein, the link between Wnt signaling and FOXC1 and its potential in regulating cancer stem cell (CSC) biology in basal-like/claudin-low breast cancer was investigated.
  • CSC cancer stem cell
  • FIG. 3 The proposed mechanism of FOXC1 regulation by Wnt/ ⁇ catenin signaling is shown in Figure 3.
  • Figure 4 shows that FOXC1 acts as a downstream mediator of Wnt-driven regulation of CSCs in basal-like/claudin-low breast cancer.
  • Beta-catenin (CTNNB1 ) expression level and survival was analyzed using a breast cancer transcriptomic database (see Figure 5; Curtis et al., 2012). Additionally, it was observed that exposure of the MDA-MB-231 basal-like/claudin-low cell line (low constitutive FOXC1 expressor) to Wnt3a (a canonical Wnt signaling ligand), resulted in increased expression of FOXC1 (see Figure 6D). Reciprocally, overexpression of FOXC1 in MCF10A human mammary epithelial cells led to a pronounced increase in Wnt signaling activity, strongly suggestive of a direct or indirect positive feedback loop between Wnt signaling and FOXC1.
  • BT549 and HS578T basal- like/claudin-low cells proved to be more sensitive to treatment with the Wnt inhibitor iCRT3 as evidenced by decreased cell viability when compared to MCF7 (luminal) or SKBR3 (HER2) breast cancer cell lines (see Figures 7A and 7B). Furthermore the decrease in cell viability appeared to be proportionate to the level of FOXC1 expression (see Figures 7A and 7B).
  • the tumor cells of a patient with cancer may be screened for FOXC1 expression to select patients with basal-like cancers.
  • the patients may be treated with a combination therapy of a Wnt inhibitor and a proteasome inhibitor.

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Abstract

L'invention concerne des procédés de traitement de cancer du sein chez un sujet. Dans certains modes de réalisation, les procédés peuvent consister à déterminer un niveau d'expression de FOXC1 dans une population de cellules tumorales prélevées sur le sujet, et à administrer, au sujet, un ou plusieurs inhibiteurs de protéasome et, éventuellement, un ou plusieurs inhibiteurs de Wnt pour traiter le cancer du sein si la population de cellules tumorales exprime FOXC1. Dans certains modes de réalisation, le cancer du sein peut être un cancer du sein de type basal. Dans certains modes de réalisation, l'inhibiteur de protéasome peut être le bortézomib. L'invention concerne également des traitements combinés pour le traitement de cancer du sein, comprenant un ou plusieurs inhibiteurs de Wnt et un ou plusieurs inhibiteurs de protéasome.
PCT/US2015/064573 2009-08-06 2015-12-08 Procédés de traitement de cancer du sein de type basal et pauvre en claudine et traitement combiné de celui-ci WO2016094457A1 (fr)

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US11725184B2 (en) 2014-05-16 2023-08-15 Koninklijke Nederlandse Akademie Van Wetenschappen Culture method for organoids
US11130943B2 (en) 2014-11-27 2021-09-28 Koninklijke Nederlandse Akademie Van Wetenschappen Culture medium
CN109477070A (zh) * 2016-03-01 2019-03-15 荷兰皇家科学院 改进的分化方法
CN109477070B (zh) * 2016-03-01 2022-05-27 荷兰皇家科学院 改进的分化方法
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