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WO2024192470A1 - Méthode de traitement du glioblastome ou d'autres cancers exprimant le récepteur de la neurotrophine p75 - Google Patents

Méthode de traitement du glioblastome ou d'autres cancers exprimant le récepteur de la neurotrophine p75 Download PDF

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Publication number
WO2024192470A1
WO2024192470A1 PCT/AU2024/050248 AU2024050248W WO2024192470A1 WO 2024192470 A1 WO2024192470 A1 WO 2024192470A1 AU 2024050248 W AU2024050248 W AU 2024050248W WO 2024192470 A1 WO2024192470 A1 WO 2024192470A1
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Prior art keywords
p75ntr
methyl
pentanamide
amino
lm11a
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Hubert Hondermarck
Chen Chen JIANG
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The University of Newcastle
Newcastle University of Upon Tyne
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The University of Newcastle
Newcastle University of Upon Tyne
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Priority claimed from AU2023900767A external-priority patent/AU2023900767A0/en
Application filed by The University of Newcastle, Newcastle University of Upon Tyne filed Critical The University of Newcastle
Publication of WO2024192470A1 publication Critical patent/WO2024192470A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes

Definitions

  • the invention relates to a method of treating a cancer expressing p75 neurotrophin receptor (p75NTR, also known as CD271) by administering a p75NTR inhibitor such as LM11A-31 (2-amino-3-methyl-N-(2-morpholinoethyl)pentanamide) or a pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof.
  • p75NTR p75 neurotrophin receptor
  • the cancer may be glioblastoma or other malignancies such as prostate cancer or pancreatic cancer.
  • the p75 neurotrophin receptor is a transmembrane receptor and a member of the tumor necrosis factor (TNF) receptor superfamily that exerts a variety of functions.
  • TNF tumor necrosis factor
  • p75NTR has no catalytic activity, but may recruit specific protein partners, which can bind intracellular chopper and death domains.
  • p75NTR is not only expressed in nervous tissues, it is also expressed in non-neuronal tissues and in several cancer cases, such as thyroid carcinoma, melanoma, bladder, pancreatic, prostate, stomach and liver cancers. However, p75NTR may have opposing functions depending on tumor type. Hence, it has been described to exert a tumor-promoting activity by favouring survival and metastasis in brain, prostate cancer and melanomas and been identified as a potential tumor suppressor in bladder, stomach and liver cancers.
  • Glioblastoma is a highly malignant brain tumor arising from astrocytes and is the most common form of primary brain cancer in adults. It is a highly aggressive malignancy with a very poor prognosis and currently no effective treatment. About 15 percent of all primary brain tumors are glioblastomas that arise de novo or, occasionally, from a low- grade astrocytoma. Common presenting signs include headaches, nausea, seizures, blurred vision, vomiting, and personality changes.
  • the treatment of glioblastoma is a combination of surgery, radiotherapy, and chemotherapy.
  • the patient is initially treated by surgical removal of the tumor tissue (where possible), followed by chemotherapy and/or radiotherapy.
  • the effectiveness of surgery is limited by the challenge of complete tumor resection and the presence of residual tumor cells. If surgical ablation is not an option because of tumor size, tumor location, or poor patient health, a combination of radiation and chemotherapy is typically used.
  • TMZ temozolomide
  • TMZ is an alkylating agent, and an imidazotetrazine derivative of dacarbazine.
  • Other agents such as bevacizumab and lomustine have been used as second-line therapy. However, treatment with these agents have only shown minor increases in survival.
  • the p75NTR (also called NGFR or CD271) is a membrane protein receptor to neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3). Signalling from the receptor can promote either neuron survival or death by apoptosis, depending on its ligand and cellular context.
  • NGF nerve growth factor
  • BDNF brain-derived neurotrophic factor
  • NT-3 neurotrophin-3
  • LM11A-31 (2-amino-3-methyl-N-(2-morpholinoethyl)pentanamide) is a non-peptide p75NTR ligand that is orally available and can cross the blood brain barrier. LM11A-31 blocks p75-mediated cell death and has been shown to promote neuron survival and is in clinical trials as a potential therapy for Alzheimer's disease (AD). LM11A-31 has shown therapeutic effects in a number of animal models of neurologic diseases characterized by loss of neurons, including posttraumatic brain injury, Huntington's disease, and AD.
  • the present inventors have demonstrated that the p75NTR inhibitor LM11A-31 inhibits survival of glioblastoma cells and have developed methods of treating glioblastoma by administering LM11A-31.
  • the invention relates to a method of treating a cancer expressing p75 neurotrophin receptor (p75NTR) in a subject comprising administering to the subject a therapeutically effective amount of a p75NTR inhibitor.
  • p75NTR p75 neurotrophin receptor
  • the p75NTR inhibitor is 2-amino-3-methyl-N-(2-morpholinoethyl)- pentanamide (LM11A-31) or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
  • the LM11A-31 salt may be a dihydrochloride salt.
  • the 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide may be (2S,3S)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide, (2R,3R)-2-amino-3-methyl- N-(2-morpholinoethyl)-pentanamide, (2R,3S)-2-amino-3-methyl-N-(2-morpholino-ethyl)- pentanamide, (2S,3R)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide, or any combination thereof.
  • the p75NTR inhibitor is selected from the group consisting of:
  • the cancer may be glioblastoma, prostate cancer or pancreatic cancer.
  • the p75NTR inhibitor may be capable of crossing the blood-brain barrier of the subject.
  • the method may further comprise administering a therapeutically effective amount of temozolomide, bevacizumab, carmustine, hydroxyurea, or procarbazine to the subject.
  • the temozolomide, bevacizumab, carmustine, hydroxyurea, or procarbazine may be administered separately, sequentially, or simultaneously with the p75NTR inhibitor.
  • the glioblastoma is temozolomide resistant glioblastoma or unmethylated methyl guanine methyltransferase (MGMT) promoter glioblastoma.
  • MGMT unmethylated methyl guanine methyltransferase
  • the invention in a second aspect relates to a method for suppressing the development of temozolomide resistant glioblastoma in a subject with glioblastoma, the method comprising administering to the subject a therapeutically effective amount of a p75NTR inhibitor.
  • the p75NTR inhibitor of the second aspect is 2-amino-3-methyl- N-(2-morpholinoethyl)-pentanamide (LM11A-31), or a pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof.
  • the 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide is (2S,3S)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide, (2R,3R)-2-amino-3-methyl- N-(2-morpholinoethyl)-pentanamide, (2R,3S)-2-amino-3-methyl-N-(2-morpholino-ethyl)- pentanamide, (2S,3R)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide, or any combination thereof.
  • the p75NTR inhibitor of the second aspect is selected from the group consisting of:
  • the p75NTR inhibitor of the second aspect may be capable of crossing the bloodbrain barrier of the subject.
  • administration of the p75NTR inhibitor may be orally or intravenously, preferably orally.
  • administration of the p75NTR inhibitor may be intratumorally or to an area surrounding the glioblastoma.
  • the p75NTR inhibitor may be administered into an area from which the tumor or a portion thereof has been surgically resected.
  • the method may further comprise administering a therapeutically effective amount of radiotherapy.
  • the glioblastoma overexpresses CD271 (i.e. , p75NTR).
  • the invention relates to a formulation comprising a therapeutically effective amount of a p75NTR inhibitor when used for the treatment of a cancer expressing p75 neurotrophin receptor (p75NTR) , wherein the p75NTR inhibitor is 2-amino-3-methyl-N-
  • SUBSTITUTE SHEET (RULE 26) (2-morpholinoethyl)-pentanamide (LM11A-31), or a pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof or selected from the group consisting of: pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.
  • the invention relates to use of 2-amino-3-methyl-N-(2- morpholinoethyl)pentanamide (LM11A-31), or a pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof, in the manufacture of a medicament for the treatment of a cancer expressing p75 neurotrophin receptor (p75NTR).
  • L11A-31 2-amino-3-methyl-N-(2- morpholinoethyl)pentanamide
  • p75NTR p75 neurotrophin receptor
  • the invention relates to use of 2-amino-3-methyl-N-(2- morpholinoethyl)pentanamide (LM11A-31), or a pharmaceutically acceptable salt, ester,
  • SUBSTITUTE SHEET (RULE 26) crystal form, prodrug or solvate thereof, in the manufacture of a medicament for suppressing resistance to temozolomide in a subject with temozolomide resistant glioblastoma.
  • the 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide may be (2S,3S)-2-amino- 3-methyl-N-(2-morpholinoethyl)-pentanamide, (2R,3R)-2-amino-3-methyl-N-(2- morpholinoethyl)-pentanamide, (2R,3S)-2-amino-3-methyl-N-(2-morpholino-ethyl)- pentanamide, (2S,3R)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide, or any combination thereof.
  • the cancer overexpresses CD271 (i.e. , p75NTR).
  • glioblastoma or "glioblastoma multiforme” (GBM) is also known as astrocytomas grade IV, which is a tumor arising from astrocytes, and encompasses but is not limited to proneural glioblastoma, classic glioblastoma, neural glioblastoma, or mesenchymal glioblastoma.
  • the terms "glioblastoma” or “GBM” encompasses both methylated and unmethylated methyl guanine methyltransferase (MGMT) promoter glioblastoma.
  • MGMT is also known as O 6 - methylguanine DNA methyltransferase, O 6 -alkylguanine-DNA alkyltransferase, AGT, or AGAT.
  • the presence of methylation at the promoter region of the MGMT gene in a subject having glioblastoma is correlated with improved response outcome and longer overall survival relative to the response outcome of a subject having glioblastoma without the presence of methylation at the promoter region of the MGMT gene (i.e., unmethylated MGMT promoter glioblastoma).
  • Certain p75NTR inhibitors of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates, enantiomers, diastereomers and mixtures thereof, are intended to be within the scope of the subject matter of the invention.
  • a reference to 'temozolomide and/or radiotherapy' can refer, in one embodiment, to temozolomide only and, in another embodiment, to radiotherapy only and in yet another embodiment, to temozolomide and radiotherapy.
  • a and “an” are used to refer to one or more than one (i.e. , at least one) of the grammatical object of the article.
  • an element means one element, or more than one element.
  • the term "about” means that reference to a figure or value is not to be taken as an absolute figure or value, but includes margins of variation above or below the figure or value in line with what a skilled person would understand according to the art, including within typical margins of error or instrument limitation.
  • use of the term “about” is understood to refer to a range or approximation that a person or skilled in the art would consider to be equivalent to a recited value in the context of achieving the same function or result.
  • treating means: (1) preventing or delaying one or more symptoms of glioblastoma from developing in a subject that may be predisposed to glioblastoma but does not yet experience or display symptoms of glioblastoma, (2) inhibiting glioblastoma, i.e., arresting or reducing the development or progression of glioblastoma or at least one or more symptoms thereof, or (3) relieving glioblastoma, i.e., causing regression or reversing glioblastoma or at least one of its symptoms.
  • treating or “treatment” and the like is to be considered in their broadest context and encompasses curing, ameliorating, or tempering the severity of glioblastoma or one or more of its associated symptoms.
  • “treating” or “treatment” may mean increasing the survival rate compared to the expected survival rate when not receiving treatment.
  • Effective amount and “therapeutically effective amount” refer to an amount of a therapy (e.g., radiotherapy) or a therapeutic compound (e.g., temozolomide or LM11A-31) sufficient to produce a desired therapeutic or pharmacological effect in the subject being treated.
  • a therapy e.g., radiotherapy
  • a therapeutic compound e.g., temozolomide or LM11A-31
  • the terms are synonymous and are intended to qualify the amount of each therapy or compound that will achieve the goal of improvement in disease severity and/or the frequency of incidence over treatment of each therapy or compound by itself while preferably avoiding or minimizing adverse side effects, including side effects typically associated with other therapies.
  • the "effective amount” or “therapeutically effective amount” will vary depending on the therapy or compound, the disease severity, and the age, weight, physical condition and responsiveness of the individual to be treated.
  • pharmaceutically acceptable salt refers to those salts which, within the scope of sound medical judgement, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds of the invention are known to one of skill in the art.
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, hydrochloric, lactic, malic, tartaric, citric, ascorbic, glucoronic, fumaric, maleic, pyruvic, alkyl sulfonic, arylsulfonic, aspartic, glutamic, benzoic, anthranilic, mesylic, methanesulfonic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, ambonic, pamoic, pantothenic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, p-hydroxybutyric, galactaric, and galacturonic acids.
  • Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include metallic salts made from lithium, sodium, potassium, magnesium, calcium, aluminium, and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine.
  • suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, ammonium salts, quaternary salts such as tetramethylammonium salt, amino acid addition salts such as salts with glycine and arginine.
  • the compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.
  • prodrug refers to any compound that when administered to a biological system generates the drug substance (a biologically active compound) in one or more steps including but not limited to spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), or both.
  • Standard prodrugs are formed using groups attached to functionality groups, e.g., HO-, HS-, HOOC-, R2N-, associated with the drug substance that cleave in-vivo. Prodrugs for these groups are well known in the art and are often used to enhance bioavailability or other pharmacological properties beneficial to the formulation, delivery, or activity of the drug.
  • Standard prodrugs include, but are not limited to, carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate.
  • the prodrug can have its own biological activity that can be similar to or different from the active drug.
  • crystal form or “crystal” as used herein refers to any solid substance with order in three dimensions. In contrast to the amorphous substance, the crystal form has characteristic X-Ray Powder Diffraction (XRPD) pattern with peak(s) having clear boundaries.
  • XRPD X-Ray Powder Diffraction
  • stereoisomer refers to any two or more isomers that have the same molecular constitution and differ only in the three-dimensional arrangement of their atomic groupings in space. Stereoisomers may be diastereoisomers or enantiomers. It will be recognized that the compounds described herein may possess asymmetric centers and are therefore capable of existing in more than one stereoisomeric form. The invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centers e.g., greater than about 90% enantiomeric excess (ee), such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers may be naturally occurring or may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution.
  • solvate means a complex formed by solvation (the combination of solvent molecules with molecules or ions of the LM11A-31), or an aggregate that consists of a solute ion or molecule with one or more solvent molecules.
  • hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, and hexahydrate.
  • the pharmaceutically acceptable salt of the LM11A-31 may also exist in a solvate form.
  • the solvate is typically formed via hydration which is either part of the preparation of the present compound or through natural absorption of moisture by the LM11A-31.
  • Solvates including hydrates may be in stoichiometric ratios, for example, with two, three, four salt molecules per solvate or per hydrate molecule. Another example is that two salt molecules are stoichiometrically related to three, five, seven solvent or hydrate molecules.
  • Solvents used for crystallization such as alcohols (e.g., methanol and ethanol); aldehydes; ketones, (e.g., acetone); esters (e.g., ethyl acetate) may be embedded in the crystal grating.
  • a "pharmaceutical carrier, diluent or excipient” includes, but is not limited to, any physiological buffered (i.e. , about pH 7.0 to 7.4) medium comprising a suitable water soluble organic carrier, conventional solvents, dispersion media, fillers, solid carriers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents.
  • suitable water soluble organic carriers include, but are not limited to, saline.
  • Other conventional additives include buffers and stabilizing agents.
  • Subject includes any human or non-human mammal.
  • the compounds of the present invention may also be useful for veterinary treatment of mammals, including companion animals and farm animals, such as, but not limited to dogs, cats, horses, cows, sheep, and pigs.
  • the subject is a human.
  • administering includes contacting, applying, delivering, or providing a therapy (e.g., radiotherapy) or a therapeutic compound to a subject by any appropriate means.
  • a therapy e.g., radiotherapy
  • FIG. 1 p75NTR expression is increased in GBM.
  • C Receiver operating characteristic (ROC) analysis for p75NTR in GBM patient samples was performed to evaluate the accuracy of the statistical model.
  • ROC Receiver operating characteristic
  • the median p75NTR concentration was 142.8 pg/mL (IQR 0.00 - 8286 pg/mL) in combined grades 1-3 verses 144.0 pg/mL (IQR 0.00 - 9565 pg/mL) in GBM. Mann-Whitney test was performed.
  • FIG. 1 GBM cells with unmethylated MGMT promoter are more sensitive to the p75NTR inhibitor LM11A-31.
  • C-D Correlation analysis of cell death and relative p75NTR protein expression in unmethylated MGMT (C) and methylated MGMT GBM cells (D). The R values as well as P values for Pearson correlation are indicated.
  • E Immunoprecipitation assay confirmed that treatment of LM11A-31 (200nM) for 24 or 48 hours inhibited the binding of proNGF and sortilin to p75NTR.
  • F-G Knockdown of p75NTR by p75 siRNA
  • F also induced cell death in MN1 (unmethylated MGMT promoter) (G-left panel) and BAH1 (methylated MGMT promoter) (G-right panel) by cell death assay and colony formation assay (H).
  • Data are representative of three independent experiments or data shown are the mean ⁇ SD of three independent experiments. *P ⁇ 0.05, Student’s t- test or ANOVA.
  • FIG. 3 LM11A-31 potentiates the efficacy of TMZ in GBM cells.
  • MN1 , RN1 , FPW1 , MMK1 , WK1, PB1 and SJH1 unmethylated MGMT gene promoter
  • FIG. 4 The effect of LM11A-31 on the efficacy of other chemotherapeutic reagents in GBM cells.
  • A-C Cell death was studied in patient-derived GBM cells MN1 (unmethylated MGMT promoter) (A), BAH1 (methylated MGMT promoter) (B) and BAH1.TMZ (C) treated with LM11A-31 (200nM), Bevacizumab (25ptg/ml), Carmustine (25ptM), Hydroxyurea (25ptM) or Procarbazine (10ptM) and combination LM11A- 31+Bevacizumab, LM11A-31+Carmustine, LM11A-31+Hydroxyurea or LM11A- 31+Procarbazine for 72 hours.
  • FIG. 5 The neuroprotective role of LM11A-31 in GBM.
  • LM11A-31 inhibits TMZ-induced neurite outgrowth in Neuro2A cells in BAH 1.
  • TMZ cells Neurite outgrow was studied in Neuro2A cells cultured in conditioned media from BAH1.
  • D representative pictures. Scale bar, 50ptm.
  • E quantification of neurite outgrowth in Neuro2A cells. Data are representative of three independent experiments or data shown are the mean ⁇ SD of three independent experiments. *P ⁇ 0.05, **P ⁇ 0.01, Student’s t-test or ANOVA.
  • LM11A-31 reduces GBM tumour growth and improves the efficacy of Temozolomide in animal models. This is a confirmation in vivo of the in vitro data.
  • Patient-derived GBM cells FPW1 and BHA1 were injected into the flank of NSG mice. Mice were then treated with Temozolomide (TMZ, 50mg/kg), LM11A-31 (10mg/kg), TMZ+LM11A-31 or vehicle control.
  • FIG. 7 LM11A-31 shows neuroprotective role in GBM animal model. This is a confirmation in vivo of the in vitro data.
  • Patient-derived GBM cells BHA1
  • mice were injected into the right hemisphere of BALB/c nude mice to establish orthotopic GBM model. Mice were then treated with Temozolomide (TMZ, 50mg/kg) + Radiation (2Gy), LM11A-31 (10mg/kg), TMZ Radiation+LM11A-31 or vehicle control.
  • TMZ Temozolomide
  • 2Gy 2Gy
  • LM11A-31 10mg/kg
  • TMZ Radiation+LM11A-31 or vehicle control.
  • A) Novel object test was performed in mice of the orthotopic GBM model. The figure shown is the time of the mice spending to explore the novel object.
  • FIG. 8 LM11A-31 reduces pancreatic cancer growth.
  • Human pancreatic cancer cells (MIA PaCa-2 and PaCa-44) were injected into the flank of NSG mice. Mice were then treated with Gemcitabine (50mg/kg), LM11A-31 (10mg/kg), Gemcitabine+LM11A- 31 or vehicle control.
  • B Volume of MIA PaCa-2 (top) and PaCa-44 (bottom) tumour samples harvested from mice at the end of treatment. Data shown are the mean ⁇ SD of tumours in 40 mice per cell line. *P ⁇ 0.05, Student’s t-test or ANOVA.
  • FIG. 9 LM11A-31 reduces prostate cancer growth.
  • Human prostate cancer cells PC3 and DU 145) were injected into the flank of NSG mice. Mice were then treated with Docetaxel (8mg/kg), LM11A-31 (10mg/kg), Docetaxel+LM11A-31 or vehicle control.
  • the present inventors have demonstrated that the p75NTR inhibitor LM11A-31 inhibits survival of glioblastoma cells. Accordingly, the present invention relates to the use of a p75NTR inhibitor such as LM11A-31 or a pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof for the treatment of glioblastoma.
  • the present inventors have also demonstrated that the p75NTR inhibitor LM11A-31 potentiates the activity of temozolomide, and other chemotherapeutic agents (e.g., bevacizumab, carmustine, hydroxyurea, and procarbazine), in glioblastoma cells and can restore response to temozolomide in temozolomide-resistant glioblastoma.
  • the present invention also relates to the use of a p75NTR inhibitor such as LM11A-31 or a pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof for the treatment of TMZ-resistant glioblastoma.
  • the methods described herein involve treatment of glioblastoma in a patient by administering a therapeutically effective amount of a p75NTR inhibitor such as LM11A-31 or pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof to the patient.
  • a p75NTR inhibitor such as LM11A-31 or pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof
  • the methods described herein also involve treatment of temozolomide-resistant glioblastoma or unmethylated methyl guanine methyltransferase (MGMT) promoter glioblastoma in a patient, the method comprising administering a therapeutically effective amount of LM11A-31 or a pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof to the patient.
  • MGMT unmethylated methyl guanine methyltransferase
  • the p75NTR inhibitor e.g., LM11A-31 or a pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof induces cell death, or decreases survival of glioblastoma cells.
  • the methods disclosed herein involve the treatment of glioblastoma and protecting non-glioblastoma neurons from neurodegeneration and neuron loss.
  • the p75NTR inhibitor e.g., LM11A-31
  • a pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof may be administered as a formulation comprising a pharmaceutically effective amount of the compound, in association with one or more pharmaceutically acceptable excipients including carriers, vehicles and diluents.
  • excipient herein means any substance, not itself a therapeutic agent, used as a diluent, adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dosage form such as a tablet, capsule, or a solution or suspension suitable for oral, parenteral, intradermal, subcutaneous, or topical application.
  • Excipients can include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, glidants, stabilizers, and substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition.
  • Acceptable excipients include (but are not limited to) stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, magnesium carbonate, talc, gelatin, acacia gum, sodium alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starches, gelatin, cellulosic materials, such as cellulose esters of alkanoic acids and cellulose alkyl esters, low melting wax, cocoa butter or powder, polymers such as polyvinyl-pyrrolidone, polyvinyl alcohol, and polyethylene glycols, and other pharmaceutically acceptable materials.
  • excipients examples include Remington's Pharmaceutical Sciences, 20th Edition (Lippincott Williams & Wilkins, 2000). The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • Various routes of administration of the p75NTR inhibitor are contemplated herein.
  • Exemplary routes of administration of the p75NTR inhibitor include oral, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular, and intracerebral), and intratumoral.
  • the p75NTR inhibitor e.g., LM11A-31
  • LM11A-31 is capable of crossing the blood-brain barrier and is administered orally or intravenously to the subject.
  • the p75NTR inhibitor e.g., LM11A-31
  • the p75NTR inhibitor is administered directly into the tumor (intratumorally).
  • LM11A-31 or a pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof is administered to an area from which the tumor or a portion thereof has been surgically resected.
  • LM11A-31 or a pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof is administered into an area surrounding the tumor.
  • fluid unit dosage forms may be prepared by combining the compound (e.g., a p75NTR inhibitor) and a sterile vehicle, typically a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
  • a sterile vehicle typically a sterile aqueous solution which is preferably isotonic with the blood of the recipient.
  • the compound may be either suspended or dissolved in the vehicle or other suitable solvent.
  • the compound may be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition may be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilized powder may then be sealed in the vial and an accompanying vial of water for injection or other suitable liquid may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
  • the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent may be included in the composition to facilitate uniform distribution of the compound.
  • the compounds of the invention are formulated as an injectable solution. In preferred embodiments, the compounds of the invention are formulated for intravenous injection.
  • the p75NTR inhibitor (e.g., LM11A-31) may be formulated for oral administration.
  • Solid formulations such as the tablets or capsules may contain any number of suitable pharmaceutically acceptable excipients or carriers described above.
  • the compounds of the invention may also be formulated for sustained delivery.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example, magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example, potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • the compound or composition of the invention is formulated in a sustained release formulation or depot.
  • sustained release formulations or depots include a microsphere; matrix; emulsion; lipid-based; polymer-based; nanomicelle; micelle; nanovesicle such as a liposome, noisome, transfersome, discome, pharmacosome, emulsome or spanlastic, especially a liposome; microparticle; nanoparticle such as a nanocapsule or nanosphere composed of e.g. lipids, proteins, natural or synthetic polymers such as albumin, sodium alginate, chitosan, PLGA, PLA and/or polycaprolactone; or in situ gel such as an in situ hydrogel drug delivery system.
  • the therapeutically effective amount of the p75NTR inhibitor (e.g., LM11A-31) that is administered and the dosage regimen for treating glioblastoma with the p75NTR inhibitor and/or pharmaceutical composition of the invention depends on a variety of factors, including the age, weight, sex, and medical condition of the subject, the severity of the disease, the route and frequency of administration, as well as the pharmacokinetic properties of the p75NTR inhibitor or composition such as adsorption, distribution, metabolism, and excretion in the individual treated, and thus may vary widely. Such treatments may be administered as often as necessary and for the period of time judged necessary by the treating physician.
  • the dosage regime or therapeutically effective amount of the p75NTR inhibitor (e.g., LM11A-31) to be administrated may need to be optimized for each individual.
  • the pharmaceutical composition as described herein may contain the p75NTR inhibitor (e.g., LM11A-31) in the range of about 0.1 mg to 2000 mg, typically in the range of about 100 mg to 800 mg and more typically between about 200 mg and 400 mg.
  • a daily dose of about 100 mg/ day to 1000 mg/day, typically about 400 mg/ day to 800 mg/ day may be appropriate, depending on the route and frequency of administration.
  • the daily dose will typically be administered in one or multiple, e.g., two, three or four, doses per day.
  • the pharmaceutical composition as described herein containing the p75NTR inhibitor (e.g., LM11A-31) may be administered orally at 200 mg or 400 mg capsules and taken twice daily.
  • the p75NTR inhibitor or a pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof may be administered to a subject multiple times per day (e.g., two, three or four times per day), daily, every two days, every three days, every four days, or every 5 days, once weekly, or once monthly.
  • dosage will depend on the particular compound, and its potency.
  • the dosage is understood to be large enough to produce the desired effect in which the glioblastoma and the symptoms associated therewith are ameliorated and/or cell death of glioblastoma cells is achieved, but not be so large as to cause unmanageable side effects.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs or therapy which have previously been administered; and the severity of the patient's disease undergoing therapy, as is well understood by the skilled person in the art.
  • the dosage can also be adjusted by the individual physician in the event of any complication.
  • LM11A-31 has been reported to be safe for human use and has been tested in clinical trials for its neuroprotective effect in Alzheimer's disease.
  • p75NTR seems to be absent in as many cancers as it is present.
  • the expression of p75NTR is not an indication of a cancerous phenotype per se but can be p75NTR can be used as a marker for some cancers as it has limited expression in normal adult tissues where it is present primarily in the nervous system.
  • cancers that express p75NTR consistently or variably include glioblastoma, prostate cancer, pancreatic cancer, breast cancer, rhabdomyosarcoma, synovial sarcoma, Schwann cell, ganglioneuroma, granular cell turmor, adenoid cystic carcinoma, fibrosarcoma, solitary fibrous tumor, hemangiopericytoma, Spindle cell lipoma, mesenchymal chondrosarcoma, melanoma.
  • the cancer is are glioblastoma, prostate cancer, or pancreatic cancer.
  • the cancer is temozolomide resistant glioblastoma.
  • LM11A- 31 LM11A- 31 and one or more pharmaceutical agents or therapies is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single formulation having a fixed ratio of these active agents, or in multiple, separate formulations of each agent.
  • LM11 A-31 may be formulated or administered in combination with one or more therapeutic agents such as TMZ, bevacizumab, carmustine, hydroxyurea, or procarbazine.
  • LM 11 A-31 may be included in combination treatment regimens with surgery and/or other known treatments or therapeutic agents, and/or adjuvant or prophylactic agents.
  • a number of agents are available in commercial use, in clinical evaluation and in pre-clinical development, which could be selected for treatment of glioblastoma as part of the combination therapy. Suitable agents which may be used in the combination therapy will be recognized by those of skill in the art. Suitable agents are listed, for example, in the Merck Index, An Encyclopaedia of Chemicals, Drugs and Biologicals, 15th Ed., 2103, and subsequent editions, the entire contents of which are incorporated herein by reference.
  • Suitable compounds include KU-60019, sonidegib, cilengtide, laromustine, pexidartinib, temosirolimus, abemaciclib, TMZ, bevacizumab, carmustine, hydroxyurea, procarbazine, and radiotherapy.
  • LM11A-31 when used in the treatment of glioblastoma, LM11A-31 may be administered with an additional agent such as one or more of KU-60019, sonidegib, cilengtide, laromustine, pexidartinib, temosirolimus, abemaciclib, TMZ, bevacizumab, carmustine, hydroxyurea, procarbazine, and radiotherapy.
  • the LM11A- 31 may be administered with TMZ, and/or in combination with radiotherapy.
  • an agent such as KU-60019
  • sensitizes cells to radiation may additionally be administered.
  • Combination regimens may involve the active agents or therapies being administered together, sequentially, or spaced apart as appropriate in each case.
  • Combinations of active agents including LM 11 A-31 may be synergistic.
  • the choice of the additional therapeutic agent is within the skill of the treating physician and requires consideration of the severity of the glioblastoma among other factors. A wide range of permissible dosages are contemplated herein for the additional therapeutic agent.
  • LM 11 A-31 may be effected by the LM 11 A-31 being in the same unit dose as another active agent, or the LM11A-31 and one or more other active agent(s) may be present in individual and discrete unit doses administered at the same, or at a similar time, or at different times according to a dosing regimen or schedule chosen by the treating physician.
  • Sequential administration may be in any order as required, and may require an ongoing physiological effect of the first or initial compound to be current when the second or later compound is administered, especially where a cumulative or synergistic effect is desired.
  • LM11A-31 or a pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof, is administered to a subject with glioblastoma in combination with a chemotherapy and/or radiotherapy.
  • chemotherapy and/or radiotherapy is administered separately, sequentially, or simultaneously with LM11A-31.
  • the chemotherapy is temozolomide.
  • administration of LM11A-31 or a pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof supresses resistance to temozolomide in a subject with temozolomide resistant glioblastoma.
  • “simultaneously” refers to an administration of at least 2 therapeutic agents (e.g., LM11A-31 and temozolomide) by the same route (e.g., orally) and at the same time or at substantially the same time.
  • at least 2 therapeutic agents e.g., LM11A-31 and temozolomide
  • “separately 1 refers to an administration of at least 2 therapeutic agents or therapy (e.g., LM11A-31 , temozolomide, and radiotherapy) at the same time or at substantially the same time by different routes.
  • therapeutic agents or therapy e.g., LM11A-31 , temozolomide, and radiotherapy
  • “sequential" therapeutic use refers to administration of at least 2 therapeutic agents or therapy (e.g., LM11A-31, temozolomide, and radiotherapy) at different times, the administration route being identical or different.
  • the whole administration of one of the therapeutic agent or therapy is carried out before administration of the other or others commences. It is thus possible to administer one of the therapeutic agent or therapy over several months before administering the other therapeutic agent or therapy.
  • the subject may be pre-treated with one or more other therapeutic agents or therapy.
  • chemotherapy and radiotherapy may begin several weeks prior to administration of LM11A-31.
  • treatment with a therapeutic agent or therapy e.g., a chemotherapy or radiotherapy continues after the administration of LM11A-31.
  • Combinations of the therapeutic agents as described herein may be synergistic.
  • combinations of LM11A-31 or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent may prevent (i.e. , inhibit) or suppress (i.e. , reduce) anticancer drug resistance.
  • LM11A-31 or a pharmaceutically acceptable salt thereof is administered to the subject in combination with temozolomide to suppress resistance to temozolomide in a subject with temozolomide resistance glioblastoma.
  • Radiotherapy intended in the present invention is commonly used in the treatment of glioblastoma, and can be performed according to protocols known to those skilled in the art.
  • radiotherapy as referred to herein, includes but is not limited to irradiation with cesium, iridium, iodine, or cobalt.
  • Radiotherapy may be systemic irradiation or local irradiation.
  • Radiotherapy may be divided into 25 to 30 fractions, over about 5 to 6 weeks, and performed for 2 to 3 minutes per day.
  • the radiotherapy comprising 60 Gy in 30 fractions over six weeks may be used.
  • 60 Gy in 6 Gy fractions within 2 weeks with concomitant and adjuvant TMZ may be used.
  • 40 Gy in 15 fractions or 25 Gy in 5 fractions may be used at the discretion of the treating physician.
  • the combination therapy comprises administration of a p75NTR inhibitor (e.g. LM11A-31), TMZ , and radiotherapy.
  • a p75NTR inhibitor e.g. LM11A-31
  • TMZ TMZ
  • radiotherapy dose may be 60 Gy in 30 fractions.
  • Other options for radiotherapy in this context include a hypofractionated schedule of 34 Gy in 10 fractions, or 30 Gy in 5 fractions.
  • the combination therapy may include turn or- treating fields (TTFields), a non-invasive treatment approach involving alternating electrical fields proposed to inhibit cancer cell proliferation by interfering with microtubule polymerization.
  • TFields turn or- treating fields
  • pulsed radiotherapy may be used in a combination therapy. Pulsed radiotherapy divides 2 Gy fractions into ten 0.2 Gy pulses. This treatment modality may result in superior normal-tissue sparing compared to stereotactic radiotherapy. p75NTR inhibitors
  • Suitable p75NTR inhibitors for use in the presently disclosed methods include LM11A-31 (2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide) and related molecules.
  • LM11A-31 is available commercially or can be prepared according to known methods such as those described in PCT/US2010/026372, the contents of which are herein incorporated by reference in their entirety.
  • the methods described herein can use any form of LM11 A-31 , for example a crystalline form, a salt and/or a solvate of 2-amino-3-methyl-N-(2- morpholinoethyl)-pentanamide.
  • the method utilizes crystalline forms, a salt and/or a solvate of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide monosulfate, such as a dihydrochloride salt or those described in US patent application No 14/432,183, Publication No 20150259278.
  • the present invention provides crystalline forms of a salt and/or solvate of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide disulfate, such as those described in US patent application No 14/432,183, Publication No 20150259278.
  • the 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide is selected from the group consisting of: (2S,3S)-2-amino-3-methyl-N-(2-morpholinoethyl)- pentanamide (i.e., L-isoleucine); (2R,3R)-2-amino-3-methyl-N-(2-morpholinoethyl)- pentanamide (i.e., D-isoleucine); (2R,3S)-2-amino-3-methyl-N-(2-morpholino-ethyl)- pentanamide (i.e., D-alloisoleucine); (2S,3R)-2-amino-3-methyl-N-(2-morpholinoethyl)- pentanamide (i.e., L-alloisoleucine); and any combination thereof.
  • Scheme A shows the chemical structures and absolute stereochemistry of 2-amino-3-methyl-N-(2-morpholinoe
  • 'LM11A-31' encompasses all forms of the compound as described above including pharmaceutically acceptable salts, esters, crystal forms, prodrugs or solvates thereof.
  • molecules that are structurally similar to LM11A-31 may also be useful in the methods described herein. Suitable related molecules include those described in US patent application Publication No 20150259278 A1 , which is incorporated herein by reference in its entirety. Molecules that are structurally similar to LM11A-31 that may be useful include, but are not limited to, those set out in Table 1, or a pharmaceutically acceptable salt, ester, crystal form, prodrug or solvate thereof.
  • the p75NTR inhibitors for use in the presently disclosed methods are capable of crossing the blood-brain barrier
  • Example 1 Tissue and plasma preparations and assays
  • Formalin-fixed paraffin-embedded tumour tissue from maximal safe surgical resection was sourced from the Hunter Cancer Biobank (HCB) for 70 cases of glioblastoma, 12 cases of grade III glioma, 6 cases of grade II glioma, and 2 cases of grade I glioma.
  • HAB Hunter Cancer Biobank
  • SUBSTITUTE SHEET (RULE 26) glioma grade was confirmed on hematoxylin and eosin (H&E) stained sections by a neuropathologist. Matching plasma samples were also obtained at the time of diagnosis. Sample processing mirror standard diagnostic processing for plasma including a 15 mins centrifugation at 1500 rpm followed by 10 mins at 2500 rpm. Samples were processed immediately upon receipt into the laboratory and stored in -80°C prior to retrieval.
  • Formalin-fixed paraffin-embedded tumour tissue was sliced into 4 pm full face sections and processed for 3',3'-diaminobenzidine (DAB) immunohistochemistry using a Ventana Discovery Ultra (Roche, USA) by the HCB. Sections were labelled for anti-p75NTR antibody (1:200, catalogue number ab52987, Abeam, Melbourne, VIC, Australia). All steps, from baking to chromogen addition, were performed automatically by the instrument. Tissue sections were baked to slides and deparaffinized, and antigen retrieval occurred at 95°C/pH 9 with a total incubation time of 24 mins prior to the addition of the primary antibody.
  • DAB 3',3'-diaminobenzidine
  • sample slides were digitized using the Aperio AT2 scanner (Leica Biosystems, VIC, Australia) at 40x absolute resolution. Quantitative IHC analyses were performed using the HALOTM image analysis platform (version 3.3, Indica Labs, Albuquerque NM, USA). Tissue classification algorithms were used to differentiate tissues, and pixel intensity values corresponding to DAB staining were calculated using the Cytonuclear module which detects and quantifies protein expression in the cytoplasm. Pixel intensity values were then used to determine the h-scores for each core (index calculated as the sum of 3x% of pixels with strong staining + 2x% pixels with intermediate staining + 1x% pixels with weak staining).
  • H-scores were analyzed as continuous variables with summary statistics presented as group level medians and interquartile ranges (IQR). H- score distributions were compared using the Wilcoxon RankSum (dichotomous) or Kruskal Wallis (multiple comparisons) tests. To assess the primary hypothesis (difference in p75NTR expression between pathological subtypes), a two-sided alpha of 0.05 was used. Statistical analyzes were based on complete cases and performed using Prism (version 8.2.0, GraphPad Software, Boston, MA, USA).
  • Plasma concentrations of p75NTR was determined using an ELISA kit (catalogue number DY008 and DY367, R&D systems, Minneapolis, MN, USA). This sandwich assay allows quantification of p75NTR using a sensitive and specific pre-coated plate with capture antibody, a biotinylated detection antibody and horseradish peroxidase-conjugated streptavidin. All kits were used as per the manufacturer's instructions. Although all controls have been performed by the manufacturers, standard curve validation, spike recovery, linearity of dilution, intraplate reproducibility, limit of detection, and limit of quantitation were independently validated in our laboratory. All serum samples were tested 1:10 dilution. Plates were read with a Spectramax plate reader (Molecular Devices LLC, M3).
  • TMB (3,3', 5,5;-tetramethylbenzidine) incubation step was performed with every ELISA experiment. Plates were incubated in a box, and absorbance at 650 nm was first read at the minimum incubation time specified in the kit protocol, and then every 5 mins thereafter. TMB stop solution was added when the absorbance value (650 nm) of the highest concentration of the standard curve either reached 1.0 or above, or plateaued, and the rate of increase in absorbance was less than 0.3 every 5 mins. Concentration distributions were compared using the Wilcoxon RankSum (dichotomous) or Kruskal Wallis (multiple comparisons) tests.
  • Example 2 Cell culture preparations, assays and xenogaft models
  • glioblastoma cell lines RN1 , MN1, FPW1, HW1 , MMK1 , WK1, PB1 , BAH1 , SJH1 , RK11 , and SB2b were obtained from QIMR Berghofer Medical Research Institute (Dr Bryan Day, Brisbane, QLD, Australia).
  • Human astrocyte (HA) cell line (catalogue number 1800) was obtained from ScienCell Research Laboratories (Wangara, WA, Australia).
  • Mouse Albino neuroblastoma cell line Neuro2A was obtained from Merck (catalogue number 89121404, Merck, Bayswater, VIC Australia).
  • Patient-derived glioblastoma cell lines together with the methylation status of MGMT promoter have previously been described (6, 7).
  • Patient-derived cells were maintained in Knockout DM EM glutamine with 2% Stempro Neural Supplement, 5% penicillin-streptomycin, 2mmol/L L- glutamine.
  • BAH1.TMZ cells were cultured by exposing BAH1 to Temozolomide (TMZ, 50pM) for 3 months until resistant cells were stable.
  • HA cells were maintained in Astrocyte Medium from ScienCell Research Laboratories (catalogue number 1801, Carsbad, CA, USA), which contains basal medium, 10% Fetal Bovine Serum (FBS), 2% astrocyte growth supplement, and 5% penicillin-streptomycin solution; they were also seeded on Poly-L- Lysine (catalogue number P4707, Sigma-Aldrich, Macquarie Park, NSW, Australia) coated flasks.
  • Neuro2A cells were maintained in MEM medium, 2mmol/L L-glutamine, 1% Non Essential Amino Acids (NEAA) and 10% FBS. All cell cultures were kept in a humidified incubator at 37°C with 5% CO2.
  • Routine Mycoplasma testing was performed using the MycoAlert Mycoplasma Detection Kit (catalogue number LT07-118, Lonza, Basel, Switzerland). Cells were not maintained in culture for longer than 3 months to ensure passage number remained fit for purpose.
  • Human ancreatic cancer cell lines (MIA PaCa-2 and PaCa-44) and human prostate cancer cell lines (PC3 and DU 145) were purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA). The prostate cancer and prostate cancer cells were maintained in DM EM with 10% (v/v) foetal bovine serum and GlutaMAX Supplement. All cell cultures were kept in a humidified incubator at 37°C with 5% CO2.
  • Routine Mycoplasma testing was performed using the MycoAlert Mycoplasma Detection Kit (catalogue number LT07-118, Lonza, Basel, Switzerland). Cells were not maintained in culture for longer than 3 months to ensure passage number remained fit for purpose.
  • Cell death assay was carried out using Cell Titer-Blue® (Promega, Hawthorn, VIC, Australia) according to the manufacturer’s instructions.
  • Cells were plated at 5000 cells per well in a Corning Costar 96-well plate followed by treatment with LM11A-31 (200nM, catalogue number P4707, Sigma-Aldrich; vehicle control: DMSO), TMZ (50pM, catalogue number S1237, Selleck Chem, Sapphire Bioscience, NSW, Australia; vehicle control: DMSO) or LM11A-31 + TMZ for 72 hrs.
  • Cell Titer-Blue® reagent was added into each well followed with detection of fluorescent signal by Fluostar Optima (BMG Labtech, Ortenberg, Germany) with a 560/590nm filter set. Cell death was calculated based on the loss of the fluorescent intensity.
  • Cancer cells (5*10 3 cells) were seeded in 6-well plates following treatment. Control cells were similarly treated with an equal volume of vehicle. After 2 weeks, cells were washed with ice cold PBS and fixed with methanol. Plates were stained using 0.5% crystal violet and colonies were counted. T ransfection
  • SiRNA transfection was carried out using lipofectamine RNAiMAX (13778150; Life Technologies, Carlsbad, CA) according to the manufacturer’s instructions.
  • RNAiMAX lipofectamine RNAiMAX
  • Three siRNA duplexes against human NGFR were from Origene (Rockville, MD, USA).
  • Corresponding Control siRNAs were also from Origene.
  • Glioblastoma cells (4x10 5 cells) were seeded in a 6 well plate, and 24 hrs later, cells were washed three times with PBS and then incubated in KO DM EM for another 48 hrs. Conditioned medium was centrifuged for 10 mins at 2000 rpm and then filtered through a 0.22pm filter (Merck, Bayswater, VIC, Australia) to remove the contaminating cells or cell debris.
  • Neuro2A cells (5 x 10 4 cells) were seeded in 24-well plate. Cells were serum starved in MEM + 0.5% NEAA for 24 hrs. Cell-free conditioned medium was then added into the starved cells for 24-72 hrs. Neuro2A cells were considered differentiated when they exhibited neurites of at least twice the length of the cell body. Pictures were taken using a Zeiss Axiovert 200 inverted microscope fitted with an AxioCam HRm digital camera (Zeiss, Jena, Germany).
  • Protein extraction from cell lines and Western blotting experiments were performed as previously described (8).
  • Anti-p75NTR antibody (1:200, catalogue number ab52987, Abeam, Melbourne, VIC, Australia), Anti-proNGF antibody (1:500, catalogue number M- 1738, Biosensis, Thebarton, SA, Australia), or Anti-sortilin antibody (1:500, catalogue number ANT-009, Alomone labs, Jerusalem, Israel) was used at a dilution of 1 :300 and a - actin antibody (catalogue number A1978, Sigma-Aldrich) was used at a 1:5000 dilution as the egual loading control.
  • the patient-derived glioblastoma cells (FPW1 and BAH1), human pancreatic cancer cells (MIA PaCa-2 and PaCa-44) and prostate cancer cells (PC3 and DU 145) (5x10 6 cells per mouse) were injected into the flank of 6-8 weeks old NOD/SCID gamma (NSG) mice.
  • mice When the smallest tumour reached a size of 100mm 3 , the mice were randomly divided into groups followed by treatment with Temozolomide (TMZ, 50mg/kg body weight, IP daily for 5 days), LM11A-31 (10mg/kg body weight, oral gavage daily for 28 days), Gemcitabine (50mg/kg body weight, IP twice/week for 4 weeks), Docetaxel (8mg/kg body weight, IP twice/week for 4 weeks), TMZ+LM11A-31, Gemcitabine+LM11A-31, Docetaxel +LM11A-31 or vehicle control. Tumours and body weight were measured every 2 days.
  • TMZ Temozolomide
  • LM11A-31 10mg/kg body weight, oral gavage daily for 28 days
  • Gemcitabine 50mg/kg body weight, IP twice/week for 4 weeks
  • Docetaxel 8mg/kg body weight, IP twice/week for 4 weeks
  • Tumours and body weight were measured every 2 days.
  • mice were euthanized, and tumour tissues were collected, measured, and processed for histological examination.
  • tumour volume at the start of the treatment was normalized at 100%.
  • mice Six-week-old female BALB/c nude mice were implanted with BAH1 cells (2x10 5 cells) into the right hemisphere. Briefly, mice were anesthetized and fixed in a stereotaxic frame. A burr hole was drilled using a surgical high-speed drill (at 2 mm to the right of the bregma and 1 mm anterior to the coronal suture) (5), and cells were injected using a Manipulate Hamilton syringe.
  • mice were randomly divided into groups followed by treatment with Temozolomide (TMZ, 50mg/kg body weight, IP daily for 5 days) + Radiation (2Gy daily for 5 days), LM11A-31 (10mg/kg body weight, oral gavage daily for 28 days), TMZ+Radiation+LM11A-31or vehicle control. Body weight was measured every 2 days.
  • TMZ Temozolomide
  • LM11A-31 10mg/kg body weight, oral gavage daily for 28 days
  • TMZ+Radiation+LM11A-31or vehicle control Body weight was measured every 2 days.
  • mice were euthanized, and mouse brain were collected, measured, and processed for histological examination. This study was approved by the Animal Care and Ethics Committee of University of Newcastle (A-2022-222) and all experiments were performed in accordance with relevant guidelines and regulations.
  • mice The cognitive performance of mice was tested using the Novel object recognition test. A mouse was presented within a cage with two similar objects during the first session for 10 minutes for formalization with the arena. Then the mouse was removed from the arena for 1 hour. The mouse was presented back to the cage with one of the two objects replaced by a new object for 10 minutes. The amount of time taken to explore the new object provides an index of recognition memory.
  • Example 4 Increased p75NTR expression in glioblastoma tissue
  • Example 5 Certain glioblastoma cells are more sensitive to LM11A-31
  • LM11A-31 a small pharmacological inhibitor of p75NTR, was used to treat a panel of 11 patient-derived GBM cell lines.
  • LM 11 A-31 induced significant amount of cell death in GBM cells ( Figure 2A).
  • the sensitivity of GBM cells to LM11A-31 was not related to the mutational status of the frequent mutations in GBM, such as TP53, PTEN, NF1 (2).
  • Example 6 LM 11 A-31 potentiates the efficacy of chemotherapeutic agents in glioblastoma
  • LM11A-31 The effects of LM11A-31 on the second-line therapeutic agents for GBM: Bevacizumab (anti-Vascular endothelial growth factors (VEGF) antibody), Carmustine (alkylating agent), Hydroxyurea (antimetabolites) and Procarbazine (alkylating agent) were also tested. Cell death was studied in patient-derived GBM cells MN1 (unmethylated MGMT promoter), BAH1 (methylated MGMT promoter) and BA H1. TMZ treated with LM11A-31 in combination with Bevacizumab, Carmustine, Hydroxyurea or Procarbazine. LM11A-31 sensitized GBM cells to Carmustine in all the tested cell lines ( Figures 4A to 4C), which was supported by colony formation assay ( Figure 4D).
  • VEGF vascular endothelial growth factors
  • Carmustine alkylating agent
  • Hydroxyurea antimetabolites
  • Procarbazine alkylating agent
  • Example 6 Neuroprotective role of LM11A-31 in glioblastoma
  • LM11A-31 treatment has shown neuroprotective effect in Alzheimer’s disease. Therefore, the neuroprotective benefit of LM11A-31 was then also studied in neurons in GBM. First, mouse neural crest-derived cells Neuro2A was exposed to TMZ alone or in combination with LM11A-31. Cell death induced by TMZ in Neuro2A cells could be blocked by LM11A-31 ( Figure 5A), indicating that LM11A-31 protects neuronal cells from TMZ- induced cell death.
  • Neuro2A cells were cultured in the conditioned media harvested from MN1 or BAH1 cells treated with TMZ alone or in combination with LM11A-31. Neurite outgrowth, which was measured in neuronal cells exposed to conditioned media as a percentage of cells with elongated neurites, was observed in neuronal cells cultured in TMZ c.m. ( Figure 5B). Neuro2A cells significantly showed more neurites in the presence of TMZ c.m. compared with control media ( Figure 50). LM11A-31 decreased neurite outgrowth induced by TMZ- treated GBM cells ( Figures 5B and 5C). In addition, LM11A-31 also reduced neurite outgrowth-induced by BAH.1. TMZ cells ( Figures 5D and 5E). Neural activity within the tumour is modulated by chemotherapy and participates in tumour cell dissemination and cancer relapse. These data indicate that LM11A-31 reduces TMZ-induced neural activity in GBM, which is likely to contribute to the relapse of GBM.
  • Example 7 LM11A-31 reduces GBM tumour growth and improves the efficacy of Temozolomide in vivo.
  • the effect of LM11A-31 was tested using a subcutaneous model of GBM.
  • the patient-derived GBM cells FPW1 (unmethylated methyl guanine methyltransferase (MGMT) promoter) and BAH1 (methylated MGMT promoter) were injected into the flank of 6-8 weeks old female NOD/SCID gamma (NSG) mice.
  • TMZ Temozolomide
  • LM11A-31 also significantly reduced tumour volume.
  • Figs. 6A and 6B Importantly, co-treatment of LM11A-31 further reduced GBM growth compared to TMZ alone (Figs. 6A and 6B).
  • Example 8 LM11A-31 shows neuroprotective role in GBM model in vivo.
  • LM11A-31 has been shown to augment neuronal survival and preserve neuronal health and function in patients with various neurological diseases (12).
  • the patient-derived BAH1 cells were intracerebrally injected into the BALB/c nude mice (2mm to the right of the bregma and 1mm anterior to the coronal sutures (13)) to establish orthotopic GBM model.
  • mice were treated with Radiation+TMZ with or without LM11A-31.
  • the Novel Object Recognition Test was performed to explore the cognitive functions, such as learning and memory, in mouse model. Mice treated with Radiation and TMZ spent less amount of time to explore the novel object (Fig. 7A), demonstrating the neurotoxicity induced by the standard GBM treatment. Importantly, co-treatment with LM11A-31 restored the exploration time (Fig. 7A), indicating the ability of LM11A-31 to limit cognitive impairments induced by GBM treatment. Consistently, the brain weight of the mice that were co-treated with LM11A-31 was significantly higher than that of the mice treated with Radiation and TMZ (Fig. 2B), indicating that LM11A-31 shows a neuroprotective role in GBM treatment-related neurotoxicity.
  • Example 9 LM11A-31 reduces the growth of pancreatic cancer in vivo.
  • LM11A-31 reduces the growth of prostate cancer in vivo.
  • the human prostate cancer PC3 and DLI145 cells were injected into the flank of 6-8 weeks old male NOD/SCID gamma (NSG) mice. Treatment with Docetaxel significantly reduced tumour growth. LM11A-31 also significantly reduced tumour volume. (Figs. 9A and 9B). However, co-treatment of LM11A-31 could not further reduce prostate cancer growth compared to Docetaxel alone (Figs. 9A and 9B).
  • Soreide K Receiver-operating characteristic curve analysis in diagnostic, prognostic and predictive biomarker research. J Clin Pathol. 2009;62(1):1-5.
  • ProNGF correlates with Gleason score and is a potential driver of nerve infiltration in prostate cancer. Am J Pathol. 2014;184(12):3156-62.

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Abstract

L'invention concerne une méthode de traitement d'un cancer exprimant le récepteur de la neurotrophine p75 (par exemple, le glioblastome, le cancer de la prostate ou le cancer du pancréas) chez un sujet, comprenant l'administration au sujet d'une quantité thérapeutiquement efficace de 2-amino-3-méthyl-N-(2-morpholinoéthyl)-pentanamide (LM11A-31), ou d'un sel, d'un ester, d'une forme cristalline, d'un promédicament ou d'un solvate pharmaceutiquement acceptables de celui-ci.
PCT/AU2024/050248 2023-03-20 2024-03-20 Méthode de traitement du glioblastome ou d'autres cancers exprimant le récepteur de la neurotrophine p75 Pending WO2024192470A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018039641A1 (fr) * 2016-08-25 2018-03-01 Pharmatrophix, Inc. Procédés et composés pour le traitement de troubles d'utilisation d'alcool et de maladies associées
WO2023002008A1 (fr) * 2021-07-22 2023-01-26 Fundación Del Sector Público Estatal Centro Nacional De Investigaciones Oncológicas Carlos III (F.S.P. CNIO) Thx-b pour le traitement et la prévention du cancer et de la métastase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018039641A1 (fr) * 2016-08-25 2018-03-01 Pharmatrophix, Inc. Procédés et composés pour le traitement de troubles d'utilisation d'alcool et de maladies associées
WO2023002008A1 (fr) * 2021-07-22 2023-01-26 Fundación Del Sector Público Estatal Centro Nacional De Investigaciones Oncológicas Carlos III (F.S.P. CNIO) Thx-b pour le traitement et la prévention du cancer et de la métastase

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Title
AHN B Y, SALDANHA-GAMA R F G, RAHN J J, HAO X, ZHANG J, DANG N-H, ALSHEHRI M, ROBBINS S M, SENGER D L: "Glioma invasion mediated by the p75 neurotrophin receptor (p75NTR/CD271) requires regulated interaction with PDLIM1", ONCOGENE, NATURE PUBLISHING GROUP UK, LONDON, vol. 35, no. 11, 1 March 2016 (2016-03-01), London , pages 1411 - 1422, XP093215415, ISSN: 0950-9232, DOI: 10.1038/onc.2015.199 *
BERGHOFF JANINA; JAISIMHA ANIRUDH VINAY; DUGGAN STEPHEN; MACSHARRY JOHN; MCCARTHY JUSTIN V.: "Gamma-secretase-independent role for cadherin-11 in neurotrophin receptor p75 (p75NTR) mediated glioblastoma cell migration", MOLECULAR AND CELLULAR NEUROSCIENCES., SAN DIEGO, US, vol. 69, 1 January 1900 (1900-01-01), US , pages 41 - 53, XP029307741, ISSN: 1044-7431, DOI: 10.1016/j.mcn.2015.10.003 *
CROOKS AMANDAM, MEEKER RICKB: "The new wave of p75 neurotrophin receptor targeted therapies", NEURAL REGENERATION RESEARCH, MEDKNOW PUBLICATIONS AND MEDIA PVT. LTD., CN, vol. 17, no. 1, 1 January 2022 (2022-01-01), CN , pages 95, XP093215418, ISSN: 1673-5374, DOI: 10.4103/1673-5374.314304 *
JIA CHEN.: "Expression of p75 neutrophin receptor in human neuroblastoma cells under condition of oxygen-glucose deprivation and its significance", ACADEMIC JOURNAL OF SECOND MILITARY MEDICAL UNIVERSITY, DI-ER JUN-YI DAXUE, SHANGHA, CN, vol. 12, 1 January 2019 (2019-01-01), CN , pages 1325 - 1329, XP009557733, ISSN: 0258-879X *

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