WO2020023800A1 - Clinical methods and pharmaceutical compositions employing ampa receptor antagonists to treat glioblastoma and other cancers - Google Patents

Clinical methods and pharmaceutical compositions employing ampa receptor antagonists to treat glioblastoma and other cancers Download PDF

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WO2020023800A1
WO2020023800A1 PCT/US2019/043525 US2019043525W WO2020023800A1 WO 2020023800 A1 WO2020023800 A1 WO 2020023800A1 US 2019043525 W US2019043525 W US 2019043525W WO 2020023800 A1 WO2020023800 A1 WO 2020023800A1
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cancer
ampar
pmp
perampanel
substituted
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PCT/US2019/043525
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French (fr)
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Daniel Pierce RADIN
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With Great Power, Llc
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Priority to AU2019310122A priority Critical patent/AU2019310122A1/en
Priority to US17/261,857 priority patent/US20210308111A1/en
Priority to EP19841117.5A priority patent/EP3829567A4/en
Priority to CA3145507A priority patent/CA3145507A1/en
Publication of WO2020023800A1 publication Critical patent/WO2020023800A1/en

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    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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    • 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
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • 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
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Definitions

  • the invention relates to drugs and clinical methods for treating cancer in mammalian subjects. More specifically the invention relates to treating glioblastoma and other cancers that are positive for expression of AMPA-receptors.
  • GBM Glioblastoma
  • CNS central nervous system
  • GBM tumors often exhibit resistance to chemotherapy and/or radiotherapy , w hich resistance may be acquired during a course of treatment (Ishiuchi et al, 2007).
  • Temozolomide is a DNA methylating agent that is the current standard of care drug for treating GBM.
  • TMZ mediates anti-cancer effects through genotoxic activity, and is effective in GBM treatment due in part to the drug ' s ability to bypass the blood-brain barrier (BBB) (Prasad ct al. 201 1 ).
  • BBB blood-brain barrier
  • TMZ show s limited efficacy for long-term treatment of GBM, and many patients appear to be refractory to TMZ treatment.
  • the A MPA -type glutamate receptor may be overexpressed in certain types of cancer, including some forms of CNS cancers (Liu et al, 2015) and non-CNS cancers (Stepulak ct al, 2007: Herner et al. 201 1 ; Romeling et al, 2014; Hu et al, 2014).
  • AMPAR activation ma be linked to increased cancer cell invasiveness (Piao et al. 2008). proliferation, and/or activation of the PI3 K/Akt/mTOR signaling axis (Ishiuchi et al. 2007).
  • the P13K/Akt/mTOR signaling axis has been implicated in chemotherapy resistance in GBIVl. and available drugs reported to disrupt this pathway, such as rapamycin. do not penetrate the BBB.
  • GBM cancer stem cells (suspected to be capable of re-establishing tumors after ablation with surgery, chemotherapy or radiotherapy) may express strikingly high amounts of functional AMPARs (Oh et al, 2012).
  • the instant invention satisfies the foregoing needs and fulfills additional objects and advantages by providing novel AMPAR antagonist drugs effective to treat AMPAR positive cancers and AMPAR dependent cancers, including AMPAR positive and AMPAR dependent cancers of the central nervous sy stem (CNS).
  • the invention provides compositions and methods employing a novel anti-cancer drug, Perampanel (PMP) [2-(2-oxo- 1 -phenyl-5-pyridin-2-yl- 1 ,2-d i hydropy rid i n-3 -> 1 ) ben/onitrile], heretofore reported for limited clinical use as an antispasmodic drug.
  • PMP Perampanel
  • AMPA receptor antagonists have been investigated for antiseizure activity both preclinically and clinically, with mixed success.
  • the prototypical competitive AMPA receptor antagonist 2.3-dihydroxy-6-nitro-7-sulfamoyl-benzo[ f] quinoxaline (NBQX) showed activity in maximal electroshock (MBS) and pentylenetetrazole (PTX)- induced seizure models (Yainaguchi et al.. 1993). but has poor solubility resulting in precipitation in the kidney at therapeutic plasma levels.
  • Derivatives of NBQX with polar constituents have shown improved solubility, but these molecules exhibit reduced blood-brain barrier (BBB) penetration (Weiser, 2005).
  • Prototypical noncompetitive AMPA receptor antagonists such as 2.3-benzodiazepine-type compounds, have show n weak in vitro efficacy compared with competitive antagonists (Weiser. 2005).
  • Talampanel. a recently developed noncompetitive AMPA receptor antagonist has been evaluated in a number of cl inical trials (l lovves & Bell. 2007). but has a relatively short half-life militating against its potential clinical utility (Langan et al.. 2003). More recently. Steinhoff et al.. 201 3. reported beneficial activity of Peramplanel. a noncompetitive selective AMPA receptor antagonist as an antiepileptic drug undergoing clinical study for refractory partial-onset seizures.
  • PMP peramplanel
  • the invention provides novel compositions and methods for treating cancer using AMPAR antagonist compounds such as PMP to reduce or prevent the occurrence remission growth severity and/or one or more adverse symptom(s) of AMPA-receptor positive cancers in mammalian subjects, including humans.
  • the AMPAR antagonist comprises a PMP compound (including anti-cancer effective chemical analogs, derivatives, conjugates, solid crystalline forms solvates and/or different salt forms of a PMP compound), which is clinically effective as an anti-cancer agent to treat or prevent cancer in mammalian subjects.
  • PMP is administered to a human patient presenting with an AMPAR positive cancer condition in a delivery mode, formulation and dosage sufficient to alleviate one or more symptoms of the targeted cancer condition in the patient.
  • the PMP compound is perampanel [2-(2-oxo- 1 -phenyl-5- pyridin-2-yl- 1.2-dihydropyridin-3-yl) benzonitrile] formulated in a biologically acceptable composition for administration to a human subject.
  • novel clinical methods employing a peramplanel or related compound administered to a mammalian subject, wherein the peramplanel compound exerts oncolytic effects against a targeted cancer cell or tumor sufficient to kill a targeted cell or tumor reduce size of a tumor, impair tumor growth, prevent or reduce cancer invasiveness, reduce or delay cancer recurrence, and/or alleviate one or more symptoms associated with the treated cancer condition.
  • peramplanel and related compounds are employed in effective anti-cancer methods for treating glioblastoma (GBM).
  • the peramplanel compound is administered to a mammalian subject with current or prior diagnosis of GBM in a dosage form amount and regimen sufficient to prevent or reduce the occurrence severity, recurrence and/or related sy mptoms of GBM in the subject.
  • pharmaceutical compositions and delivery methods arc provided that yield surprisingl high therapeutic concentrations of the peramplanel compound in a CNS compartment of the subject e.g., in the brain yielding potent anti-CNS-cancer therapeutic effects.
  • a peramplanel compound is administered w ith a secondary therapeutic agent in combinatorial formulations or coordinate treatment methods to yield desired therapeutic advantages.
  • a peramplanel compound is coordinately administered with a second anti-cancer drug to treat cancer, whereby anti cancer efficacy is enhanced and/or adverse side effects are reduced.
  • peramplanel is coordinately administered with temozolomide (TMZ) to treat GBM, pancreatic cancer, or another form of cancer.
  • TMZ temozolomide
  • peramplanel is coordinately administered with cisplatin to treat an AMPAR positive cancer for example an AMPAR positive pancreatic cancer.
  • peramplanel is coordinately administered with hydroxyurea to treat an AMPAR positive cancer.
  • peramplanel is coordinately administered with Carmustine (BCNU) to treat an AMPAR positive cancer.
  • BCNU Carmustine
  • a peramplanel compound is coordinately administered before or after a conventional cancer treatment for example surgery, chemotherapy or radiation treatment with or w ithout a secondary anti-cancer agent or other secondary therapeutic drug.
  • a peramplanel compound to reduce oncogenic activity by disrupting a glutamate- induced cancer potentiation process (e.g.. glutamate-stimulated cancer cell proliferation, tumor grow'th. cancer invasion or other cancer-potentiation activity).
  • a glutamate- induced cancer potentiation process e.g. glutamate-stimulated cancer cell proliferation, tumor grow'th. cancer invasion or other cancer-potentiation activity.
  • AM PAR antagonist compounds are employed in novel clinical methods and compositions to treat lung cancers, breast cancers, pancreatic cancers, liver cancers colorectal cancers and other forms and symptoms of cancer conditions in human subjects.
  • Figure 1 is a related graph series documenting the effects of PMP on T98G GBM cell viability.
  • Figure 2 is a related graph series documenting the effects of PMP on Pane l cell viability.
  • Data are presented as mean +/- SEM of 2 or more independent experiments performed in quadruplicate. ANOVA. PO.OO l for PMP and glutamate, indicating a significant dose-dependent response.
  • *p ⁇ 0.01. t-test compared to viability of glutamate- or PMP-treated cells alone.
  • Figure 3 is a flow chart illustrating seven candidate anti-cancer chemical derivatives (D 1 -D7) of peramplanel (PMP). wherein PMP is modified according to known methods of conventional rational design chemistry to yield ne candidate compounds for testing to determine anti-cancer activity and other beneficial properties.
  • PMP peramplanel
  • the invention provides AMPAR antagonist, compounds exemplified by peramplanel (PMP), shown to be surprisingly effective in treating cancers, including CNS cancers, in mammalian subjects.
  • PMP peramplanel
  • peramplanel is shown to exert potent direct oncolytic effects against cancer cells in assays accepted to predict clinical anti cancer activity in human subjects. More speci fically the examples below show that PMP potently disables viability of CNS and non-CNS cancers, as demonstrated by direct oncolytic effects against glioblastoma (GBM) and pancreatic cancer cells.
  • GBM glioblastoma
  • pancreatic cancer cells relate studies further evince that peramplanel exerts surprisingly potent additive or synergistic anti-cancer effects in coordinate use with other chemotherapeutic drugs.
  • CNS central nervous system
  • AMT acute myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • mesothelioma pancreatic cancer.
  • Hodgkin's disease testicular cancer; Waldenstrom's disease: head/neck cancer: cancer of the tongue, viral-induced malignancies (e.g.. cancers induced by SV 40 virus), and other candidate types and forms of cancers that will be apparent to skilled artisans.
  • viral-induced malignancies e.g.. cancers induced by SV 40 virus
  • Subjects amenable to treatment may have cancer of any stage of development and etiology, including, but not limited to, cancers marked by rapid increases in
  • stage 111 and stage IV cancers e.g.. to effectively subjects with cancers, such as glioblastoma, persisting or relapsing after ineffective, conventional anti cancer treatment(s) (e.g.. surgery, radiation and/or chemotherapy)).
  • an effective AMPAR antagonist drug such as PMP effectively prevents or treats (i.e., reduces the severity, progression and/or adverse side effects of) cancer in treatment resistant subjects, defined as subjects presenting after one or more rounds of conventional oncotherapy (e.g.. chemotherapy, radiation, surgery and/or hormonal therapy), with actively progressing or unstable metastatic disease.
  • conventional oncotherapy e.g.. chemotherapy, radiation, surgery and/or hormonal therapy
  • the compositions and methods of the invention are useful for treating other refractory " patients w ho ma ⁇ not otherwise tolerate or be fit for conventional cancer treatments such as chemotherapy.
  • AMPAR antagonist drugs and methods of the invention are particularly effective against "AMPAR dependent " cancers.
  • AMPAR dependent cancers.
  • AMPAR dependent refers to cancers that distinctly overexpress AMPA receptors, or whose appearance growlh. and/or disease progression may otherwise be determined to be AMPAR- dependent.
  • AMPAR-dependenf cancers are not limited to cancers wliose occurrence, persistence or progression require abnormal ly elevated AMPAR receptor expression or activity, indeed they may include cancers with normal or even subnormal expression of AMPARs. hich through disease-associated changes in AMPAR structure or function or any other disease-associated change affecting AMPAR metabolism or pathology, are particularly susceptible to AMPA receptor interference or blockade using PMP or other candidate AMPAR drugs of the invention.
  • AMPAR antagonist drugs exemplified by PMP effectively treats or prevents a wide range of cancers contemplated to represent "AMPAR-dependent cancers "including but not limited to brain cancer, breast cancer colorectal cancer, hepatocellular cancer, leukemia, melanoma, lung cancer, pancreatic cancer, renal cancer, and other candidate cancer types or cases determined to be clinically susceptible to AM PAR interference or blockade by PMP or another useful AMPAR antagonist.
  • Each of the anti-cancer methods of the invention involves administration of a suitable, effective dosage amount of PMP or another useful AMPAR antagonist to a subject.
  • an effective amount will comprise an amount of the active compound (e.g., PMP) which is therapeutically effective, in a single or multiple unit dosage form, over a specified period of therapeutic intervention to measurably alleviate the targeted cancer condition.
  • PMP is used as the sole or primary active drug.
  • an intermediary or precursor compound to PMP. or a rationally-designed analog or derivative of PMP i.e.. a related compound having close structural and functional similarity to PMP is employed.
  • the PMP or other effective AMPAR antagonist is typically formulated in a pharmaceutical composition with one or more pharmaceutically acceptable carriers, excipients, vehicles, emulsifiers, stabilizers preservatives, buffers, and/or other additives that may enhance stability, delivery, absorption, half-life, efficacy,
  • pharmacokinetics and/or pharmacodynamics, reduce adverse side effects, or provide other advantages for pharmaceutical use.
  • Anti-cancer effective dosage amounts of PMP and other effective, anti-cancer AMPAR antagonists of the invention will be readil determined by those of ordinary skill in the art, depending on clinical and patient-specific factors. Suitable effective unit dosage amounts of the active compounds for administration to mammalian subjects, including humans, may range from a minimum daily dose of 1 -2 mg up to a maximum prospective dose between about 200-500 or 300- 1 .000 mg/da . or greater. In certain embodiments, the anti cancer effective dose is between about 2 mg-200 mg/day, in other embodiments between about 20-400 mg/day. 50-500 mg/day. 200-600 mg/day, or another anti-cancer effective dose or dosage range that can be adjusted based on patient specific factors to optimize efficacy and minimize adverse side effects.
  • the PMP or other AMPAR antagonist may be administered in a single dose, or in the form of a multiple periodic dosing protocol, for example in a dosing regimen comprising from 1 to 5, or 2-3 doses administered per day. per week, or per
  • the amount, timing and mode of delivery of the anti-cancer compositions of the invention will be routinely adjusted on an individual basis depending on such factors as patient weight age. gender, and condition of the individual, the acuteness of the subject ' s disease and severity symptoms whether the administration is prophylactic or therapeutic, prior treatment history (including e.g., any prior history and responsiveness to chemotherapy or other cancer treatment treatment) and on the basis of other factors known to effect drug delivery, absorption, pharmacokinetics and efficacy.
  • An effective dose or multi-dose treatment regimen for the instant AMPAR antagonist formulations will ordinarily be selected to approximate a minimal dosing regimen necessary and sufficient to substantially prevent or alleviate the cancer condition, and/or to substantially prevent or alleviate one or more symptoms associated w ith that condition.
  • a dosage and administration protocol w ill often include repeated dosing therapy over a course of several days or even one or more weeks up to several months, or even a year or more.
  • An effective treatment regime may also involve prophylactic dosage administered on a daily or multi-dose per day basis lasting over a course of days, weeks, months or even a year or more.
  • Various assays and pre-clinical and clinical model systems can be readily employed to determine therapeutic effectiveness of the anti-cancer compositions and methods invention. For example these may detect/monitor a decrease in overt symptoms, such as pain (e.g., as measured using any of a variety of pain scales including but not limited to, the Visual Analog Scale. McGill Pain Questionnaire, Descriptor Differential Scale. Faces Pain Scale. Verbal Rating Scale. Simple Descriptive Pain Scale. Numerical Pain Scale (NPS), or Dolorimeter Pain Index). More detailed detection/monitoring may document, for example, a decrease in circulating tumor cells (CTCs).
  • CTCs circulating tumor cells
  • Effectiveness of the anti-cancer methods and compositions of the invention are generally demonstrated by a decrease in incidence severity and/or associated symptoms of cancer which will typically involve a decrease of 5%. 10%. 25%. 30%. 50%, 75%, 90% or more in comparison to incidence/levels of the same diagnosed indicator/state, or attendant symptom(s) in suitable control subjects (or compared to known baseline or median data for like, treated or untreated subjects).
  • PMP-treated cancer patients will often exhibit a decrease in number or size of targeted tumors, a decrease in circulating tumor cells (C ' TCs) or Cancer Stem Cells (CSC ' s) in successive blood assays, and/or a decrease in one or more tumor-associated cytological.
  • histochemical or blood markers during a course of treatment, of from 25%-30%, 50%. 75% or higher. 90% and up to total absence of the disease indicator(s) to a limit of detectability associated with the employed assay(s).
  • Monitoring for effective cancer prevention and treatment of the invention can employ any of a vast array conventional detection and monitoring tools and indicia as will be apparent to those skilled in the art.
  • CTC monitoring using blood samples of patients can utilize flow cytometry, immunobead capture, fluorescence microscopy standard and density
  • tumor monitoring can employ x-ray. MRI. CT or PET scans, among other methods and tools. For economy these and other routine well-know n cancer disease detection and monitoring technologies will not be reiterated here.
  • exemplary embodiments of the invention employ peramplanel (PMP) as an anti-cancer effective AM PAR antagonist compound.
  • PMP peramplanel
  • Perampanel is structurally distinct from other AMPAR antagonists which as a group show a great deal of structural diversity (for example, as illustrated in Table I comparing the structure of PMP to two other AMPAR antagonists, Telampanel and NBQX.
  • PMP potently reduces or prevents the occurrence, remission, growth and/or severity of targeted cancers in mammalian subjects, including humans.
  • PMP is effective to prevent or treat (including to reduce one or more adverse symptom(s) of), an AMPAR positive cancer in a human cell population tissue, organ or whole patient.
  • effective anti-cancer for clinical use, effective anti-cancer
  • compositions may comprise a prototypical PMP compound [2-(2-oxo- l -phenyl-5-pyridin-2- yl- 1 ,2-dihydropyridin-3-yl) benzonitrile], or any effective prodrug, metabolite, analog, derivative, conjugate, solid crystal line form, solvate and/or advantageous salt form of PMP shown to be clinically effective as an anti-cancer agent.
  • a prototypical PMP compound [2-(2-oxo- l -phenyl-5-pyridin-2- yl- 1 ,2-dihydropyridin-3-yl) benzonitrile]
  • any effective prodrug, metabolite, analog, derivative, conjugate, solid crystal line form, solvate and/or advantageous salt form of PMP shown to be clinically effective as an anti-cancer agent or any effective prodrug, metabolite, analog, derivative, conjugate, solid crystal line form, solvate and/or advantageous salt form of PMP shown to
  • the invention further provides various chemical analogs and derivatives of PMP that actively treat or prevent cancer, and in certain cases provide additional clinical advantages, for example improved solubility enhanced blood-brain barrier penetration, prolonged half-life, increased AMPAR antagonist activity among other functional improvements.
  • FIG. 3 provides a flow chart illustrating seven candidate anti-cancer chemical derivatives (D 1 -D7) of peramplanel (PMP) contemplated for anti-cancer testing within the clinical methods herein.
  • the illustrated compounds, D 1 -D7 can be readily produced, along with many additional PMP analogs and derivatives, employing known methods of conventional rational design chemistry. Such routine design and synthesis efforts will yield a diverse array of ne candidate compounds for testing ithin the methods of the invention, to determine anti-cancer activity and other beneficial properties.
  • each of the available R groups identified w ithin or attached to each of the aromatic rings of PMP can be altered (e.g.. by chemical deletion, substitution or addition) to yield new candidate PMP derivative drugs as described.
  • the exemplar ⁇ derivatives shown in Figure 3 - PMP D 1 may be designed, tested and selected to have increased solubility improved half-life, better delivery or penetration to desired targets or compartments (e.g.. to deliver an effective dose wdthin a tumor mass, to transit the blood brain barrier (BBB) in anti-cancer effective amounts, to survive first pass metabolism and transport to a target organ in effective plasma concentration, etc.).
  • desired targets or compartments e.g. to deliver an effective dose wdthin a tumor mass, to transit the blood brain barrier (BBB) in anti-cancer effective amounts, to survive first pass metabolism and transport to a target organ in effective plasma concentration, etc.
  • BBB blood brain barrier
  • D3 and D4 are designed to have more hydrophilic character, whereby they will have improved BBB penetration and accumulate to an effective concentration greater in the CNS to mediate clinical benefits of treating and/or preventing CNS related cancers such as GBM.
  • PMP D5 is designed to provide increased solubility for improved drug delivery,
  • PMP D6 is an exemplar prodrug (a glycine ester) of PMP D5. which will be rapidly hydrolyzed into PMP D5 in the blood by plasma glycine esterases, thus providing the contemplated prodrug benefits in addition to increased solubility.
  • PMP D7 and D8 are likewise more hydrophilic derivatives of PMP which will penetrate the BBB and accumulate in effective concentrations for anti-cancer drug effects in the CNS.
  • each R group may be modified to a same or different derivative or analog R group identity.
  • Rational design chemical alterations to PMP can include alterations wherein an original PMP R group is altered to a ne structural identity selected from for example: a substituted or unsubstituted lower hydrocarbon including an alkyl alkenyl alkanoy l. alkynyl, aryl aroyi. aralkyl, alkylamino. aryloxy, hydrogen, carboxy l nitro thioalkoxy. thioaryloxy. thiol, cycloalkenyl cycloalkyl, heterocycloalkyl, heteroaryl aralkyl, amino acid peptide dye.
  • fluorophore carbohydrate or polypeptide
  • a substituted or unsubstituted lower hydrocarbon containing 1 to 20 carbons such as alkoxycarbonyl. allkoxycarbonylamino. amino, amino acid, aminocarbonyl. aminocarbonyloxy. aralkyl aryloxy.
  • one or more R group(s) of PMP can be modified to a hydrogen hydroxyl, sulfyhydryl. benzyl, 2- bromovinyl amino, hydroxymethyl methoxy. halogen pseudohalogen, cyano, carboxyl, nitro, thioalkyl.
  • combinatorial formulations and coordinate treatment methods are provided that emplo an effective amount of PMP or another anti- cancer effective AMPAR antagonist compound or composition, and one or more secondary or adjunctive agcnt(s) combinatorial! ⁇ formulated or coordinately administered with the AMPAR antagonist compound or composition to yield an enhanced anti-cancer composition or method.
  • exemplary combinatorial formulations and coordinate treatment methods in this context employ a PMP compound in combination w ith the one or more secondary anti-cancer, anti-viral and/or immune-stimulator ⁇ effective agents or drugs.
  • Exemplary combinatorial formulations and coordinate treatment methods of the invention employ PMP or another anti-cancer effective AMPAR antagonist compound or composition in combination with one or more secondary or adjunctive anti-cancer effective agents, for example one or more chemotherapeutic agents.
  • these secondary agents/therapies for use within the invention may include any anti-cancer or anti-proliferative agent agents that destroy or reprogram ” cancer cells agents that destroy blood vessels associated with neoplasms or hyperproliferative conditions and other classes of drugs harmful to neoplastic cellular targets.
  • useful chemotherapcutics and adjunctive therapies for use within the invention include, but are not limited to:
  • VDAs Anti-angiogenic agents and vascular disrupting agents
  • Anti-inflammatory agents such as COX inhibitors:
  • Ceil cycle regulators eg. check point regulators and telomerase inhibitors.
  • coordinate anti-cancer treatment methods of the invention can include coordinate administration of one or more anti-cancer AMPAR antagonist compounds with a secondary anti-cancer agent selected from azacitidine. bevacizumab. bortezomib. capecitabine. cetuximab. clofarabine. dasatinib. decitabine, docetaxel, emend, erlotinib hydrochloride excmcstane. fulvestrant. gefitinib. gemcitabine hydrochloride, imatinib mesylate imiquimod. lenalidomide. letrozole . nelarabine.
  • oxaliplatin paclitaxel, docetaxel, palifermin, panitumumab. pegaspargase, pemetrexed disodium, rituximab, sorafenib tosylate, sunitinib malate, tamoxifen citrate, targretin, temozolomide, thalidomide, and/or topotecan hydrochloride.
  • Additional contemplated secondary anti-cancer effective agents in this context include but are not limited to. interleukin-2 interferon a. filgrasten. G- CSF, epoetin alfa, erythropoietin. Il.- l . oprelvekin. trastuzumab. vorinostat, antibiotics, coenzyme q. palladium lipoic complexes including, for example. poly-MVA®,
  • antineoplastins cartilage hydrazine sulfate; milk thistle, electrolytes such as calcium carbonate, magnesium carbonate sodium bicarbonate and potassium bicarbonate; oxidizing agents including, but not limited to. cesium chloride potassium chloride, potassium orotate and potassium aspartate; immunoglobulins; colostrum: and vitamin and mineral supplements, including but not limited to. zinc chloride magnesium chloride, pyridoxine, vitamin B- 12. B complexes folic acid, sodium ascorbate, and probiotics. Additional secondary therapies may include conventional chemotherapy, radiation therapy, and/or surgery.
  • the PMP or other AMPAR antagonist is coordinate! ⁇ administered with temozolomide (TMZ).
  • TTZ temozolomide
  • the PMP or other AMPAR antagonist is coordinately administered with cisplatin to treat an AMPAR-dependent cancer for example an AMPAR-positive pancreatic cancer.
  • an anti-cancer effective PMP or other AMPAR antagonist compound is coordinately administered with hydroxyurea to treat an AMPAR positive cancer.
  • the PMP or other AMPAR antagonist is coordinately administered with Carmustine (BCNU) to treat an AMPAR positive cancer.
  • BCNU Carmustine
  • anti-cancer effective AMPAR antagonist administration is combined with a secondary anti-cancer agent or therapy, e.g.. selected from a transcription inhibitor (e.g.. Terameprocol). a telomere disrupting agent (e.g., TRF 1 inhibitors such as F.TP-4707). an inhibitor of a gene splicing protein (e.g., a PRMT5 inhibitor) an indoleamine 2. 3. dioxegenase (IDO) inhibitor, lapatinib ditosylate enzyme blocker anti-cancer antibodies antibody fragments and related biologies " , for example Adavosertib.
  • a transcription inhibitor e.g. Terameprocol
  • a telomere disrupting agent e.g., TRF 1 inhibitors such as F.TP-4707
  • an inhibitor of a gene splicing protein e.g., a PRMT5 inhibitor
  • an indoleamine e.g., a PRMT5
  • coordinate anti-cancer treatment methods of the invention can include coordinate administration of one or more anti-cancer AMPAR antagonist compounds, such as PMP. in combination with one or a plurality of any combination of secondary therapeutic agent(s) or therapy(ies) selected from: NMDA antagonists such as memantine for the treatment of various cancer: anti PD- l /PDI .- l therapy; CSF 1 R inhibitors such as PLX3397 and PLX5622; cannabinoid drugs: anti-malarials such as mefloquine, primaquine, chloroquine, hydroxychloroquine; Riluzole/troriluzole treatment; antihistamines such as clemastine: biguanides such as metformin or phenformin; anti-cancer biologies such as Pembrolizumab or Nivolumab: selective serotonin reuptake
  • NMDA antagonists such as memantine for the treatment of various cancer: anti PD- l /
  • levetiracetam (Keppra), and other agents, therapies and combinations contemplated herein.
  • typical drug doses or combinatorial drug doses may include, for example, peramplanel administered at about 12mg/day (exemplary range 5-50 mg/day).
  • Memantine at about 20 mg/day (exemplary range 5-75 mg/day)
  • Riluzoie at about 50mg/day (exemplary range 10- 100 mg/day)
  • PLX3397 at about 1000 mg/day (exemplary range 300 2500 mg/day).
  • Anti-malarials at about 250 mg every other day exemplary range 50-200 mg/day or every other day
  • Metformin at about 2 g/day (exemplary range 300 mg-4 g/day)
  • Pembrolizumab at about 2 mg/kg every 3 weeks (exemplary range 0.05- 10 mg/kg every 1 -4 weeks)
  • Nivolumab at about 3 mg/kg every 2 weeks (exemplary range 1 -5 mg/kg every 1 -3 weeks)
  • Levetiracetam at about 500 mg twice a day.
  • Clemastine fumarate at about 2.5 mg per day (exemplary range 1 -5 mg per day)
  • Lscitalopram at about 20 mg/day (exemplary range 5-75 mg/day).
  • sertraline at about 200 mg/day (exemplary range 50-800 mg/day)
  • fluoxetine at about 20 mg/day (exemplary range 5-200 mg/day).
  • operable ampakines can be selected from a w ide variety of known ampakine compounds.
  • Ampakines while structurally diverse as a whole, show many shared structural and functional features within classes.
  • useful drug candidates operable within the anti-cancer methods and compositions of the invention can be identified selected and proven effective according to the detailed teachings and guidance herein.
  • anti-cancer active ampakines can be selected among positive allosteric LMRL receptor modulators from within a variety of known ampakine groups.
  • ampakine classes from which operable ampakine candidates for use within the invention can be selected include ampakines generally classified as: sulfonamide compounds and derivatives, (bis)sulfonamide compounds and derivatives, N- substituted sulfonamide compounds and derivatives: heterocyclic sulfonamide compounds and derivatives; heterocyclyl sulfonamide compounds and derivatives: alkenyl sulfonamide compounds and derivatives; cycloalkenyl sulfonamide compounds and derivatives;
  • cyclopentyl sulfonamide compounds and derivatives cycloalkylfluoro sulfonamide compounds and; acetylenic sulfonamide compounds and derivatives; 2-propane-sulfonamide compounds and derivatives: 2-aminobenzenesulfonamide compounds and derivatives;
  • anti-cancer effective ampakines effective within the invention are selected and characterized from among various structural classes of ampakines, for example to demonstrate lo impact convulsant risk and therapeutically effective anti-cancer activity.
  • ampakines from the know n class of benzofurazan ampakine compounds and derivatives e.g., as disclosed in U.S. Pat. Nos. 6. 1 10.935: and 6,3 13.1 15; and PCX Inf I Pub. No. WO9835950
  • lo impact ampakines are selected for combinatorial treatment methods of the invention from another ampakine group know n collectively as "di-substituted amide ampakines. " These ampakines were first described by Cortex (now RespireRx). as detailed in USSN 12/45 15 15, US Publication No.
  • Exemplary di-substituted amide ampakines for use within the invention include N-Methyl-N-tetrahydro-2I l-pyran-4-yl-[2. l .3]-benzoxadiazole-5-carboxamide ("CX I 739"), Trans-4-[(2.1.3-benzoxadiazol-5-y lcarbony 1)( methyl )amino
  • W is oxygen, sulfur or Cl 1 ( I I;
  • X. Y and Z are independently selected from the group consisting of -N, or -CR, wherein:
  • R is H, -Br. -Cl. -F. -CN. -NC , -OR 1 . -SR 1 . -NR . -C
  • R 1 is H, -C ] -C ( 5 branched or un-branched alkyl which, may be un-substituted or substituted.
  • A is H, or -C i -Cg branched or un-branched alkyl, which may be un-substituted or substituted.
  • -C2-Cg branched or un-branched alkenyl which may be un-substituted or substituted
  • -C2-Cg branched or un-branched alkynyl which may be un-substituted or substituted.
  • -C3-C7 cycloalkyl which may be un-substituted or substituted.
  • alkylcycloalky 1 which may be un-substituted or substituted
  • aryl or heterocycle which may be un-substituted or substituted alkylary 1 which may be un-substituted or substituted alkylheterocycle which may be un-substituted or substituted
  • n 0. 1. 2. 3. 4. 5. or 6; is a -C3-C7 cycloalkyl, which may be un-substituted or substituted, a -C4-C7 azacycloalkyl, w hich may be un-substituted or substituted, a C7-C 10 bicycloalkyl which may be un-substituted or substituted, a -C7-C J Q azabicycloalkyl which may be un-substituted or substituted aryl which may be un-substituted or substituted or a heterocycle which may be un-substituted or substituted;
  • R a is H. a halogen (preferably F). OH. O-alkyl. cyano. or a -Ci-G, alkyl group which is un-substituted or substituted and which optionally forms a C 3 -C 7 cycloalkyl group with D: and
  • a halogen preferably F
  • OR b a -C i -Cg branched or un- branched alkyl, which may be un-substituted or substituted and which optionally, forms a C 3 -C 7 cycloalkyl group with R a , a -C ⁇ -Cg branched or un-branched alkenyl, which may be un-substituted or substituted, a -C2-C5 branched or un-branched alkynyl, w hich may be un-substituted or substituted a -C3-C7 cycloalky l which may be un-substituted or substituted an aryl which may be un-substituted or substituted ,
  • R c is H or an unsubstituted or substituted C 1 -C 7 alkyl group, or when B is -C-R a .
  • R c is H or an unsubstituted or substituted C1-C7 alkyl group
  • R b is H, a -C1 -C7 alkyl group which may be branched or un-branched, un-substituted or substituted or a -C2-C7 acyl group which may be un-substituted or substituted.
  • ampakines useful within the combinatorial methods herein include include compounds according to formula II below:
  • A is -C
  • n 0, 1. 2. or 3;
  • B is C-R- . O or ( O;
  • R a is FI, F, -OH or alkyl
  • D is absent (when B is O), is H or OH when R a is H or alkyl, or is F when R a is F, or a pharmaceutically acceptable salt solvate, or polymorph thereof.
  • A is a C j -C ⁇ alkyl which may be substituted or un-substituted
  • R a is FI, F, -Ol I or alkyl
  • D is absent (when B is O), is H or OH w hen R a is 1 1 or alkyl or is F when R a is F. or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • R a is 1 1 or alkyl or is F when R a is F. or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • Other exemplary ampakines for use within the invention include compounds according to formula iV below :
  • A is a C ] -Cg alkyl which may be substituted or un-substituted.
  • n 0. 1 or 2. or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • A is a C ] -Cg alkyl which may be substituted or un-substituted.
  • R 1 is H, F. or Ci -CA alkyl.
  • R 2 is I. F. CN. a heterocycle which may be substituted or un-substituted or OR 3 .
  • R 3 is H. C ] -Cg alkyl which may be substituted or un-substituted, or a
  • A is a C ] -C6 alkyl which may be substituted or un-substituted.
  • R is H, or C 1 -C 4 alkyl, or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • B is C-R a . O or ( ⁇ >:
  • R a is H, F. -OH or alkyl
  • D is absent (when B is O), is H or OH when R a is H or alkyl, or is F when R a is F, or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • R a is H. F. -OH or alkyl and D is absent (when B is O). is H or Ol I when R u is 1 1 or alkyl or is F when R a is F. or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
  • A is a C ] -C ( , alkyl which may be substituted or un-substituted,
  • R 1 is H. or C 1 -C 4 alkyl.
  • R 2 is H. or a C j -C ⁇ alkyl which may be substituted or un-substituted.
  • R ? is 1 1. or a C
  • R 4 is 1 1. or a C 1 -C alkyl which may be substituted or un-substituted, or a
  • anti-cancer active compounds are selected from compounds of Formulas I -IX above that are already isolated and characterized, selected from: /V-Cycloheptyl-/V-methyl-[2.1 ,3 ]-benzoxadiazole-5-carboxamide; A'-(4.4- Dimethylcyclohexyl-/v-methyl-[2, 1 ,3
  • [2.1 ,3 ]-benzoxadiazole-5-carboxamide A'-Cyclopentyl-[2.1.3
  • [2.1.3]-benzoxadiazole-5-carbothioamide (CX 1739); /ram-4-[(2, 1 ,3-Benzoxadiazol-5- ylcarbonyl)(methyl)amino]cyclohexyl L-valinate hydrochloride; /ra -4-[(2, l ,3- Benzoxadiazol-5-ylcarbonyl)(methyl)amino]- l -methyl cyclohexyl A',A'-dimethyl glycinate hydrochloride; A-Methyl-A-tetrahydro-2//-pyran-4-yhnethyl-f2.
  • low impact ampakines are employed in the methods and compositions of the invention selected from yet additional ampakine groups including bicyclic amide ampakines.
  • bicyclic amide ampakines candidates for use within the invention are the following exemplary species; 8-Azabicyclo[3.2.1 ]oct-8-yl([2.
  • Additional bicyclic amide ampakines for prospective use within the anti-cancer methods and compositions of the invention include, but are not limited to. the follow ing exemplary species: [2.1.3 )-Benzoxadiazol-5-yl(3-fluoro-8- azabicyclo[3.2. l ]oct-2-en-8-y])methanone; 2-Azabicyclo[2.2.
  • the anti-cancer effective AMPAR antagonist compound is co-administered. simultaneously or sequentially, in a coordinate treatment protocol with one or more of the secondary or adjunctive therapeutic agents contemplated herein.
  • the anti-cancer effective AMPAR antagonist compound is administered coordinately with a conventional cancer chemotherapeutic agent using separate formulations or a combinatorial formulation. Coordinate administration may be done simultaneously or sequentially in either order, and there may be a time period while only one or both (or all) active therapeutic agents individually and/or collectively exert their therapeutic activities.
  • a distinguishing aspect of all such coordinate treatment methods is that the anti-cancer effective AMPAR antagonist compound exerts at least some measurably distinct anti-cancer therapeutic activity, yielding a distinct clinical response, in addition to any complementary clinical response provided by the secondary or adjunctive therapeutic agent.
  • the coordinate administration of the anti cancer effective AMPAR antagonist compound with the secondary or adjunctive therapeutic agent will yield improved anti-cancer therapeutic or prophylactic results in the subject beyond a therapeutic or prophylactic effect elicited by the secondary or adjunctive therapeutic agent alone, which benefit contemplates both direct effects, as well as indirect effects.
  • anti-cancer effective AMPAR antagonist compounds and pharmaceutical compositions of the present invention may be administered by any means that achieve the contemplated anti-cancer therapeutic or prophylactic purpose. Suitable routes of
  • compositions of the invention include, but arc not limited to, oral, buccal, nasal, aerosol, topical, transdermal, mucosal injectable, and intravenous, as well as all other practicable delivery routes devices and methods.
  • the anti-cancer effective AMPAR antagonist compounds of the present invention may be formulated ith a pharmaceutically acceptable carrier appropriate for the particular mode of administration employed.
  • Dosage forms of the compositions of the invention include excipients recognized in the art of pharmaceutical compounding as being suitable for the preparation of dosage units as discussed herein. Such excipients include, without limitation, solvates buffers, binders, tillers, lubricants, emulsifiers, suspending agents, sweeteners, flavorings, preservatives, wetting agents, disintegrants, effervescent agents and other conventional pharmaceutical excipients and additives.
  • Anti-cancer effective AMPAR antagonist compounds of the invention will often be formulated and administered in an oral dosage form optionally in combination w ith a carrier and/or other additive(s).
  • Suitable carriers for pharmaceutical formulation of oral dosage forms include for example, microcrystalline cellulose lactose, sucrose, fructose, glucose, dextrose, or other sugars di-basic calcium phosphate, calcium sulfate, cellulose,
  • exemplary unit oral dosage forms include ingestible and sublingual liquids, tablets, capsules, and films, among other options, which may be prepared by any
  • release modifying agents gl idants optionally including additional ingredients such as release modifying agents gl idants. compression aides, disintegrants. lubricants, binders. flavor enhancers sweeteners and/or preservatives (e.g.. stearic acid magnesium stearate, talc, calcium stearate, hydrogenated vegetable oils sodium benzoate leucine carbowax, magnesium lauryl sulfate, colloidal silicon dioxide glyceryl monostearate, colloidal silica, silicon dioxide, and glyceryl monostearate).
  • release modifying agents gl idants optionally including additional ingredients such as release modifying agents gl idants. compression aides, disintegrants. lubricants, binders. flavor enhancers sweeteners and/or preservatives (e.g.. stearic acid magnesium stearate, talc, calcium stearate, hydrogenated vegetable oils sodium benzoate leucine carbowa
  • Oral dosage forms may further include an enteric coating that dissolves after passing through the stomach, for example, a polymer agent, methacrylate copolymer cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP). polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate. hydroxypropyl methylcellulose succinate cellulose acetate succinate cellulose acetate hexahydrophthalate, cellulose propionate phthalate. cellulose acetate maleate.
  • a polymer agent methacrylate copolymer cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP). polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate. hydroxypropyl methylcellulose succinate cellulose acetate succ
  • cellulose acetate butyrate cellulose acetate propionate
  • copolymer of methylmethacryiic acid and methyl methacrylate copolymer of methyl acrylate methy lmethacrylate and methacrylic acid copolymer of methyl vinyl ether and maleic anhydride (Gantrez ES series) and natural resins such as zein, shellac and copal collophorium.
  • oral, mucosal, gastric transdermal, topical and injectable compositions of the invention can be administered in a controlled release form by use of such well known technologies as slow release carriers and controlled release agents.
  • the anti-cancer effective AMPAR antagonist compound is administered to patients in an injectable or intravenous (iv) formulation and delivery mode.
  • a therapeutic unit dosage of PMP is formulated in a physiological solution amenable for injection or iv delivery to human subjects for example in an aqueous buffered solution such as saline.
  • Alternative formulations of anti-cancer effective AMPAR antagonist compounds for administration to patients intravenously intramuscularly, subcutaneously or intraperitoneally can include nonaqueous sterile injectable solutions and optionally contain anti-oxidants buffers, bacteriostats and/or solutes which render the formulation isotonic with the blood of the subject, as well as aqueous and non-aqueous sterile suspensions which may include suspending agents and/or thickening agents.
  • Additional injectable compositions and formulations of the invention may include polymers and other controlled deliver ⁇ additives or carriers for extended release follow ing administration.
  • Parenteral preparations may be solutions, dispersions or emulsions suitable for such administration.
  • Extemporaneous injection solutions emulsions and suspensions may be prepared from sterile powders granules and tablets.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose or an appropriate fraction thereof of the anti-cancer effective AMPAR antagonist compound and/or active ingredient(s).
  • localized delivery of anti-cancer effective AMPAR antagonist compounds may be achieved by injecting the parenteral formulation directly into an area surrounding a cellular malignancy, directly into a tumor into the vasculature supplying a malignancy itself, or into a pleural or peritoneal cavity or cerebrospinal compartment proximal or fluidly connected to a targeted malignancy.
  • compositions of the invention may employ a pharmaceutically acceptable salt of an anti-cancer effective AMPAR antagonist compound, for example an acid addition or base salt of a PMP compound, derivative or analog.
  • an anti-cancer effective AMPAR antagonist compound for example an acid addition or base salt of a PMP compound, derivative or analog.
  • Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts. Suitable acid addition salts are formed from acids which form non-toxic salts, for example, hydrochloride, hydrobromide, hydroiodide sulphate, hydrogen sulphate, nitrate, phosphate, and hydrogen phosphate salts. Additional pharmaceutically acceptable salts include, but are not limited to. metal salts such as sodium salts, potassium salts, cesium salts and the like; alkaline earth metals such as calcium salts magnesium salts and the like;
  • organic amine salts such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts. N.N'-dibenzylethylenediamine salts and the like; organic acid salts such as acetate citrate lactate, succinate tartrate, maleate, fumarate. mandelate, acetate dichloroacetate. trifluoroacetate, oxalate, and formate salts; sulfonates such as methanesulfonate. benzenesulfonate. and p-toluenesulfonate salts; and amino acid salts such as arginate. asparginate. glutamate tartrate, and gluconate salts.
  • Suitable base salts are formed from bases that form non-toxic salts for example aluminum, calcium lithium magnesium, potassium, sodium, zinc and diethanolamine salts.
  • optional salt forms of an anti-cancer effective AMPAR antagonist compound will yield enhanced properties e.g., improved stability, solubility, tolerability, etc.
  • prodrugs of the anti-cancer effective AMPAR antagonist compound e.g., prodrugs of a PMP compound or derivative or of an intermediary compound, or precursor compound of a PMP compound or derivative.
  • prodrugs of anti-cancer effective AMPAR antagonist compounds can include the active compound reversibly linked (e.g., covalently bonded) to any carrier compound or moiety that functions to release the active anti-cancer effective AMPAR antagonist compound in vivo (for example to effectively mediate delivery of more active drug to enhance in vivo half-life of the drug or otherwise enhance pharmacokinetics or pharmacodynamics of the drug following administration.
  • prodrugs useful within the invention include esters or amides with hydroxyalkyl or aminoalkyl as a substituent, among many other prodrug constructs known in the art.
  • the invention will also be understood to encompass methods and compositions comprising biologically active metabolites and in vivo conversion products of the anti-cancer effective AMPAR antagonist compound (either generated in vivo after administration of the compound, or directly administered in the form of the metabolite or conversion product itself).
  • Such secondary active products may result for example from oxidation, reduction, hydrolysis, amidation, esterification and the like, of the administered compound, primarily due to enzymatic processes.
  • T9G (Glioblastoma) and Panc- 1 (pancreatic adenocarcinoma) were obtained from ATCC. They were maintained in DMEM media (ATCC) and supplemented with 10% FBS (ATCC) and 1 % Penicillin/Streptomycin and maintained in an incubator at 37°C with 95% air and 5% CCT.
  • Temozolomide, cisplatin and glutamate were purchased from Sigma and dissolved in complete media on the day of treatment.
  • T98G or Pane l cells were seeded in quadruplicate at a density of 6.000 cells/well in complete DMEM and incubated overnight. T98G cells were then treated with increasing concentrations of PMP and temozolomide for 72 hours.
  • pane l cells were treated with PMP. cisplatin or glutamate for 48 hours.
  • AMPAR antagonists exemplified by peramplanel (PMP). induce dose-dependent reductions in cell viability of T98G cells (Fig l a. ANOVA p ⁇ 0.0001 ).
  • the surprisingly potent oncolytic effects of peramplanel are mediated in part by antagonistic activity against AMPAR physiology in AMPAR positive cancer cell targets.
  • Perampanel exhibited significant inhibitory activities against GBM cancer cell viability, even at concentrations of 1 - 1 OuM, demonstrating the clinical utility of this drug at relevant plasma levels for effective cancer chemotherapy.
  • PMP additively complements anti-cancer effects of temozolomide (TMZ) at 30uM, and synergistically potentiates TMZ anti-cancer efficacy at l OOuM (Fig l b).
  • PMP effectively disrupted the oncogenic activity of exogenous glutamate, thereby inhibiting glutamate-potentiated pancreatic cancer activation (e.g.. as demonstrated by impairment of cancer cell
  • Potent anti-cancer efficacy of PMP compounds and other effective AMPAR antagonists is readily demonstrated using a range of animal models that are well known and w idely accepted in the art as predictive of anti-cancer activity in humans.
  • One such model employ s subcutaneous xenografts of tumor eells into useful study animals such as mice, to study efficacy of candidate anti-cancer drugs in reducing growth or proliferation of xenografted tumor cells in test versus control subjects.
  • These studies can include monitoring of a range of indicia of therapeutic efficacy, for example to demonstrate a dose-dependent decrease (e.g.. based on average values observed in test versus control subjects) in xenografted tumor number, tumor size tumor metastases.
  • cancer markers refers to any biomolecule such as a growth factor, genetic regulatory protein cytokine hormone receptor etc. whose presence, expression, structure, level or activity is correlated with cancer incidence severity progression, or another etiologic or therapeutic factor indicative of cancer growth metabolic activity, metastasis etc.
  • glioblastoma In useful study protocols relating to central nervous system (CNS) cancers such as glioblastoma (GBM).
  • CNS central nervous system
  • GBM glioblastoma
  • conventional xenograft study designs may be modified to include intracranial xenografting, to better capitulate clinical conditions of GBM (see, for example, Ozawa et ah, 2010).
  • modified from Ozawa et ah. we employ T98G cells, a GBM cell line expressing the enzyme MGMT. which functions to repair DNA damage from temozolomide (TMZ). rendering this cell type intrinsically resistant to TMZ chemotherapy.
  • TMZ temozolomide
  • These cells are engineered to express the bioluminescent enzyme luciferase to allow in vivo xenograft detection and quantification.
  • mice A study total of 24 mice are used, divided into four study groups of 6 members per group.
  • the mice are anesthetized using ketamine/zylazine on a warming plate to maintain core body temperature. Once anesthetized the scalp is swabbed with chlorohexidine and a sagittal incision is made over the parieto-occipital bone about 1 cm long on the left side.
  • the exposed skull is cleaned using a cotton swab with 3% hydrogen peroxide.
  • Xenograft cells are provided at a concentration of 300.000-500.000 cells in 3uL serum-free media, and this cell suspension is drawn into a syringe and injected at a depth of 3mm into the cortical tissue.
  • the injection is carried out slow ly over a period of one minute to localize the xenografted cells focally to specific brain region and prevent dissemination of the cells into the ventricles and spinal cord.
  • the skull is cleaned with 3% hydrogen peroxide and sterile bone wax is to the incised skull defect.
  • the scalp is drawn over the skull and stapled closed. Buprenorphine is optionally administered for post-operative pain relief, and recovery time is about 30 minutes.
  • mice receive placebo saline for the duration of the experiment.
  • Group 2 receives 20mg/kg/day TMZ.
  • Group 3 receives 5 or l Omg/kg/day PMP depending on what dose produces a partial effect in monotherapy experiments.
  • Group 4 is a combination group that receives both the TMZ and PMP treatments. Mice are bioluminescent monitored every 4 days during the study, for example using D-luciferin and an in vivo imaging system such as 1VIS-200 (PerkinElmer. Inc,
  • PMP and other anti-cancer effective AMPAR antagonists potently prevent and treat AMPAR positive CNS cancers, including GBM. in mammalian subjects.
  • Particular results will demonstrate a dose-dependent reduction in overall luminescence over an effective course of AMPAR antagonist treatment, correlated w ith reduced tumor size, reduced tumor cell number and/or reduced xenograft proliferative and/or metastatic capacity mediated by the anti-cancer AMPAR antagonist for example PMP.
  • PMP and other selected AMPAR antagonist will also significantly decrease tumor cell survival, viability and proliferation, and increase correlated indicia including time to tumor doubling and tripling, as well as subject survival (e.g. by time and/or numbers of subjects), in addition to mediating significant therapeutic benefits corresponding to all other anti-cancer activity indicators described herein above
  • PMP will exhibit significant inhibitory activity against GBM xenograft cell viability, proliferative capacity, tumor growth and metastases at concentrations of 1 -1 OuM or greater, i.e., at plasma levels that are safe and effective for cancer chemotherapy.
  • PMP will be shown to be combinatorially effective to complement anti-GBM effects of secondary anti-cancer drugs and treatments, for example temozolomide (TMZ).
  • TMZ temozolomide
  • PMP will complement, potentiate or even synergistically enhance anti-cancer activities of other drugs, for example to significantly increase overall anti-cancer effects in combination with TMZ, compared to anti-cancer effects mediated by TMZ alone.
  • the combinatorial use of PMP and TMZ e.g.. at therapeutic dosage levels of PMP between about 30uM- 100uM.
  • the foregoing intracranial xenograft study design is adapted to include one individual test group of 6 mice receiving 100mg/kg/day EPZO 15666. one group treated with l Omg/kg/day PMP, and a combinatorial group treated with both EPZO 1 5666 and PMP. Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that PMP is anti-cancer effective alone, and combinatorially effective (e.g.. complementary, additive potentiating or synergistic) in coordinate administration with EPZO 15666.
  • the efficacy of anti-cancer AMPAR antagonists such as PMP is demonstrated in combinatorial methods with tumor treating fields.
  • Recent studies report that electrical fields using insulated electrodes applying frequencies of 200kHz can inhibit cell cycle progression in GBM cells (see, e.g., Kirson et al, 2007; and Stupp et al, 2015).
  • the intracranial xenograft protocol is adapted to include one individual test group of 6 mice receiving an external insulated electrode closest to the area of the xenograft applying a 200kl Iz current for the duration of the study, one group treated with l Omg/kg/day PMP. and a combinatorial group treated with both therapies. Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that PMP is anti-cancer effective alone and combinatorially effective in coordinate administration with tumor treating fields.
  • telomere function of tumors for example the TRE I inhibitor ETP-47037.
  • TRE I inhibitor ETP-47037 proteins that interfere with telomere function of tumors.
  • telomeres are the caps of chromosomes made of repetitive DNA. which serve to prevent protein-coding DNA loss or damage during cell division.
  • proteins are implicated in maintaining telomeres, one of which is a protein designated TRE E
  • TRE E Recent studies report that pharmacological or genetic ablation of this TRF 1 reduces tumor formation and growth in animal models (see, e.g.. Bejarano et al, 2017).
  • 75mg/kg of ETP-47037 prevented tumor growth in mice.
  • the intracranial xenograft protocol above is adapted to include one test group of mice receiving a therapeutic dosage of 75mg/kg of ETP-47037. one group treated with l Omg/kg/day PMP. and a combinatorial group treated with both therapies. Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that PMP is anti-cancer effective alone and combinatorial! ⁇ ' effective in coordinate administration with ETP-47037.
  • the efficacy of anti-cancer AMPAR antagonists such as PMP is demonstrated in coordinate protocols with a transcription inhibitor, such as terameprocol.
  • a transcription inhibitor such as terameprocol.
  • Terameprocol is a global transcription inhibitor that affects proliferation, apoptosis and drug resistance, currently being clinically evaluated for treatment of GBM (Grossman et al. 2012).
  • the intracranial xenograft study includes one test group of mice treated with 20mg/kg/day Terameprocol, one group treated ith l Omg/kg/day PMP. and a combinatorial group treated with both therapies.
  • Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that PMP is anti-cancer effective alone and combinatorially effective in coordinate administration with Terameprocol. Additional studies will show that combinatorial treatment with PMP provides for low er dosing of Terameprocol to achieve the same or greater clinical benefits, with fewer side effects.
  • EZH2 is vital for maintaining glioma stem cells, a subset of glioma cells that are responsible for chemo- and radiotherapy resistance due to their ability to regenerate new tumor cells after existing tumor cells are destroyed.
  • NEK2 is responsible for guarding EZH2 against premature breakdown, allow ing EZH2 to exert a longer and more robust oncogenic effect.
  • an inhibitor of NEK2, Cmp3a exerts anti-cancer effects as demonstrated by prolongation of cancer survival time in mice (Wang et al. 201 7).
  • one group of mice receives l Omg kg /day Cmp3a.
  • one group received l Omg/kg/day PMP. and a combinatorial group is treated with both therapies.
  • Bioluminescent imaging and other measures of anti cancer efficacy w ill demonstrate that PMP is anti-cancer effective alone and combinatorially effecti ⁇ e in coordinate administration with NEK2 inhibitors such as Cmp3a. Additional studies will show ' that combinatorial treatment with PMP provides for lower dosing of NEK3 inhibitors to achieve the same or greater clinical benefits, with fewer side effects.
  • anti-cancer effective AMPAR antagonist treatment will be combined with secondary anti-cancer therapy comprising standard of care (SOC) glioma treatments.
  • SOC standard of care
  • patients are initially treated with SOC maximal safe surgical resection, followed by an aggressive SOC chemoradiation protocol.
  • Temozolomide Temodar
  • Patients additionally receive 200cGy focal radiation per day for the first five days of the week over a 6 week timespan (30 fractions) lor a total of 60Gy radiation.
  • Radiation targets the tumor area as well as surrounding edema plus a 1 cm margin.
  • patients are administered 150-200mg/m2/day temozolomide for the first 5 days of every month followed by 3 weeks rest as well as antiemetic prophylaxis treatment as needed.
  • Treatments are stopped if platelet count drops belo 100.000/uL. or if there is evidence of disease progression or severe treatment-related toxicity (Grossman et al, 2009).
  • patients receive 8mg peramplanel orally 1 hour prior to the first radiation session.
  • Perampanel is further administered once per day, and weekly titrated up 2 mg/day until patients receive the maximally tolerated approved dose (MTD) of 12 mg (Gidal et al, 2015) (though this range can be adjusted up or dow n based on patient-specific tolerance and other clinical factors determined by the managing physician).
  • MTD maximally tolerated approved dose
  • patients receive the M FD throughout an initial 6-week treatment period, during the 1 month SOC rest period, and w hile patients are taking maintenance Temodar. Patients are maintained on perampanel treatment as determined by the managing physician, unless disease progression or evidence of pcramplanel-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-glioma therapy.
  • Eevetiracetain Co-Treatment In additional clinical examples patients are treated concomitantly with an AMPAR antagonist such as peramplanel and Levetiracetam (Keppra). which has been shown to augment temozolomide efficacy (Bobustuc et al. 2010) and reduce aggression-related adverse events in patients taking perampanel (Kanemura et al. 2019; Kim et al. 2015). Patients are administered perampanel as described above along with 500mg levetiracetam 1 hour prior to the first radiation session. Levetiracetam is administered twice a day. the second time being at night before bed.
  • an AMPAR antagonist such as peramplanel and Levetiracetam (Keppra). which has been shown to augment temozolomide efficacy (Bobustuc et al. 2010) and reduce aggression-related adverse events in patients taking perampanel (Kanemura et al. 2019; Kim et al. 2015).
  • Patients are administered perampanel as
  • patients receive 200- 500mg levetiracetam twice a day throughout the first 6-week treatment period, during the 1 month rest period and while patients are taking maintenance Temodar. Patients continue to receive levetiracetam and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will sho substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
  • NMDA N-methyl-D-aspartate
  • memantine has been reported to exert anti-cancer effects, possibly by abrogating constitutive! ⁇ ' active growth pathways in cancer (Stepulak et al, 2005; Maraka et al, 2019).
  • Patients receive perampanel along w ith 5-20mg memantine orally prior to the first radiation session.
  • perampanel and memantine are administered once a day throughout the first 6-week treatment period during the 1 month rest period and while patients are taking maintenance Temodar. Patients are maintained on memantine and perampanel unless disease progression or evidence of drug-related toxicity is observed.
  • NMDA-antagonist used in the setting of pharmacoresistant depression may also be used.
  • Ketamine is given at doses ranging from 5-500mg/day and started prior to the first radiation session. Ketamine and its active metabolite
  • hydroxynorketamine may provide anti-cancer benefits (Malsy et al,
  • Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with Ri!uzole/ troriluzole (see, e.g., Khan et al, 2019). Patients receive perampanel as above in coordinate treatment with with 20-50mg
  • Riluzole/troriluzole orally prior to the first radiation session within illustrative methods for treating GBM.
  • perampanel and Riluzole/troriluzole arc administered once a day throughout the first 6-week treatment period during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on Riluzole/troriluzole and perampanel unless disease progression or evidence of drug-related toxicity is observed.
  • Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
  • Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with a colony stimulating factor 1 receptor (CSF 1 R) inhibitor such as PLX3397 (plexidartinib) or PEX5562 (see, e.g., Yan et al, 2017; Butowski et al, 2016).
  • CSF 1 R colony stimulating factor 1 receptor
  • Patients are administered perampanel as above in coordinate treatment with 100- 1000 mg PLX3397 orally prior to the first radiation session.
  • perampanel and PLX3397 are administered together or separately once a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar.
  • IGF 1 insulin-like growth factor 1
  • PLX3397 may inhibit PDGFRB signaling in cancer
  • PLX3397 will be beneficially combined with glutamate antagonists like memantine, within AMPAR antagonist methods of the invention, to bolster combined efficacy by suppressing an anti-oxidant program, e.g., in glioma cells.
  • Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinate! ⁇ administered w ith one or more anti-malarial drugs such as chloroquine, hydroxychloroquine, primaquine and mefloquine (see. e.g., Johnson et al, 2015; Liu et al, 2016; Maraka et al, 2019).
  • anti-malarial drugs such as chloroquine, hydroxychloroquine, primaquine and mefloquine
  • patients receive perampanel as above along with 250mg mefloquine orally prior to the first radiation session.
  • Mefloquine is administered once every two days throughout the first 6-week treatment period, during the I month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the anti-malarial and perampanel unless disease progression or evidence of drug-related toxicity is observed.
  • Subjects treated according to this combinatorial protocol w ill show substantially improved clinical benefits over SOC or other conventional anti-can
  • Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with metformin (see, e.g., Benjamin et al, 2016: Maraka et al, 2019).
  • Patients receive perampanel as above along with 500-2000mg metformin orally prior to the first radiation session.
  • perampanel and metformin are administered once a day throughout the first 6-week treatment period during the 1 month rest period and while patients are taking maintenance Temodar. Patients are maintained on the metformin and perampanel unless disease progression or evidence of drug-related toxicity is observed.
  • Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
  • Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinate! administered with anti-cancer biologies including programmed cell death protein 1 (PD- 1 ) inhibitors such as pembrolizumab or nivolumab (see, e.g., Nghiem et al. 2016; Motzer et al, 201 5).
  • PD- 1 programmed cell death protein 1
  • resistance to PD- 1 antagonism has been attributed to TNF-a production in the tumor microenvironment (Neubert et al, 2018). Since Ampa-glutamate antagonism has been shown to reduce TNF-a secretion in a model of intraventricular hemorrhage (Dohare et al.
  • AMPAR antagonist treatment according to the invention will augment the efficacy of PD- 1 inhibitors.
  • patients are administered perampanel as above in conjunction with l -3mg/kg pembrolizumab/nivolumab intravenously prior to the first radiation session.
  • pembrolizumab/nivolumab every 2 weeks throughout the first 6- week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Treatment is continued thusly unless disease progression or evidence of drug-related toxicity appears.
  • Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti cancer therapy.
  • AMPAR antagonists such as perampanel are coordinately administered with PD- 1 inhibitors, and also with CSF 1 R inhibitors.
  • PD- 1 inhibitors reported! exhibit robust efficacy in some patients, they appear to have little to no therapeutic effects in other patients.
  • CSF 1 and TNF-a secretion by tumor cells may stanch the efficacy of PD- 1 therapy (Neubert et al, 2018).
  • patients be treated with a combination of AMPAR antagonists PD- 1 inhibitors and CSF 1 R inhibitors (e.g.. with perampanel.
  • pembrolizumab, and PLX3397 will benefit by reduced CSF I signaling in the tumor microenvironment, combined with ampa-glutamate antagonist repression of TNF signaling (see, e.g., Dohare et al, 2016).
  • Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinated administered with clemastine fumarate (see, e.g., Dobbeling et al, 2013; Le Joncour et al. 2019). Patients are administered perampanel as above along with 0.5- 2.68mg clemastine fumarate orally prior to the first radiation session.
  • perampanel and clemastine are taken once a day throughout the first 6- week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the clemastine fumarate and perampanel unless disease progression or evidence of drug-related toxicity is observed.
  • Subjects treated according to this combinatorial protocol w ill show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
  • Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinated administered with one or more selective serotonin reuptake inhibitors (SSRIs) (see. e.g.. Sun et al. 201 8; Huang et al. 201 1 ; Lin et al. 2010; Liu et al, 201 5; Yuan et al. 2018; Raabe & Gentile. 2008).
  • SSRIs serotonin reuptake inhibitors
  • Additional clinical methods of the invention employ an AMPAR antagonist such as peram panel coordinately administered with one or more tricyclic antidepressants (TCAs) (see, e.g.. Jahchan et al, 2013; Jeon et al. 201 1 ; Raabc & Gentile, 2008; Reynolds & Miller, 1988: Sernagor et al. 1989; Stoll et al. 2007).
  • TCAs tricyclic antidepressants
  • Patients receive perampanel along with the TCA(s) orally prior to the first radiation session.
  • the perampanel and TCA are then each administered once a day throughout the first 6-week treatment period, during the I month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the TCA and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this
  • Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with one or more positive allosteric AMPA receptor modulators (Ampakines).
  • Ampakines positive allosteric AMPA receptor modulators
  • patients are administered perampanenl in combination with one or more ampakines, such as 2.3.6a.7.8.9-hexahydro- l 1 H- 1 ,4- dioxino[2,3-g]pyrrolo[2.1 -b][ 1.3 ]benzoxazine- l 1 -one ( CX614") (see. e.g., Radin et al,
  • ampakines are thought to augment AMPA-mediated currents in neurons, they have also been reported to induce AMPA receptor desensitization and down regulation via endocytosis and degradation after prolonged treatment (Jourdi et al. 2005). whereby they may serve as functional antagonists.
  • GBM GBM-derived neurotrophic factor
  • patients are administered perampanel along with CX614 or another amplakine orally prior to the first radiation session then once a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the ampakine(s) and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti cancer therapy.
  • Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with one or more cannabinoids, for example tetrahydrocannabinol ( I I 1C) and/or cannabidiol (CBD) (see. e.g.. Scott et al, 2014; Marcu et al. 2010; Shrivastava et al. 201 I ).
  • cannabinoids for example tetrahydrocannabinol ( I I 1C) and/or cannabidiol (CBD)
  • I I 1C cannabidiol
  • exemplary protocols for treating GBM patients are administered perampanel along ith 100-600mg CBD and 1 - I OOmg THC prior to the first radiation session, then once a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the cannabinoid and perampanel therapy unless disease progression or evidence of drug-related toxicity is observed
  • cannabinoids have been reported to potent effects on glioma stem cells (Lopez-Valero et al. 201 8). Considering that AMPA receptors are overexpressed on glioma stem cells (Oh et al. 2012), the combinatorial treatment methods and compositions described here w ill sensitize resistant tumor cells to the DNA-damaging effects of Temodar and radiation therapy (McLendon et al. 2006; Chen et al, 2012) and thereby enhance clinical benefits. Further, cannabinoids reportedly exert oncolytic effects through induction of harmful reactive oxygen species (Shrivastava et al, 201 1 ;
  • Disulfiram Co-Treatment Yet additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with disulfiram (see, e.g., Lun et al, 2016; Triscott et al, 2012).
  • Disulfiram targets cancer stem cells and reportedly inhibits MGMT to boost efficacy of Temodar (Paranjpe et al, 2014).
  • both disulfiram and perampanel augment Temodar s efficacy and refine targeting of cancer cells, yielding surprisingly enhanced benefits for treating SOC treatment-resistant cancers.
  • GBM Global System for treating
  • patients are administered perampanel along with 50- 500mg disulfiram orally prior to the first radiation session, then once daily throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the perampanel and disulfiram unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show' substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
  • NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth. Proceedings of the National Academy of Sciences of the United States of America, 77/2(43), 15605- 15610.
  • the glutamate release inhibitor riluzole increases DNA damage and enhances cytotoxicity in human glioma cells, in vitro and in vivo. Oncotarget, 77/(29), 2824- 2834.
  • the tumor microenvironment underlies acquired resistance to CSF- 1 R inhibition in gliomas. Science. 252(6288).
  • AMPA antagonists inhibit the extracellular signal regulated kinase pathway and suppress lung cancer growth. Cancer Biology & Therapy, (5(12), 1908.
  • Mefloquine effectively targets gastric cancer cells through phosphatase-dependent inhibition of PI3K/Akt/mTOR signaling pathway. Biochemical and Biophysical Research Communications, 470(2), 350-355.
  • Fluoxetine induces autophagic cell death via eEF2K-AMPK-mTOR-ULK complex axis in triple negative breast cancer. Cell Proliferation, 5/(2), e l 2402.
  • antidepressant sertraline inhibits translation initiation by curtailing mammalian target of rapamycin signaling. Cancer Research, 7/9(8), 3199-3208.
  • Escitalopram oxalate inhibits proliferation and migration and induces apoptosis in non-small cell lung cancer cells. Oncology Letters, 15(3), 3376-3382.
  • Fluoxetine induces autophagic cell death via eEF2K-AMPK-mTOR-ULK complex axis in triple negative breast cancer. Cell Proliferation, 51(2), e l 2402.
  • Fluoxetine an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium- dependent apoptosis.
  • the tricyclic antidepressant imipramine induces autophagic cell death in U-87MG glioma cells. Biochemical and Biophysical Research Communications, 413(2), 31 1 - 317.
  • Tricyclic antidepressants block N-methyl-D- aspartate receptors: Similarities to the action of zinc. British Journal of
  • Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy.
  • Molecular Cancer Therapeutics 10(7), 1 161 - 1 172.
  • Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444( 7120), 756-760.
  • Disulfiram a drug widely used to control alcoholism, suppresses the selfrenewal of glioblastoma and over-rides resistance to
  • Disulfiram is a direct and potent inhibitor of human 06-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage.
  • MGMT 06-methylguanine-DNA methyltransferase
  • AMPA receptors promote perivascular glioma inv asion v ia betal integrin-dependent adhesion to the extracellular matrix.

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Abstract

Disclosed herein are compositions and methods employing AMPA Receptor (AMPR) antagonist compounds to treat AMPAR positive cancers in mammalian subjects. In certain detailed embodiments the AMPAR antagonist is a Perampanel compound, effective to mediate potent oncolytic effects to prevent or reduce the severity or recurrence of a variety of cancer forms, including central nervous system (CNS) cancers.

Description

CLINICAL METHODS AND PHARMACEUTICAL COMPOSITIONS
EMPLOYING AMPA RECEPTOR ANTAGONISTS TO TREAT GLIOBLASTOMA AND O THER CANCERS
Technical Field
The invention relates to drugs and clinical methods for treating cancer in mammalian subjects. More specifically the invention relates to treating glioblastoma and other cancers that are positive for expression of AMPA-receptors.
Cross-Reference To Related Applications
This application is related to and claims the priorit benefit of prior US Provisional Patent Application No. 62/703.952. filed July 27. 2018. and prior US Provisional Patent Application No. 62/796,032. filed January 23, 2019. each incorporated herein by reference in its entirety for all purposes.
Background of the Invention
Cancer remains a principal mortality risk in human populations, with available drugs and treatment methods falling well short of goals to effectively treat and manage all forms of cancer in diverse patients. Today cancer persists as the second leading cause of death in the United States and in other developed nations. The US National Cancer Institute (NCI) reported 8.2 million cancer-related deaths worldwide and 14. 1 million new cases diagnosed in 2012. New cancer diagnoses are projected to rise globally to roughly 24 million by 2030. According to current NCI statistics an estimated 1.735.350 new cases of cancer will have been diagnosed and 609.640 cancer deaths tolled in the US for the year 2018.
The economic burdens of diagnosing and treating cancer on healthcare systems around the world are enormous w ith estimated national expenses for cancer care in the United States in 201 7 approaching $ 150 billion. Cancer health costs w ill continue to rise as mean population age and cancer prevalence increase and more expensive treatments are adopted as standards of care.
Conventional treatments for cancer typically involve a combination of surgery, chemotherapy radiation and hormonal therapy. Each of these treatment modalities imposes signi ficant morbidity and added risks for example adverse metabolic and reproductive impacts on healthy cells, immunosuppression and attendant increased risks of infection, and many other adverse health conditions that attend the rigors and insults of conventional cancer therapy. Despite considerable advances in detection and treatment of cancer over the past several decades, conventional treatments like surgery chemotherapy and radiation often achieve only modest improvements in survival while imposing significant adverse impacts on quality of life— raising questions about cost-effectiveness and overall clinical benefits of such treatments.
In view of the foregoing there persists a dire and compelling need in the medical arts for alternative tools and methods to prevent, treat and clinically manage cancer.
Glioblastoma (GBM) is a high-grade cancer of the central nervous system (CNS) characterized by a highly invasive and treatment resistant phenotype. Patients almost always relapse after an either initially successful surgical resection with or without chemo- and radiotherapy (Ishiuchi et al, 2007). GBM tumors often exhibit resistance to chemotherapy and/or radiotherapy , w hich resistance may be acquired during a course of treatment (Ishiuchi et al, 2007).
Temozolomide (TMZ) is a DNA methylating agent that is the current standard of care drug for treating GBM. TMZ mediates anti-cancer effects through genotoxic activity, and is effective in GBM treatment due in part to the drug's ability to bypass the blood-brain barrier (BBB) (Prasad ct al. 201 1 ). Unfortunately, TMZ show s limited efficacy for long-term treatment of GBM, and many patients appear to be refractory to TMZ treatment.
While considerable research has been attempted to elucidate the pathophysiology of GBM, a vast majority of drugs tested against GBM are unable to pass the BBB to yield sufficient drug levels in the brain to mediate anti-cancer effects (Liu et al, 2015).
Previous reports have suggested a role for glutamate in the proliferation and migration of glioma cells, in a manner similar to glutamate function in neuronal development (Rzeski et al, 2001 : Ishiuchi et al, 2002). Tumors of the CNS that release glutamate may cause cytotoxicity and cell death in neighboring neurons, which is postulated to facilitate cancer invasion into neighboring tissues (Takano et al. 2001 ). Glutamate positive tumors may also gro at an enhanced rate, potentially implicating glutamate signaling as an important mechanism in the etiology of GBM (Takano et al. 2001 ).
Among man types of known glutamate receptors (GRs). the A MPA -type glutamate receptor (AMPAR) may be overexpressed in certain types of cancer, including some forms of CNS cancers (Liu et al, 2015) and non-CNS cancers (Stepulak ct al, 2007: Herner et al. 201 1 ; Romeling et al, 2014; Hu et al, 2014). AMPAR activation ma be linked to increased cancer cell invasiveness (Piao et al. 2008). proliferation, and/or activation of the PI3 K/Akt/mTOR signaling axis (Ishiuchi et al. 2007). The P13K/Akt/mTOR signaling axis has been implicated in chemotherapy resistance in GBIVl. and available drugs reported to disrupt this pathway, such as rapamycin. do not penetrate the BBB. GBM cancer stem cells (suspected to be capable of re-establishing tumors after ablation with surgery, chemotherapy or radiotherapy) may express strikingly high amounts of functional AMPARs (Oh et al, 2012).
In view of the foregoing, a compelling need exists in the art for new drugs and therapeutic methods for treating cancer. Related needs arc unmet for new drugs for treating refractory or treatment-resistant forms of cancer, including cancers of the CNS. For CNS cancers, particularly brain cancers such as GBM. there is a particularly urgent need for anti cancer drugs capable of transiting the BBB to yield effective drug concentrations within protected CNS compartments, most notably w ithin the brain.
Summ a Hmbpdi m ents of the Invention
Figure imgf000004_0001
The instant invention satisfies the foregoing needs and fulfills additional objects and advantages by providing novel AMPAR antagonist drugs effective to treat AMPAR positive cancers and AMPAR dependent cancers, including AMPAR positive and AMPAR dependent cancers of the central nervous sy stem (CNS). In exemplary embodiments the invention provides compositions and methods employing a novel anti-cancer drug, Perampanel (PMP) [2-(2-oxo- 1 -phenyl-5-pyridin-2-yl- 1 ,2-d i hydropy rid i n-3 -> 1 ) ben/onitrile], heretofore reported for limited clinical use as an antispasmodic drug.
AMPA receptor antagonists have been investigated for antiseizure activity both preclinically and clinically, with mixed success. The prototypical competitive AMPA receptor antagonist 2.3-dihydroxy-6-nitro-7-sulfamoyl-benzo[ f] quinoxaline (NBQX) showed activity in maximal electroshock (MBS) and pentylenetetrazole (PTX)- induced seizure models (Yainaguchi et al.. 1993). but has poor solubility resulting in precipitation in the kidney at therapeutic plasma levels. Derivatives of NBQX with polar constituents have shown improved solubility, but these molecules exhibit reduced blood-brain barrier (BBB) penetration (Weiser, 2005). Prototypical noncompetitive AMPA receptor antagonists such as 2.3-benzodiazepine-type compounds, have show n weak in vitro efficacy compared with competitive antagonists (Weiser. 2005). Talampanel. a recently developed noncompetitive AMPA receptor antagonist has been evaluated in a number of cl inical trials (l lovves & Bell. 2007). but has a relatively short half-life militating against its potential clinical utility (Langan et al.. 2003). More recently. Steinhoff et al.. 201 3. reported beneficial activity of Peramplanel. a noncompetitive selective AMPA receptor antagonist as an antiepileptic drug undergoing clinical study for refractory partial-onset seizures. According to the surprising discoveries herein, peramplanel (PMP) has now been identified to possess novel and potent anti-cancer activity. Within the compositions and methods of the invention. PMP. along with its active analogs and derivatives, and other selected AMPAR antagonists disclosed herein, potentl inhibit AMPAR positive and AMPAR dependent cancers, including CNS cancers such as GBM.
The invention provides novel compositions and methods for treating cancer using AMPAR antagonist compounds such as PMP to reduce or prevent the occurrence remission growth severity and/or one or more adverse symptom(s) of AMPA-receptor positive cancers in mammalian subjects, including humans. In illustrative embodiments, the AMPAR antagonist comprises a PMP compound (including anti-cancer effective chemical analogs, derivatives, conjugates, solid crystalline forms solvates and/or different salt forms of a PMP compound), which is clinically effective as an anti-cancer agent to treat or prevent cancer in mammalian subjects. In exemplary embodiments. PMP is administered to a human patient presenting with an AMPAR positive cancer condition in a delivery mode, formulation and dosage sufficient to alleviate one or more symptoms of the targeted cancer condition in the patient.
In certain embodiments the PMP compound is perampanel [2-(2-oxo- 1 -phenyl-5- pyridin-2-yl- 1.2-dihydropyridin-3-yl) benzonitrile] formulated in a biologically acceptable composition for administration to a human subject.
In related embodiments novel clinical methods are provided herein employing a peramplanel or related compound administered to a mammalian subject, wherein the peramplanel compound exerts oncolytic effects against a targeted cancer cell or tumor sufficient to kill a targeted cell or tumor reduce size of a tumor, impair tumor growth, prevent or reduce cancer invasiveness, reduce or delay cancer recurrence, and/or alleviate one or more symptoms associated with the treated cancer condition.
In more detailed embodiments peramplanel and related compounds are employed in effective anti-cancer methods for treating glioblastoma (GBM). The peramplanel compound is administered to a mammalian subject with current or prior diagnosis of GBM in a dosage form amount and regimen sufficient to prevent or reduce the occurrence severity, recurrence and/or related sy mptoms of GBM in the subject. In related embodiments, pharmaceutical compositions and delivery methods arc provided that yield surprisingl high therapeutic concentrations of the peramplanel compound in a CNS compartment of the subject e.g., in the brain yielding potent anti-CNS-cancer therapeutic effects. In other detailed embodiments a peramplanel compound is administered w ith a secondary therapeutic agent in combinatorial formulations or coordinate treatment methods to yield desired therapeutic advantages. In exemplary embodiments a peramplanel compound is coordinately administered with a second anti-cancer drug to treat cancer, whereby anti cancer efficacy is enhanced and/or adverse side effects are reduced. In one illustrative embodiment, peramplanel is coordinately administered with temozolomide (TMZ) to treat GBM, pancreatic cancer, or another form of cancer. In another embodiment, peramplanel is coordinately administered with cisplatin to treat an AMPAR positive cancer for example an AMPAR positive pancreatic cancer. In other exemplary embodiments, peramplanel is coordinately administered with hydroxyurea to treat an AMPAR positive cancer. In other embodiments, peramplanel is coordinately administered with Carmustine (BCNU) to treat an AMPAR positive cancer.
In related treatment methods a peramplanel compound is coordinately administered before or after a conventional cancer treatment for example surgery, chemotherapy or radiation treatment with or w ithout a secondary anti-cancer agent or other secondary therapeutic drug.
In other detailed aspects of the invention, methods and compositions are provided employing a peramplanel compound to reduce oncogenic activity by disrupting a glutamate- induced cancer potentiation process (e.g.. glutamate-stimulated cancer cell proliferation, tumor grow'th. cancer invasion or other cancer-potentiation activity).
In yet additional embodiments of the invention. AM PAR antagonist compounds are employed in novel clinical methods and compositions to treat lung cancers, breast cancers, pancreatic cancers, liver cancers colorectal cancers and other forms and symptoms of cancer conditions in human subjects.
Brief Description of the Drawings
Figure 1 is a related graph series documenting the effects of PMP on T98G GBM cell viability. Dose-response curve of A) PMP on cell viabilit B) Interactions with PMP and TMZ. Data are presented as mean +/- SEM of 2 or more independent experiments performed in quadruplicate. ANOVA, P<0.001 for PMP suggesting a significant dose-dependent response. *p<0.05. **p<0.01. t-test. compared to vehicle-treated control or singular drug treatment. +p<0.05. king’s synergy test, demonstrating significant synergistic interaction.
Figure 2 is a related graph series documenting the effects of PMP on Pane l cell viability. Dose-response curve of: A) PMP on cell viability: B) Interactions with PMP and 3uM cisplatin: C) Effects of glutamate on pane l cell viability: and D) Interactions between glutamate and PMP. Data are presented as mean +/- SEM of 2 or more independent experiments performed in quadruplicate. ANOVA. PO.OO l for PMP and glutamate, indicating a significant dose-dependent response. *p<0.05, **p<0.01 , t-test, compared to vehicle-treated control or singular drug treatment. +p<0.05, + +p<0.01 , king's synergy test, demonstrating significant synergistic interaction. *p<0.01. t-test, compared to viability of glutamate- or PMP-treated cells alone.
Figure 3 is a flow chart illustrating seven candidate anti-cancer chemical derivatives (D 1 -D7) of peramplanel (PMP). wherein PMP is modified according to known methods of conventional rational design chemistry to yield ne candidate compounds for testing to determine anti-cancer activity and other beneficial properties.
Detailed Description of Exemplary Embodiments of the Invention
The invention provides AMPAR antagonist, compounds exemplified by peramplanel (PMP), shown to be surprisingly effective in treating cancers, including CNS cancers, in mammalian subjects. Among the discoveries presented here, peramplanel is shown to exert potent direct oncolytic effects against cancer cells in assays accepted to predict clinical anti cancer activity in human subjects. More speci fically the examples below show that PMP potently disables viability of CNS and non-CNS cancers, as demonstrated by direct oncolytic effects against glioblastoma (GBM) and pancreatic cancer cells. Related studies further evince that peramplanel exerts surprisingly potent additive or synergistic anti-cancer effects in coordinate use with other chemotherapeutic drugs.
The clinical methods and pharmaceutical compositions and formulations of the invention provide novel tools to treat, prevent and clinically manage a wide range of cancers in mammalian subjects, including humans. Any type and form of cancer occurring in humans and veterinary subjects may be amenable to treatment according to the teachings herein, including but not limited to: central nervous system (CNS) cancers including various forms of brain cancer: lung cancer; prostate cancer; breast cancer: skin cancers, for example melanoma; liver cancer: thyroid cancer; esophageal cancer; sarcomas; colon and rectal cancers; bladder cancer; gall bladder cancer: stomach cancer: renal cancer; ovarian cancer; uterine cancer: cervical cancer; non-Hodgkin's lymphoma; acute myelogenous leukemia (AMT): acute lymphocytic leukemia: chronic lymphocytic leukemia (CLL); myeloma:
mesothelioma; pancreatic cancer. Hodgkin's disease: testicular cancer; Waldenstrom's disease: head/neck cancer: cancer of the tongue, viral-induced malignancies (e.g.. cancers induced by SV40 virus), and other candidate types and forms of cancers that will be apparent to skilled artisans.
Subjects amenable to treatment may have cancer of any stage of development and etiology, including, but not limited to, cancers marked by rapid increases in
cellular/histological abnormalities and/or elevated tumor marker expression in biopsies or blood samples, rapid tumor proliferation and/or grow th metastasis among other disease progression indicators, up to and including stage 111 and stage IV cancers, even refractory stage I II and IV shown to be treatment resistant cancers'' (e.g.. to effectively subjects with cancers, such as glioblastoma, persisting or relapsing after ineffective, conventional anti cancer treatment(s) (e.g.. surgery, radiation and/or chemotherapy)). In exemplary embodiments of the invention an effective AMPAR antagonist drug such as PMP effectively prevents or treats (i.e., reduces the severity, progression and/or adverse side effects of) cancer in treatment resistant subjects, defined as subjects presenting after one or more rounds of conventional oncotherapy (e.g.. chemotherapy, radiation, surgery and/or hormonal therapy), with actively progressing or unstable metastatic disease. In other embodiments the compositions and methods of the invention are useful for treating other refractory" patients w ho ma\ not otherwise tolerate or be fit for conventional cancer treatments such as chemotherapy.
Certain cancer types and disease conditions are contemplated herein to be particularly amenable to treatment using the AMPAR antagonist drugs and methods of the invention. In certain embodiments, the AMPAR antagonist drugs and methods of the invention are particularly effective against "AMPAR dependent" cancers. As used herein the term
"AMPAR dependent refers to cancers that distinctly overexpress AMPA receptors, or whose appearance growlh. and/or disease progression may otherwise be determined to be AMPAR- dependent. In more detailed aspects. "AMPAR-dependenf" cancers are not limited to cancers wliose occurrence, persistence or progression require abnormal ly elevated AMPAR receptor expression or activity, indeed they may include cancers with normal or even subnormal expression of AMPARs. hich through disease-associated changes in AMPAR structure or function or any other disease-associated change affecting AMPAR metabolism or pathology, are particularly susceptible to AMPA receptor interference or blockade using PMP or other candidate AMPAR drugs of the invention.
In this context, the use of AMPAR antagonist drugs exemplified by PMP, according to the teachings herein, effectively treats or prevents a wide range of cancers contemplated to represent "AMPAR-dependent cancers" including but not limited to brain cancer, breast cancer colorectal cancer, hepatocellular cancer, leukemia, melanoma, lung cancer, pancreatic cancer, renal cancer, and other candidate cancer types or cases determined to be clinically susceptible to AM PAR interference or blockade by PMP or another useful AMPAR antagonist.
Each of the anti-cancer methods of the invention involves administration of a suitable, effective dosage amount of PMP or another useful AMPAR antagonist to a subject.
Typically, an effective amount will comprise an amount of the active compound (e.g., PMP) which is therapeutically effective, in a single or multiple unit dosage form, over a specified period of therapeutic intervention to measurably alleviate the targeted cancer condition. Within exemplary embodiments. PMP is used as the sole or primary active drug. In other embodiments, an intermediary or precursor compound to PMP. or a rationally-designed analog or derivative of PMP (i.e.. a related compound having close structural and functional similarity to PMP) is employed. The PMP or other effective AMPAR antagonist is typically formulated in a pharmaceutical composition with one or more pharmaceutically acceptable carriers, excipients, vehicles, emulsifiers, stabilizers preservatives, buffers, and/or other additives that may enhance stability, delivery, absorption, half-life, efficacy,
pharmacokinetics, and/or pharmacodynamics, reduce adverse side effects, or provide other advantages for pharmaceutical use.
Anti-cancer effective dosage amounts of PMP and other effective, anti-cancer AMPAR antagonists of the invention will be readil determined by those of ordinary skill in the art, depending on clinical and patient-specific factors. Suitable effective unit dosage amounts of the active compounds for administration to mammalian subjects, including humans, may range from a minimum daily dose of 1 -2 mg up to a maximum prospective dose between about 200-500 or 300- 1 .000 mg/da . or greater. In certain embodiments, the anti cancer effective dose is between about 2 mg-200 mg/day, in other embodiments between about 20-400 mg/day. 50-500 mg/day. 200-600 mg/day, or another anti-cancer effective dose or dosage range that can be adjusted based on patient specific factors to optimize efficacy and minimize adverse side effects. The PMP or other AMPAR antagonist may be administered in a single dose, or in the form of a multiple periodic dosing protocol, for example in a dosing regimen comprising from 1 to 5, or 2-3 doses administered per day. per week, or per month.
The amount, timing and mode of delivery of the anti-cancer compositions of the invention will be routinely adjusted on an individual basis depending on such factors as patient weight age. gender, and condition of the individual, the acuteness of the subject's disease and severity symptoms whether the administration is prophylactic or therapeutic, prior treatment history (including e.g., any prior history and responsiveness to chemotherapy or other cancer treatment treatment) and on the basis of other factors known to effect drug delivery, absorption, pharmacokinetics and efficacy. An effective dose or multi-dose treatment regimen for the instant AMPAR antagonist formulations will ordinarily be selected to approximate a minimal dosing regimen necessary and sufficient to substantially prevent or alleviate the cancer condition, and/or to substantially prevent or alleviate one or more symptoms associated w ith that condition.
A dosage and administration protocol w ill often include repeated dosing therapy over a course of several days or even one or more weeks up to several months, or even a year or more. An effective treatment regime may also involve prophylactic dosage administered on a daily or multi-dose per day basis lasting over a course of days, weeks, months or even a year or more.
Various assays and pre-clinical and clinical model systems can be readily employed to determine therapeutic effectiveness of the anti-cancer compositions and methods invention. For example these may detect/monitor a decrease in overt symptoms, such as pain (e.g., as measured using any of a variety of pain scales including but not limited to, the Visual Analog Scale. McGill Pain Questionnaire, Descriptor Differential Scale. Faces Pain Scale. Verbal Rating Scale. Simple Descriptive Pain Scale. Numerical Pain Scale (NPS), or Dolorimeter Pain Index). More detailed detection/monitoring may document, for example, a decrease in circulating tumor cells (CTCs). reduction in tumor size, collapse or disappearance of tumors softening of tumors, liquefaction of tumors, or a decrease in cytological or histochemical cancer markers, among many other conventional diagnostic indicia of cancer disease stasis progression and/or remission.
Effectiveness of the anti-cancer methods and compositions of the invention are generally demonstrated by a decrease in incidence severity and/or associated symptoms of cancer which will typically involve a decrease of 5%. 10%. 25%. 30%. 50%, 75%, 90% or more in comparison to incidence/levels of the same diagnosed indicator/state, or attendant symptom(s) in suitable control subjects (or compared to known baseline or median data for like, treated or untreated subjects). For example. PMP-treated cancer patients will often exhibit a decrease in number or size of targeted tumors, a decrease in circulating tumor cells (C'TCs) or Cancer Stem Cells (CSC's) in successive blood assays, and/or a decrease in one or more tumor-associated cytological. histochemical or blood markers, during a course of treatment, of from 25%-30%, 50%. 75% or higher. 90% and up to total absence of the disease indicator(s) to a limit of detectability associated with the employed assay(s). Monitoring for effective cancer prevention and treatment of the invention can employ any of a vast array conventional detection and monitoring tools and indicia as will be apparent to those skilled in the art. For example. CTC monitoring using blood samples of patients can utilize flow cytometry, immunobead capture, fluorescence microscopy standard and density
centrifugation cell culturing, and immunocytocheinistry. Similarly, tumor monitoring can employ x-ray. MRI. CT or PET scans, among other methods and tools. For economy these and other routine well-know n cancer disease detection and monitoring technologies will not be reiterated here.
As noted above, exemplary embodiments of the invention employ peramplanel (PMP) as an anti-cancer effective AM PAR antagonist compound. Perampanel is structurally distinct from other AMPAR antagonists which as a group show a great deal of structural diversity (for example, as illustrated in Table I comparing the structure of PMP to two other AMPAR antagonists, Telampanel and NBQX.
Table 1 Diverse Chemical Structure of AM PAR Antagonists
Figure imgf000011_0001
According to the discoveries herein, PMP potently reduces or prevents the occurrence, remission, growth and/or severity of targeted cancers in mammalian subjects, including humans. In certain embodiments. PMP is effective to prevent or treat (including to reduce one or more adverse symptom(s) of), an AMPAR positive cancer in a human cell population tissue, organ or whole patient. For clinical use, effective anti-cancer
compositions may comprise a prototypical PMP compound [2-(2-oxo- l -phenyl-5-pyridin-2- yl- 1 ,2-dihydropyridin-3-yl) benzonitrile], or any effective prodrug, metabolite, analog, derivative, conjugate, solid crystal line form, solvate and/or advantageous salt form of PMP shown to be clinically effective as an anti-cancer agent.
In view of the disclosed potent anti-cancer effects of peramplanel (PMP), the invention further provides various chemical analogs and derivatives of PMP that actively treat or prevent cancer, and in certain cases provide additional clinical advantages, for example improved solubility enhanced blood-brain barrier penetration, prolonged half-life, increased AMPAR antagonist activity among other functional improvements.
Figure 3 provides a flow chart illustrating seven candidate anti-cancer chemical derivatives (D 1 -D7) of peramplanel (PMP) contemplated for anti-cancer testing within the clinical methods herein. The illustrated compounds, D 1 -D7 can be readily produced, along with many additional PMP analogs and derivatives, employing known methods of conventional rational design chemistry. Such routine design and synthesis efforts will yield a diverse array of ne candidate compounds for testing ithin the methods of the invention, to determine anti-cancer activity and other beneficial properties. In general terms, each of the available R groups identified w ithin or attached to each of the aromatic rings of PMP can be altered (e.g.. by chemical deletion, substitution or addition) to yield new candidate PMP derivative drugs as described. The exemplar} derivatives shown in Figure 3 - PMP D 1 may be designed, tested and selected to have increased solubility improved half-life, better delivery or penetration to desired targets or compartments (e.g.. to deliver an effective dose wdthin a tumor mass, to transit the blood brain barrier (BBB) in anti-cancer effective amounts, to survive first pass metabolism and transport to a target organ in effective plasma concentration, etc.). According to the illustrative embodiments here, PMP derivatives D2.
D3 and D4 are designed to have more hydrophilic character, whereby they will have improved BBB penetration and accumulate to an effective concentration greater in the CNS to mediate clinical benefits of treating and/or preventing CNS related cancers such as GBM. PMP D5 is designed to provide increased solubility for improved drug delivery,
bioavailability and clinical efficacy. PMP D6 is an exemplar prodrug (a glycine ester) of PMP D5. which will be rapidly hydrolyzed into PMP D5 in the blood by plasma glycine esterases, thus providing the contemplated prodrug benefits in addition to increased solubility. PMP D7 and D8 are likewise more hydrophilic derivatives of PMP which will penetrate the BBB and accumulate in effective concentrations for anti-cancer drug effects in the CNS.
In other exemplary PMP derivative and analog design each R group may be modified to a same or different derivative or analog R group identity. Rational design chemical alterations to PMP can include alterations wherein an original PMP R group is altered to a ne structural identity selected from for example: a substituted or unsubstituted lower hydrocarbon including an alkyl alkenyl alkanoy l. alkynyl, aryl aroyi. aralkyl, alkylamino. aryloxy, hydrogen, carboxy l nitro thioalkoxy. thioaryloxy. thiol, cycloalkenyl cycloalkyl, heterocycloalkyl, heteroaryl aralkyl, amino acid peptide dye. fluorophore, carbohydrate or polypeptide; a hydrogen, hydroxyl, sulfyhydryl, fluorine, methyl, ethyl, propyl, benzyl, 2- bromovinyl amino hydroxymethyl methoxy. halogen, pseudohalogen cyano, carboxyl, nitro. thioalkoxy. thioaryloxy, or thiol; a substituted or unsubstituted lower hydrocarbon containing 1 to 20 carbons such as alkoxycarbonyl. allkoxycarbonylamino. amino, amino acid, aminocarbonyl. aminocarbonyloxy. aralkyl aryloxy. carboxyl cycloalkenyl alkyl, cycloalkyl, heterocycloalkyl, aryl heteroaryl aralkyl amino acid, peptide, dye, fluorophore, carbohydrate or polypeptide: a heteroatom such as oxygen, sulfur or nitrogen; and/or an integral member of a new 5, or 6. member exocyclic ring structure, among other alterations where feasible to yield a viable test candidate derivative. In more detailed embodiments one or more R group(s) of PMP can be modified to a hydrogen hydroxyl, sulfyhydryl. benzyl, 2- bromovinyl amino, hydroxymethyl methoxy. halogen pseudohalogen, cyano, carboxyl, nitro, thioalkyl. thioaryl, thiol, substituted or unsubstituted hydrocarbons containing 1 to 20 carbons, alkoxycarbonyl, alkoxycarbonylamino. amino, amino acid, aminocarbonyl, aminocarbonyloxy. aryloxy. carboxyl, cycloalkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substituted or unsubstituted heteroaryl substituted or unsubstituted aralky l peptidyl. dye. fluorophore. carbohydrate or poly peptidy 1. azido. nitrile, substituted benzoyl or hydroxyl substituted with substituted or unsubstituted hydrocarbon containing 1 to 20 carbons and/or an alkanoyl of a main chain of 1 to 20 carbon atoms among many other contemplated derivative changes obtainable and testable according to the teachings herein without undue experimentation.
Within additional aspects of the invention combinatorial formulations and coordinate treatment methods are provided that emplo an effective amount of PMP or another anti- cancer effective AMPAR antagonist compound or composition, and one or more secondary or adjunctive agcnt(s) combinatorial!} formulated or coordinately administered with the AMPAR antagonist compound or composition to yield an enhanced anti-cancer composition or method. Exemplary combinatorial formulations and coordinate treatment methods in this context employa PMP compound in combination w ith the one or more secondary anti-cancer, anti-viral and/or immune-stimulator} effective agents or drugs.
Exemplary combinatorial formulations and coordinate treatment methods of the invention employ PMP or another anti-cancer effective AMPAR antagonist compound or composition in combination with one or more secondary or adjunctive anti-cancer effective agents, for example one or more chemotherapeutic agents. Employing general terminology for chemotherapeutic drugs and adjunctive anti-cancer therapies”, these secondary agents/therapies for use within the invention may include any anti-cancer or anti-proliferative agent agents that destroy or reprogram” cancer cells agents that destroy blood vessels associated with neoplasms or hyperproliferative conditions and other classes of drugs harmful to neoplastic cellular targets. In this regard useful chemotherapcutics and adjunctive therapies for use within the invention include, but are not limited to:
( 1 ) Tubulin depolymerizing agents like toxoids;
(2) DNA damaging agents and agents that inhibit DNA synthesis;
(3) Anti-metabolics;
(4) Anti-angiogenic agents and vascular disrupting agents (VDAs);
(5) Anti-cancer antibodies;
(6) Endocrine cancer therapies;
(7) Immuno-modulators;
(8) Histone deacetylase inhibitors:
(9) Inhibitors of signal transduction:
( 10) Inhibitors of heat shock proteins:
( 1 1 ) Retinoids;
( 12) Growth factors and Modulators of growth factor receptors:
( 13 ) Anti-mitotic compounds:
( 14) Anti-inflammatory agents such as COX inhibitors: and
( 15) Ceil cycle regulators (eg. check point regulators and telomerase inhibitors).
In related embodiments coordinate anti-cancer treatment methods of the invention can include coordinate administration of one or more anti-cancer AMPAR antagonist compounds with a secondary anti-cancer agent selected from azacitidine. bevacizumab. bortezomib. capecitabine. cetuximab. clofarabine. dasatinib. decitabine, docetaxel, emend, erlotinib hydrochloride excmcstane. fulvestrant. gefitinib. gemcitabine hydrochloride, imatinib mesylate imiquimod. lenalidomide. letrozole . nelarabine. oxaliplatin, paclitaxel, docetaxel, palifermin, panitumumab. pegaspargase, pemetrexed disodium, rituximab, sorafenib tosylate, sunitinib malate, tamoxifen citrate, targretin, temozolomide, thalidomide, and/or topotecan hydrochloride. Additional contemplated secondary anti-cancer effective agents in this context include but are not limited to. interleukin-2 interferon a. filgrasten. G- CSF, epoetin alfa, erythropoietin. Il.- l . oprelvekin. trastuzumab. vorinostat, antibiotics, coenzyme q. palladium lipoic complexes including, for example. poly-MVA®,
antineoplastins, cartilage hydrazine sulfate; milk thistle, electrolytes such as calcium carbonate, magnesium carbonate sodium bicarbonate and potassium bicarbonate; oxidizing agents including, but not limited to. cesium chloride potassium chloride, potassium orotate and potassium aspartate; immunoglobulins; colostrum: and vitamin and mineral supplements, including but not limited to. zinc chloride magnesium chloride, pyridoxine, vitamin B- 12. B complexes folic acid, sodium ascorbate, and probiotics. Additional secondary therapies may include conventional chemotherapy, radiation therapy, and/or surgery.
In certain illustrative embodiments directed to treatment of glioblastoma (GBM), pancreatic cancer and other AMPAR-dependent types/forms of cancer, the PMP or other AMPAR antagonist is coordinate!} administered with temozolomide (TMZ). In related embodiments, the PMP or other AMPAR antagonist is coordinately administered with cisplatin to treat an AMPAR-dependent cancer for example an AMPAR-positive pancreatic cancer. In other exemplary embodiments an anti-cancer effective PMP or other AMPAR antagonist compound is coordinately administered with hydroxyurea to treat an AMPAR positive cancer. In other embodiments the PMP or other AMPAR antagonist is coordinately administered with Carmustine (BCNU) to treat an AMPAR positive cancer.
In other coordinate methods and compositions anti-cancer effective AMPAR antagonist administration is combined with a secondary anti-cancer agent or therapy, e.g.. selected from a transcription inhibitor (e.g.. Terameprocol). a telomere disrupting agent (e.g., TRF 1 inhibitors such as F.TP-4707). an inhibitor of a gene splicing protein (e.g., a PRMT5 inhibitor) an indoleamine 2. 3. dioxegenase (IDO) inhibitor, lapatinib ditosylate enzyme blocker anti-cancer antibodies antibody fragments and related biologies", for example Adavosertib. tumor treating fields and radiation alone or in any combination with other secondary or adjunctive cancer agents and treatments described herein. In related embodiments coordinate anti-cancer treatment methods of the invention can include coordinate administration of one or more anti-cancer AMPAR antagonist compounds, such as PMP. in combination with one or a plurality of any combination of secondary therapeutic agent(s) or therapy(ies) selected from: NMDA antagonists such as memantine for the treatment of various cancer: anti PD- l /PDI .- l therapy; CSF 1 R inhibitors such as PLX3397 and PLX5622; cannabinoid drugs: anti-malarials such as mefloquine, primaquine, chloroquine, hydroxychloroquine; Riluzole/troriluzole treatment; antihistamines such as clemastine: biguanides such as metformin or phenformin; anti-cancer biologies such as Pembrolizumab or Nivolumab: selective serotonin reuptake inhibitors (SSRIs); tricyclic antidepressants (TCAs): AMPA receptor positive allosteric modulators (Ampakines);
levetiracetam (Keppra), and other agents, therapies and combinations contemplated herein.
Within exemplary embodiments, typical drug doses or combinatorial drug doses (median or average doses among a treated patient class) may include, for example, peramplanel administered at about 12mg/day (exemplary range 5-50 mg/day). Memantine at about 20 mg/day (exemplary range 5-75 mg/day), Riluzoie at about 50mg/day (exemplary range 10- 100 mg/day), PLX3397 at about 1000 mg/day (exemplary range 300 2500 mg/day). Anti-malarials at about 250 mg every other day (exemplary range 50-200 mg/day or every other day), Metformin at about 2 g/day (exemplary range 300 mg-4 g/day), Pembrolizumab at about 2 mg/kg every 3 weeks (exemplary range 0.05- 10 mg/kg every 1 -4 weeks), Nivolumab at about 3 mg/kg every 2 weeks (exemplary range 1 -5 mg/kg every 1 -3 weeks),
Levetiracetam at about 500 mg twice a day. Clemastine fumarate at about 2.5 mg per day (exemplary range 1 -5 mg per day), Lscitalopram at about 20 mg/day (exemplary range 5-75 mg/day). sertraline at about 200 mg/day (exemplary range 50-800 mg/day), fluoxetine at about 20 mg/day (exemplary range 5-200 mg/day). Imipramine hydrochloride at about 25-50 mg/day (exemplary range 2-400 mg/day), Ampakines at about 900mg/day, with high impact ampakines at about 100/day (exemplary range 25 mg- 1 .5 g/day); C'BD at about 100-600 mg/day (exemplary range 20- 1000 mg/day): I I 1C at about 5- 100 mg/day (exemplary range 1 - 800 mg/day): Ketamine/hydroxynorketamine at about 5-500mg/day (exemplary range 1 -1000 mg/day). Disulfiram at about 50-500 mg/da\ (exemplar) range 20- 1500 mg/day). or any combination of the foregoing drugs/doses.
In more detailed aspects of the invention employing coordinate treatment with Ampakines. operable ampakines can be selected from a w ide variety of known ampakine compounds. Ampakines, while structurally diverse as a whole, show many shared structural and functional features within classes. Both between and within known ampakine classes, useful drug candidates operable within the anti-cancer methods and compositions of the invention can be identified selected and proven effective according to the detailed teachings and guidance herein. Following these teachings, anti-cancer active ampakines can be selected among positive allosteric LMRL receptor modulators from within a variety of known ampakine groups. Among the ampakine classes from which operable ampakine candidates for use within the invention can be selected include ampakines generally classified as: sulfonamide compounds and derivatives, (bis)sulfonamide compounds and derivatives, N- substituted sulfonamide compounds and derivatives: heterocyclic sulfonamide compounds and derivatives; heterocyclyl sulfonamide compounds and derivatives: alkenyl sulfonamide compounds and derivatives; cycloalkenyl sulfonamide compounds and derivatives;
cyclopentyl sulfonamide compounds and derivatives: cycloalkylfluoro sulfonamide compounds and; acetylenic sulfonamide compounds and derivatives; 2-propane-sulfonamide compounds and derivatives: 2-aminobenzenesulfonamide compounds and derivatives;
benzoyl piperidine and benzoyl compounds and derivatives; pyrrolidine compounds and derivatives; benzoxazine ring compounds and derivatives; acylbenzoxazine compounds and derivatives; carbonylbenzoxazine compounds and derivatives; substituted 2.3-benzodiazepin- 4-one compounds and derivatives; amidophosphate; monofluoralkyl compounds and derivatives; substituted quinazoline compounds and derivatives; quainoxaline compounds and derivatives; 2-ethoxy-4'-[3-(propane-2-su 1 fony lamino)-thiophen-2-yl]-biphenyl-4-carboxy lie and derivatives; pyrrole and pyrazole compounds and derivatives: thiadiazine compounds and derivatives; benzofurazan compounds and derivatives: benzothiazide compounds and derivatives; substituted 5-oxo-5.6.7.8-tetrahydro-4H- l -benzopyran and benzothiopyran compounds and derivatives; benzoxazepine compounds and derivatives; among known classes of compounds comprising AMPA receptor modulator compounds prospectively useful within the invention.
According to the teachings and examples presented herein, anti-cancer effective ampakines effective within the invention are selected and characterized from among various structural classes of ampakines, for example to demonstrate lo impact convulsant risk and therapeutically effective anti-cancer activity. In illustrative embodiments provided herein, ampakines from the know n class of benzofurazan ampakine compounds and derivatives (e.g., as disclosed in U.S. Pat. Nos. 6. 1 10.935: and 6,3 13.1 15; and PCX Inf I Pub. No. WO9835950) were screened and developed to identify operable drug candidates within the compositions and methods of the invention. From these investigations exemplary anti-eancer benzofurazan candidates 1 -(benzofurazan-5-ylcarbonyl)-4,4-difluoropiperidine, and 4- (benzofurazan-5-ylcarbonyl). and 1 -(benzofurazan-5-ylcarbonyl)morpholine. Within additional compositions and methods of the invention, lo impact ampakines are selected for combinatorial treatment methods of the invention from another ampakine group know n collectively as "di-substituted amide ampakines." These ampakines were first described by Cortex (now RespireRx). as detailed in USSN 12/45 15 15, US Publication No.
IJS2010/0120764, and PCT/U S/2008/00627 (incorporated herein in their entirety, for all purposes). Exemplary di-substituted amide ampakines for use within the invention include N-Methyl-N-tetrahydro-2I l-pyran-4-yl-[2. l .3]-benzoxadiazole-5-carboxamide ("CX I 739"), Trans-4-[(2.1.3-benzoxadiazol-5-y lcarbony 1)( methyl )amino |cyclohexyl glycinate hydrochloride (CX 1942); and. N-(4-trans-hydroxycyclohcxyl)-N-methyl-[2.1 ,3]- benzoxadiazole-5-carboxamide (CX I 763). Within related embodiments of the invention, useful low impact, anti-cancer ampakines are selected and demonstrated to be active according to the teachings herein having the exemplary ampakine structure I, below:
Figure imgf000018_0001
wherein:
W is oxygen, sulfur or Cl 1 ( I I;
X. Y and Z are independently selected from the group consisting of -N, or -CR, wherein:
R is H, -Br. -Cl. -F. -CN. -NC , -OR1. -SR1. -NR . -C | -Cg branched or un-branched alkyl, which may be un-substituted or substituted,
wherein:
R1 is H, -C ] -C(5 branched or un-branched alkyl which, may be un-substituted or substituted.
F - O or S. A is H, or -C i -Cg branched or un-branched alkyl, which may be un-substituted or substituted. -C2-Cg branched or un-branched alkenyl which may be un-substituted or substituted, -C2-Cg branched or un-branched alkynyl. which may be un-substituted or substituted. -C3-C7 cycloalkyl which may be un-substituted or substituted. -C3-C7 alky lcycloalky 1 which may be un-substituted or substituted, aryl or heterocycle which may be un-substituted or substituted alkylary 1 which may be un-substituted or substituted alkylheterocycle which may be un-substituted or substituted
n = 0. 1. 2. 3. 4. 5. or 6;
Figure imgf000019_0001
is a -C3-C7 cycloalkyl, which may be un-substituted or substituted, a -C4-C7 azacycloalkyl, w hich may be un-substituted or substituted, a C7-C 10 bicycloalkyl which may be un-substituted or substituted, a -C7-C J Q azabicycloalkyl which may be un-substituted or substituted aryl which may be un-substituted or substituted or a heterocycle which may be un-substituted or substituted;
B is -C=. C-Ra, O, N. S. OO. S=0 or SO2.
Ra is H. a halogen (preferably F). OH. O-alkyl. cyano. or a -Ci-G, alkyl group which is un-substituted or substituted and which optionally forms a C3-C7 cycloalkyl group with D: and
D is absent when B is O. S. S O, ( ( ) or SO2. or if present is bonded to B when B is - C=, -C-R or N, and is 1 1. a halogen (preferably F), ORb, a -C i -Cg branched or un- branched alkyl, which may be un-substituted or substituted and which optionally, forms a C3-C7 cycloalkyl group with Ra, a -C^-Cg branched or un-branched alkenyl, which may be un-substituted or substituted, a -C2-C5 branched or un-branched alkynyl, w hich may be un-substituted or substituted a -C3-C7 cycloalky l which may be un-substituted or substituted an aryl which may be un-substituted or substituted , a heterocycle w hich may be un-substituted or substituted a -C2-C7 carboxyalkyl which may be un-substituted or substituted a carboxyaryl which may be un-substituted or substituted, a carboxyhetcroaryl which may be un-substituted or substituted a -C 1 -C7 sulfonx lalkyl which may be un-substituted or substituted a sulfonylaryl which may be un-substituted or substituted or a sulfonylheteroaryl which may be un-substituted or substituted or when B is -C-Ra. Ra and D optionally form a =N-RC or a =N-ORc group w ith B. wherein Rc is H or an unsubstituted or substituted C1-C7 alkyl group, or when B is -C-Ra. Ra and D optionally form a =N-RC or a =N-ORc group with B.
wherein Rc is H or an unsubstituted or substituted C1-C7 alkyl group; and
Rb is H, a -C1 -C7 alkyl group which may be branched or un-branched, un-substituted or substituted or a -C2-C7 acyl group which may be un-substituted or substituted.
Other exemplary ampakines useful within the combinatorial methods herein include include compounds according to formula II below:
Figure imgf000020_0001
wherein:
A is -C | -C(, branched or un-branched alkyl, which may be un-substituted or substituted, a C3-C7 cycloalky l which may be un-substituted or substituted;
n is 0, 1. 2. or 3;
B is C-R- . O or ( O;
Ra is FI, F, -OH or alkyl and
D is absent (when B is O), is H or OH when Ra is H or alkyl, or is F when Ra is F, or a pharmaceutically acceptable salt solvate, or polymorph thereof.
Yet additional exemplary ampakines for use within the invention include compounds according to formula III below:
Figure imgf000020_0002
w herein:
A is a C j -C^ alkyl which may be substituted or un-substituted;
B is C-Ra, O or 0=0;
Ra is FI, F, -Ol I or alkyl and
D is absent (when B is O), is H or OH w hen Ra is 1 1 or alkyl or is F when Ra is F. or a pharmaceutically acceptable salt, solvate, or polymorph thereof. Other exemplary ampakines for use within the invention include compounds according to formula iV below :
Figure imgf000021_0001
wherein:
A is a C ] -Cg alkyl which may be substituted or un-substituted.
n is 0. 1 or 2. or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
[0001 ] Other exemplary embodiments include compounds according to formula V below:
Figure imgf000021_0002
wherein:
A is a C ] -Cg alkyl which may be substituted or un-substituted.
R1 is H, F. or Ci -CA alkyl.
R2 is I. F. CN. a heterocycle which may be substituted or un-substituted or OR3. R3 is H. C ] -Cg alkyl which may be substituted or un-substituted, or a
pharmaceutically acceptable salt, solvate, or polymorph thereof.
Other exemplary ampakines for use within the invention include compounds according to formula VI below:
Figure imgf000022_0001
wherein:
A is a C ] -C6 alkyl which may be substituted or un-substituted.
R is H, or C1-C4 alkyl, or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
Other exemplary ampakines for use w ithin the invention include compounds according to formula VII below:
Figure imgf000022_0002
wherein:
B is C-Ra. O or ( < >:
Ra is H, F. -OH or alkyl and
D is absent (when B is O), is H or OH when Ra is H or alkyl, or is F when Ra is F, or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
Other exemplary ampakines for use w ithin the invention include compounds according to formula VI II below :
Figure imgf000022_0003
wherein:
B is C-Ra. O or C=0;
Ra is H. F. -OH or alkyl and D is absent (when B is O). is H or Ol I when Ru is 1 1 or alkyl or is F when Ra is F. or a pharmaceutically acceptable salt, solvate, or polymorph thereof.
Other exemplary ampakines for use within the invention include compounds according to formula IX below:
Figure imgf000023_0001
wherein:
A is a C ] -C(, alkyl which may be substituted or un-substituted,
R1 is H. or C1-C4 alkyl.
R2 is H. or a C j -C^ alkyl which may be substituted or un-substituted.
R? is 1 1. or a C | -C(, alkyl which may be substituted or un-substituted,
R4 is 1 1. or a C 1 -C alkyl which may be substituted or un-substituted, or a
pharmaceutically acceptable salt, solvate, or polymorph thereof.
In more detailed embodiments, anti-cancer active compounds are selected from compounds of Formulas I -IX above that are already isolated and characterized, selected from: /V-Cycloheptyl-/V-methyl-[2.1 ,3 ]-benzoxadiazole-5-carboxamide; A'-(4.4- Dimethylcyclohexyl-/v-methyl-[2, 1 ,3 |-benzoxadiazole-5-carboxamide; A'-Methyl-A- spiro[2.5]oct-6-yl-[2.1.3]-benzoxadiazole-5-carboxamide; A'-Cyclohexyl-X-methyl-[2.1.3]- benzoxad iazo le-5 -carboxam i de; A'-Cyclopentyl-A'-methyl-[2, 1 ,3 |-benzoxadiazole-5- carboxamide; A-Cyclobutyl-A?-methyl-[2. 1.3 j-benzoxad iazo le-5 -carboxamide; A'-Cyclohexyl-
[2.1 ,3 ]-benzoxadiazole-5-carboxamide: A'-Cyclopentyl-[2.1.3 |-benzoxadiazole-5- carboxamide; A'-Cyclobutyl-[2.1.3 ]-bcnzoxadiazole-5-carboxamide; V-(c/.v-4- Cyanoc\clohexyl)-,V-methyl-[2. 1.3 ]-benzoxadiazole-5-carboxamide; N-(lruns- - Cyanocyclohexyl)-A-methyl-[2. l ,3 ]-benz.oxadiazole-5-carboxamide; .V-Methyl-Ar-tetrahydro- 2/f-pyran-4-yl-[2.1.3]-benzoxadiazole-5-carboxamide (CX I 739); A'-Dj-Methyl-A'-tetrahydro- 2//-pyran-4-yl-[2.1 ,3]-benzoxad iazo le-5 -carboxamide; A'-(Tetrahydro-2/7-pyran-4-yl)- [2, 1 ,3 |-benzoxadiazole-5-carboxamide; A/-(Tetrahydro-2/7-pyran-3-yl)-[2, l ,3J- benzoxadiazole-5-carboxamide; Ai-Methyl-N-(tetrahydro-2//-pyran-3-yl)-[2, 1.3]- benzoxadiazole-5-carboxamide; V-Fthyl-A'-tetrahydiO-2H-pyran-4-yl-[2. 1 ,31- benzoxadiazole-5-carboxamide: A-Cyc lohcxy l-A'-ethyl-[2. 1 ,3 [-benzoxad iazole-5- carboxamide;/V-(Cyclohcxyimethyl)-,V-mcthyl-[2, 1.3]-benzoxadiazolc-5-carboxamide; N- Benzyl-A-methyl-[2, 1 , 3 ] -benzoxad iazo lc-5 -carboxam ide: A'-Methyl-A'-(tetrahydrofuran-2- ylmethyl)-[2. l ,3]-benzoxadiazole-5-carboxamide; A-Methyl-A-pyridin-3-yl-[2.1 ,3]- benzoxadiazole-5-carboxamide; A-Methyl-A'-phenyl-[2, l ,3]-benzoxadiazole-5-carboxamide A-CycIopropyl-Ar-tetrahydro-2/7-pyran-4-yl-[2, 1 ,3]-benzoxadiazole-5-carboxamide
A-Tetrahydro-27/-pyran-4-yl-Ar-(2.2.2-trifluoiOethyl)-[2.1.3 |-benzoxadiazole-5-carboxamide: tert-Buty l-4-[( [2.1.3]-benzoxadiazol-5-ylcarbonyl)(methyl)amino]piperidine- l -carboxyIate; A-Methyl-A'’-piperidin-4-yl-[2, 1 ,3 |-benzoxadiazole-5-carboxamide hydrochloride: A -Metln I- A-( l -mcthylpiperidin-4-y l)-[2. l ,3 ]-benzoxadiazolc-3-carboxamide: A-( 1 -Acetylpiperidin-4- yl)-A-methyl-[2. 1.3 |-benzoxadiazole-5-carboxamide: A’-( 1 -Formylpiperidin-4-yl)-Ar-methyl- [2.1.3 |-benzoxadiazole-5-carboxamide: A-Methyl-A?-| 1 -(mcthylsulfonyl]piperidin-4-yl)- [2, 1 ,3 |-benzoxadiazolc-5-carboxamide: A'-IV1cthyl-A'-(tetrahydro-2H-pyran-4-yl)-[2.1 ,3]- benzothiadiazole-5-carboxamide: A'-Mcthy]-Ar-(tetrahydro-2/7-thiopyran-4-yl)-[2. 1.3]- benzoxadiazole-5-carboxamide: Ar-Methyl-A'-( 1 -oxidotetrahydro-2//-thiopyran-4-yl)-[2, 1 ,3]- benzoxadiazole-5-carboxamide: A -\lethy l-A -( 1 , 1 -dioxidotetrahydro-2/7-thiopyran-4-yl)- [2, 1.3]-benzoxadiazole-5-carboxamide: A/- ethyl-A?-tetrahydn>27/-pyran-4-ylquinoxaline-6- carboxamide: A'-Methyl-A'-(4-oxocyclohexyl)-[2, 1 3]-benzoxadiazolc-5-carboxamide; N-[4- (Hydroxyimino)cyclohexyl]-A'-methyl-[2. 1.3 [-benzoxad iazole-5-carboxam ide; N-[4- (Methoxyimino)cyclohexylJ-A-mcthyl-[2.1.3 |-benzoxadiazole-5-carboxamide; A -(4.4- Dinuorocyclohexyl)-A/-mcthyl-[2. 1.3[-benzoxadiazolc-5-carboxamide; A'-(4-fluorocyclohex- 3-en- 1 -yl)-A'-methyl-[2. 1.3]-benzoxadiazole-5-carboxamidc: A'-(4-/nmv- Hydroxycyclohexyl)-[2. 1.3 |-benz.oxadiazolc-5-carboxamide: X-(trans-4-\ lydroxy-4- methy I cy c lohcxy I )- 12. 1.3]-benzoxadiazole-5-carboxamide; V-(c/.v-4-Hydroxy-4- methylcyclohexyl)-A-methyl-[2. 1 ,3]-benzoxadiazolc-5-carboxamide; N-(tran.s- 4-1 lydroxy-4- methylcyclohexyl)-A'-methyl-[2.1.3]-benzoxadiazole-5-carboxamide; ,A-(c/.s-4-Hydroxy-4- ethylcyclohexyl)-A'-methyl-[2.1 ,3 |-benzoxadiazole-5-carboxamide: A-(/ram-4-Hydroxy-4- ethylcyclohexyl)-A’-methyl-[2.1.3 |-benzoxadiazole-5-carboxamide: V-(c/.v-4-Ethynyl-4- hydroxv eye lohexyl)-A'-inethyl-| 2, 1.3 |-benzoxadiazole-5 -carboxam ide; A'-(c7v-4-But-3-en- l - yl-4-hydroxycyclohexyl)-Ar-methyl-[2. 1.3 |-benzoxadiazole-5-carboxamide; A-(/ram-4-But-
3-en- 1 -yl-4-hydroxycyclohexyl)-A'-methyl-[2. 1 ,3]-benzoxadiazole-5-carboxamide: A'-(4- /ra --Hydroxycyclohexyl)-A’-methyl-[2.1.3 ]-benzoxad i azole-5 -carboxam ide (CX 1763); N- (4-/ra --Hydroxycyclohexyl)-A'-I)3-methyl-[2.1.3 |-benzoxadiazole-5-carboxamide; N-(trans-
4-Methoxycyc lohcxy I )-A’-mcthyl-[2. 1.31-benzoxadiazole-5-carboxamide; N-(trans-4- Methoxycyclohexyl)-A-methyl-[2, l ,3]-benzoxadiazole-5-carbothioamide; N-(4-cis- Hydroxycyclohexyl)-A-methyl-|2, 1.3 ]-benzoxadiazole-5-carboxamide; A/-Methyl-A^-[/ram-4- (2//-tetrazol-2-yl)cyclohexyl]-[2, 1 ,3]-benzoxadiazole-5-carboxamide; N-(trans- 4- Azidocyclohexyl)-A,-methyl-| 2. l ,3]-benzoxadiazole-5-carboxamide; N-{tnms-4- Aminocyclohexyl)-/V-methyl-[2, 1.3 ]-benzoxadiazole-5-carboxamide; N-(cis-3- Hydroxycyclohexyl)-A-methyl-[2. 1.3 ]-benzoxadiazole-5-earboxamidc; N-{lrans-3- Hydroxycyclohexyl)-A'-methyl-[2, 1 ,31 -benzoxad iazo le-5 -carboxam ide ; A-Methyl-A7-(3- oxocyclohexyl)-[2.1.3]-benzoxadiazole-5-carboxamide; A'-MethyI-A'-(3.3- d inuorocyclohcxy I )-[ 2.1.3]-benzoxad iazo le-5 -carboxam ide; Ar-(2-Hydroxycyclohexyl)-A- methyl-[2.1.3J-benzoxadiazole-5-carboxamidc: A'-Methyl- V-(2-oxocycIohexyl)-[2, 1 ,3]- benzoxadiazolc-5-carboxamide: A,-Mcthyl-A'-(2,2-dinuorocyclohexyl)-[2, 1 ,3 ]- benzoxadiazole-5-carboxamide; A'-(2-Hydroxytetrahydro-2 -pyran-4-yl)-[2, 1.3]- benzoxadiazole-5-carboxamide; A,-(2-oxotetrahydiO-2//-pyran-4-yl)-[2J ,3]-benzoxadiazole- 5-carboxamide; Ar-Mcthyl-Ar-(2-oxoletrahydiO-2//-pyran-4-yl)-[2.1 ,3]-benzoxadiaz.ole-5- carboxamide; A/-(2-Hydroxytetrahydro-2/;/-pyran-4-yl)-Ai-mcthyl-[2, l ,3]-benzoxadiazole-5- carboxamide; /ram-4-[(2.1 ,3-Bcnzoxadiazol-5-ylcarbonyl)(methyl)amino]cyclohexyl N,N- dimethyl glycinate hydrochloride; //Y//7.V-4- (2.1.3-Benzoxadiazol-5- ylcarbonyl)(inethyl)amino]cyclohexyl L-alaninate hydrochloride; A'- (A)-Tetrahydrofuran-3- y I - [ 2.1.3]-benzoxadiazole-5-earboxam ide; A?-Melhyl-A-(/?)-tetrahydrofuran-3-yl-[2, 1 ,3]- benzoxadiazole-5-carboxamidc: Irons- 4-[ (2. 1 ,3-Benzoxadiazol-5- ylcarbonyl)(methyl)amino]cyclohcx l glycinate hydrochloride; A'-2-(4-Morpholinyl)ethyl-
[2.1.3]-benzoxadiazolc-5-carboxamide; A-Methyl-A',-2-(4-morpholinyl)ethyl-[2, 1 ,3]- benzoxadiazole-5-carboxamide hydrochloride; N-Mcthyl-N-tetrahydro-2H-pyran-4-yl-
[2.1.3]-benzoxadiazole-5-carbothioamide (CX 1739); /ram-4-[(2, 1 ,3-Benzoxadiazol-5- ylcarbonyl)(methyl)amino]cyclohexyl L-valinate hydrochloride; /ra -4-[(2, l ,3- Benzoxadiazol-5-ylcarbonyl)(methyl)amino]- l -methyl cyclohexyl A',A'-dimethyl glycinate hydrochloride; A-Methyl-A-tetrahydro-2//-pyran-4-yhnethyl-f2. 1.3 |-benzoxadiazole-5- carboxamide; and /ra -4-[(2. 1.3-Benzoxadiazol-5-ylcarbonyl)(methyl)amino|- 1 - methyicyclohexyl glycinate hydrochloride (CX I 42).
Within additional compositions and methods of the invention, low impact ampakines are employed in the methods and compositions of the invention selected from yet additional ampakine groups including bicyclic amide ampakines." Among the many bicyclic amide ampakines candidates for use within the invention are the following exemplary species; 8-Azabicyclo[3.2.1 ]oct-8-yl([2. 1.3 ]-bcnzoxadiazol-5-yl)methanone; 8- ([2, l ,3]-Benzoxadiazol-5-ylcarbonyl)-8-azabicyclo[3.2.1 |octan-3-one: [2, 1.3 ]- Benzoxadiazol-5-yl(3.3-difluoro-8-azabicyclo[3.2.1 ]oct-8-yl)methanonc; entlo-[ 2, 1 ,3]- Benzoxadiazol-5-yl(3-hydroxy-8-azabicyclo[3.2.1 ]oct-8-yl)methanone: e.ro-[2.1 ,3]- Benzoxadiazol-5-yl(3-hydroxy-8-a/abicyclo[ 3.2.1 ]oct-8-yl)methanone; 2- Azabicyclo[2.2. 1 ]hept-2-\i([2. l ,3-benzoxadiazol-5-yl)methanone: l -Azabicyclo[2.2. l jhept- 1 -y 1 ( [ 2 , 1 3]-benzoxadiazol-5-yl)methanone: 2-Azabicyclo[2.2.2]oct-2-yl([2, 1 ,3]- benzoxadiazol-5-yl)methanone; [2. 1 ,3]-Benzoxadiazol-5-yl(5.6-dichloro-2- azabicyclo[2.2. 1 |hept-2-yl)methanone. Additional bicyclic amide ampakines for prospective use within the anti-cancer methods and compositions of the invention include, but are not limited to. the follow ing exemplary species: [2.1.3 )-Benzoxadiazol-5-yl(3-fluoro-8- azabicyclo[3.2. l ]oct-2-en-8-y])methanone; 2-Azabicyclo[2.2. 1 ]hept-5-en-2-y 1( [2.1 ,3]- benzoxadiazol-5-yl)methanone: /?-2-Azabicyclo[2.2.1 |hept-5-en-2-yl([2.1 ,3]-benzoxadiazol- 5-yl)methanone: S-2-Azabicyclo[2.2.1 ]hept-5-en-2-yl([2.1.3 ]-benzoxadiazol-5- yl)methanone; and [2, 1.3]-Benzoxadiazol-5-\i(2-oxa-5azabicyclo| 2.2.1 ]hept-5- yl)methanone.
Yet additional ampakine compounds for use w ithin the invention will be selected according to the teachings herein using known A MPA receptor modulator compounds, reagents, preparative methods and other tools as disclosed in the follow ing publications, each of which is incorporated herein for all purposes: PCT lnt'1 Pub. No. WO 94/02475 and related U.S. Pat. Nos. 5.773,434, 5,488,049, 5.650,409, 5,736,543, 5.747.492, 5,773,434, 5,891 ,876. 6,030,968. 6,274,600, 6,329,368. 6.943, 159. and 7,026,475; U.S. Pat. Pub. No. 20020055508: U.S. Pat. Nos. 6.174,922, 6.303.816. 6,358.981 , 6.362,230, 6,500.865. 6,5 15,026. and 6.552.086: PCT lnt'l Pub. Nos. WO 0190057, WO 0190056, WO 0168592. WO 0196289. WO 02098846. WO 00061 57. WO 9833496. WO 0006083. WO 0006148. WO 0006149. WO 9943285. and WO 9833496: WO 0 194306: U.S. Pat. No. 6,525.099 and PCT lnt’l Pub. No. WO 0006537; U.S. Pat. No. 6.355.655 and PCT lnt'l Pub. Nos. WO02 14294. WO02 14275. and W00006159: U.S. Pat. No. 6,358,982 and PCT lnt'l Pub. No. W00006158; U.S. Pat. No. 6,387.954 and PCT lnt'l Pub. No. WO0006539; PCT lnt'l Pub. No. WO02098847; U.S. Pat. No. 6.639.107 and PCT lnt'l Pub. No. W00142203; PCT lnt’l Pub. No. WO0232858: PCT lnt'l Pub. No. WO0218329; U.S. Pat. No. 6,596.716 and PCT lnt’l Pub. Nos: W02006087169. W02006015827. W02006015828.
WO2006015829. W02007090840. and W02007090841 ; WO02089734: U.S. Pat. Nos. 5.650.409. 5.747.492, 5.783.587. 5.852.008. and 6,274.600 U.S. Pat. Nos. 5,736,543, 5,962.447. 5.985,871. and PCT lnt’l Pub. Nos. WO 9736907 and WQ9933469; U.S. Pat. No. 6, 124.278, and PCT lnt'1 Pub. No. WO 995 1240; PCT Int'l Pub. No. W0030453 15; U.S. Pat. No. 5.891.871 ; U.S. Pat. Nos. 6.1 10.935 and 6.3 13. 1 1 5. and PC T Int'l Pub. No. WO9835950; PCT Int’l Pub. No. WO 9812 1 85; PCT Int’l Pub. No. W00075 123; U.S. Pat. No. 6,521 ,605 and PCT Int’l Pub. No. W00006176; PCT Int’l Pub. No. WO 0066546; PCT Int’l Pub. No. WO 9944612; PCT Int’l Pub. No. W02007060144; U.S. Pat. Pub. No. 20060276532; U.S. Pat. Pub. No. 20070066573: U.S. Pat. Pub. No. 20070004709; U.S. Pat. Pub. No.
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Additional description and background pertaining also to specific positive allosteric AMPA receptor modulators their preparation, use and selection within the compositions and methods of the invention, is provided in the following references, incorporated herein in toto for all purposes: F:or benzofurazan compounds-PCT patent application PCT/US98/02713. United States patent application Serial No. 08/800, 108. now United States Patent 6, 1 10,935, United States patent application Serial No. 09/355, 139, now United States Patent 6,3 13, 1 15, United States patent application. Serial No. 09/834,349; United States patent application, Serial No. 09/845.128. now United States Patent 6,730,677; For di-substituted amide ampakines-PCT patent application PCT/US2008/006271 , United States patent application Serial No. 12/45 1.5 1 5. now United States Patent 8.013,003. United States patent application. Serial No. 13/226, 146. no issued United States Patent 8.404,682, and United States patent application. Serial No. 13/755.2 10. no issued United States Patent 8.642.633; For bicyclic amide ampakines-PCT patent application PCT/US2008/009508, United States Provisional patent application. Serial No. 60/964.362: United States patent application, Serial No. 12/657.908. now United States Patent 8, 1 19.632, United States patent application. Serial No. 12/733.073. now United States Patent 8,263,591. United States patent application. Serial No. 13/348, 171. now· United States Patent 8.507,482, United States patent application. Serial No. 13/557.681. United States patent application. Serial No. 12/657,924. no United States Patent 8.168.632, PCT patent application PCT/US2010/000255, and United States Provisional patent application. Serial No. 61 /206.642: For bicyclic amide ampakines-PCT patent application PCT/US2010/000254. and United States Provisional patent application. Serial No. 61 /206.642: For 3 -Subst ituted- [ 1 ,2.3]Benzotriazinone ampakines-PCT Patent application PCT/US2007/02641 5. United States Provisional patent application, Serial No. 60/878,626. United States patent application. Serial No. 12/448.770, PCT patent application PCT/US2007/026416. United States Provisional application. Serial No. 60/878.503. United States Provisional patent application. Serial No. 60/921 ,433. and United States patent application. Serial No. 12,448.784. now United States Patent 8, 173,644: For 3-substituted l ,2,3-triazin-4-one and 3-substituted 1.3-pyrimidinone ampakines-PCT patent application PCT/US2008/010877. United States Provisional patent application, Serial No.60/994, 548. and United States patent application. Serial No. 12/733,822; For benzoxazine ampakines-PCT patent application PCT/US98/27027, and United States patent application. Serial No. 08/998.300. now- United States Patent 5.985.871 ; for Acylbenzoxazines ampakines- PCT patent application. Serial No. PCT/US99/07325. and United States patent application 09/054.916. now- United States Patent 6.124,278; for Benzoyl
Piperid inc/Pyrrol idinc ampakines PCT patent application PCT/US96/07607, and United States patent application Serial No. 08/458.967. Hied 2 June 1995. now United States Patent 5,650.409 For benzoxazine ampakines-PCT patent application. Serial No. PCT/US97/05 1 84, United States patent application. Serial No. 08/624,335. now United States Patent 5,736,543, PCT patent application PCT/US93/06916. and United States patent application, Serial No. 07/919.5 12. no United States Patent 5.962.447: and for carbonylbenzoxazine ampakines- PCT patent application PCT7US02/37646. United States Provisional patent application. Serial No. 60/333.334. and United States patent application Serial No. 10/495,049. now United States Patent 7,799,913. Bach of the foregoing classes and distinct structural groups of ampakine compounds disclosed in the above references are suitable for evaluation to determine operability within the methods and compositions of the invention. Persons of ordinary skill in the art will recognize that these various compound groups, while being structurally diverse, share common functional characteristics of positive allosteric AMPA receptor modulation, as described here, and that because of these common functional characteristics, the compounds can be evaluated and determined for their operability according to the inventive discoveries and teachings herein. According to the Examples and other guidance provided here, anti-cancer effective ampakines. for example, can be selected and demonstrated for beneficial clinical use without undue experimentation.
To practice coordinate administration methods of the invention, the anti-cancer effective AMPAR antagonist compound is co-administered. simultaneously or sequentially, in a coordinate treatment protocol with one or more of the secondary or adjunctive therapeutic agents contemplated herein. Thus in certain embodiments the anti-cancer effective AMPAR antagonist compound is administered coordinately with a conventional cancer chemotherapeutic agent using separate formulations or a combinatorial formulation. Coordinate administration may be done simultaneously or sequentially in either order, and there may be a time period while only one or both (or all) active therapeutic agents individually and/or collectively exert their therapeutic activities. A distinguishing aspect of all such coordinate treatment methods is that the anti-cancer effective AMPAR antagonist compound exerts at least some measurably distinct anti-cancer therapeutic activity, yielding a distinct clinical response, in addition to any complementary clinical response provided by the secondary or adjunctive therapeutic agent. Often, the coordinate administration of the anti cancer effective AMPAR antagonist compound with the secondary or adjunctive therapeutic agent will yield improved anti-cancer therapeutic or prophylactic results in the subject beyond a therapeutic or prophylactic effect elicited by the secondary or adjunctive therapeutic agent alone, which benefit contemplates both direct effects, as well as indirect effects.
The anti-cancer effective AMPAR antagonist compounds and pharmaceutical compositions of the present invention may be administered by any means that achieve the contemplated anti-cancer therapeutic or prophylactic purpose. Suitable routes of
administration for the compositions of the invention include, but arc not limited to, oral, buccal, nasal, aerosol, topical, transdermal, mucosal injectable, and intravenous, as well as all other practicable delivery routes devices and methods.
The anti-cancer effective AMPAR antagonist compounds of the present invention may be formulated ith a pharmaceutically acceptable carrier appropriate for the particular mode of administration employed. Dosage forms of the compositions of the invention include excipients recognized in the art of pharmaceutical compounding as being suitable for the preparation of dosage units as discussed herein. Such excipients include, without limitation, solvates buffers, binders, tillers, lubricants, emulsifiers, suspending agents, sweeteners, flavorings, preservatives, wetting agents, disintegrants, effervescent agents and other conventional pharmaceutical excipients and additives.
Anti-cancer effective AMPAR antagonist compounds of the invention will often be formulated and administered in an oral dosage form optionally in combination w ith a carrier and/or other additive(s). Suitable carriers for pharmaceutical formulation of oral dosage forms include for example, microcrystalline cellulose lactose, sucrose, fructose, glucose, dextrose, or other sugars di-basic calcium phosphate, calcium sulfate, cellulose,
methylcellulose. cellulose derivatives, kaolin, mannitol, lactitol. maltitol. xylitol, sorbitol, or other sugar alcohols, dry starch, dextrin, maltodextrin or other polysaccharides, inositol, or mixtures thereof. Exemplary unit oral dosage forms include ingestible and sublingual liquids, tablets, capsules, and films, among other options, which may be prepared by any
conventional method known in the art. optionally including additional ingredients such as release modifying agents gl idants. compression aides, disintegrants. lubricants, binders. flavor enhancers sweeteners and/or preservatives (e.g.. stearic acid magnesium stearate, talc, calcium stearate, hydrogenated vegetable oils sodium benzoate leucine carbowax, magnesium lauryl sulfate, colloidal silicon dioxide glyceryl monostearate, colloidal silica, silicon dioxide, and glyceryl monostearate). Oral dosage forms may further include an enteric coating that dissolves after passing through the stomach, for example, a polymer agent, methacrylate copolymer cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP). polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate. hydroxypropyl methylcellulose succinate cellulose acetate succinate cellulose acetate hexahydrophthalate, cellulose propionate phthalate. cellulose acetate maleate. cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacryiic acid and methyl methacrylate copolymer of methyl acrylate methy lmethacrylate and methacrylic acid, copolymer of methyl vinyl ether and maleic anhydride (Gantrez ES series) and natural resins such as zein, shellac and copal collophorium.
If desired, oral, mucosal, gastric transdermal, topical and injectable compositions of the invention can be administered in a controlled release form by use of such well known technologies as slow release carriers and controlled release agents.
In certain embodiments the anti-cancer effective AMPAR antagonist compound is administered to patients in an injectable or intravenous (iv) formulation and delivery mode.
In illustrative aspects a therapeutic unit dosage of PMP is formulated in a physiological solution amenable for injection or iv delivery to human subjects for example in an aqueous buffered solution such as saline. Alternative formulations of anti-cancer effective AMPAR antagonist compounds for administration to patients intravenously intramuscularly, subcutaneously or intraperitoneally can include nonaqueous sterile injectable solutions and optionally contain anti-oxidants buffers, bacteriostats and/or solutes which render the formulation isotonic with the blood of the subject, as well as aqueous and non-aqueous sterile suspensions which may include suspending agents and/or thickening agents. Additional injectable compositions and formulations of the invention may include polymers and other controlled deliver} additives or carriers for extended release follow ing administration.
Parenteral preparations may be solutions, dispersions or emulsions suitable for such administration. Extemporaneous injection solutions emulsions and suspensions may be prepared from sterile powders granules and tablets. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose or an appropriate fraction thereof of the anti-cancer effective AMPAR antagonist compound and/or active ingredient(s). In some embodiments, localized delivery of anti-cancer effective AMPAR antagonist compounds may be achieved by injecting the parenteral formulation directly into an area surrounding a cellular malignancy, directly into a tumor into the vasculature supplying a malignancy itself, or into a pleural or peritoneal cavity or cerebrospinal compartment proximal or fluidly connected to a targeted malignancy.
In certain embodiments the methods and compositions of the invention may employ a pharmaceutically acceptable salt of an anti-cancer effective AMPAR antagonist compound, for example an acid addition or base salt of a PMP compound, derivative or analog.
Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts. Suitable acid addition salts are formed from acids which form non-toxic salts, for example, hydrochloride, hydrobromide, hydroiodide sulphate, hydrogen sulphate, nitrate, phosphate, and hydrogen phosphate salts. Additional pharmaceutically acceptable salts include, but are not limited to. metal salts such as sodium salts, potassium salts, cesium salts and the like; alkaline earth metals such as calcium salts magnesium salts and the like;
organic amine salts such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts. N.N'-dibenzylethylenediamine salts and the like; organic acid salts such as acetate citrate lactate, succinate tartrate, maleate, fumarate. mandelate, acetate dichloroacetate. trifluoroacetate, oxalate, and formate salts; sulfonates such as methanesulfonate. benzenesulfonate. and p-toluenesulfonate salts; and amino acid salts such as arginate. asparginate. glutamate tartrate, and gluconate salts.
Suitable base salts are formed from bases that form non-toxic salts for example aluminum, calcium lithium magnesium, potassium, sodium, zinc and diethanolamine salts. In related embodiments, optional salt forms of an anti-cancer effective AMPAR antagonist compound will yield enhanced properties e.g., improved stability, solubility, tolerability, etc.
In other detailed embodiments the methods and compositions of the invention employ prodrugs of the anti-cancer effective AMPAR antagonist compound, e.g., prodrugs of a PMP compound or derivative or of an intermediary compound, or precursor compound of a PMP compound or derivative. As contemplated herein, prodrugs of anti-cancer effective AMPAR antagonist compounds can include the active compound reversibly linked (e.g., covalently bonded) to any carrier compound or moiety that functions to release the active anti-cancer effective AMPAR antagonist compound in vivo (for example to effectively mediate delivery of more active drug to enhance in vivo half-life of the drug or otherwise enhance pharmacokinetics or pharmacodynamics of the drug following administration. Examples of prodrugs useful within the invention include esters or amides with hydroxyalkyl or aminoalkyl as a substituent, among many other prodrug constructs known in the art.
The invention will also be understood to encompass methods and compositions comprising biologically active metabolites and in vivo conversion products of the anti-cancer effective AMPAR antagonist compound (either generated in vivo after administration of the compound, or directly administered in the form of the metabolite or conversion product itself). Such secondary active products may result for example from oxidation, reduction, hydrolysis, amidation, esterification and the like, of the administered compound, primarily due to enzymatic processes.
Example I
Dose-Dependent Anti-Cancer Activity of
Exemplary AMPAR Antagonist Perampanel (PMP)
T9G (Glioblastoma) and Panc- 1 (pancreatic adenocarcinoma) were obtained from ATCC. They were maintained in DMEM media (ATCC) and supplemented with 10% FBS (ATCC) and 1 % Penicillin/Streptomycin and maintained in an incubator at 37°C with 95% air and 5% CCT.
Reagents PMP was purchased from Mcdkoo and dissolved in DMSO.
Temozolomide, cisplatin and glutamate were purchased from Sigma and dissolved in complete media on the day of treatment.
Cancer Cell Viability Assays T98G or Pane l cells were seeded in quadruplicate at a density of 6.000 cells/well in complete DMEM and incubated overnight. T98G cells were then treated with increasing concentrations of PMP and temozolomide for 72 hours.
Alternatively, pane l cells were treated with PMP. cisplatin or glutamate for 48 hours.
Following this incubation. 15uL M I'S solution (Promega) was added to each well and incubated for a further 2 hours. Plates were read at 490nM using the EEx808 microplate reader. Absorbance values of wells with only media were subtracted out as background control. Data were normalized to vehicle-treated cells.
Data analysis Data were analyzed using Microsoft excel using a student's t-test. One-way ANOVA were also performed using Statplus. King's Synergy formula was used to look for synergistic interactions among PMP and chemotherapies. Alpha value was set at p=0.05.
Results
The data presented here unexpectedly reveal that AMPAR antagonists, exemplified by peramplanel (PMP). induce dose-dependent reductions in cell viability of T98G cells (Fig l a. ANOVA p<0.0001 ). The surprisingly potent oncolytic effects of peramplanel are mediated in part by antagonistic activity against AMPAR physiology in AMPAR positive cancer cell targets. Perampanel exhibited significant inhibitory activities against GBM cancer cell viability, even at concentrations of 1 - 1 OuM, demonstrating the clinical utility of this drug at relevant plasma levels for effective cancer chemotherapy. PMP additively complements anti-cancer effects of temozolomide (TMZ) at 30uM, and synergistically potentiates TMZ anti-cancer efficacy at l OOuM (Fig l b).
Previous work w ith pancreatic cancer has suggested that ampakines may be able to reduce cell viability. Thus the results provided here demonstrating that PMP dose- dependently reduces Pane l cell viability (ANOVA p=0.0013 ). with significant reduction of cell viability seen at l OOuM (Fig 2a). are particularly surprising. Although l OuM PMP did not appear to exert potent oncolytic effect alone at this concentration it did significantly enhance oncolysis in combination w ith the drug cisplatin. Accordingly, PMP will be clinically effective to improve cancer treatments of this and other chemotherapeutic agents (Fig 2b). l OOuM PMP and 3uM cisplatin also synergistically reduced pancreatic cancer cell viability (Fig 2b).
In yet additional working examples provided here. PMP effectively disrupted the oncogenic activity of exogenous glutamate, thereby inhibiting glutamate-potentiated pancreatic cancer activation (e.g.. as demonstrated by impairment of cancer cell
proliferation). In these studies, glutamate concentrations of l OO- l OOOuM elicited a dose- dependent acceleration of pancreatic cancer cell proliferation (Fig 2c). In test samples pane l cells were exposed to I mM glutamate for 15 minutes prior to the addition of PMP to cell culture media. Perampanel addition 1 5 minutes following glutamate exposure was sufficient to profoundly disrupt oncogenic activities of glutamate (Fig 2d).
Example 11
Dose-Dependent Anti-Cancer Activity of
An Exemplary AMPAR Antagonist, Perampanel (PMP)
Potent anti-cancer efficacy of PMP compounds and other effective AMPAR antagonists is readily demonstrated using a range of animal models that are well known and w idely accepted in the art as predictive of anti-cancer activity in humans. One such model employ s subcutaneous xenografts of tumor eells into useful study animals such as mice, to study efficacy of candidate anti-cancer drugs in reducing growth or proliferation of xenografted tumor cells in test versus control subjects. These studies can include monitoring of a range of indicia of therapeutic efficacy, for example to demonstrate a dose-dependent decrease (e.g.. based on average values observed in test versus control subjects) in xenografted tumor number, tumor size tumor metastases. tissue histological and/or biochemical cancer markers (e.g.. from biopsy or necropsy) blood cancer markers mortality etc. As used herein cancer "markers" refers to any biomolecule such as a growth factor, genetic regulatory protein cytokine hormone receptor etc. whose presence, expression, structure, level or activity is correlated with cancer incidence severity progression, or another etiologic or therapeutic factor indicative of cancer growth metabolic activity, metastasis etc.
In useful study protocols relating to central nervous system (CNS) cancers such as glioblastoma (GBM). conventional xenograft study designs may be modified to include intracranial xenografting, to better capitulate clinical conditions of GBM (see, for example, Ozawa et ah, 2010). In one exemplary study protocol employed herein, modified from Ozawa et ah. we employ T98G cells, a GBM cell line expressing the enzyme MGMT. which functions to repair DNA damage from temozolomide (TMZ). rendering this cell type intrinsically resistant to TMZ chemotherapy. These cells are engineered to express the bioluminescent enzyme luciferase to allow in vivo xenograft detection and quantification. A study total of 24 mice are used, divided into four study groups of 6 members per group. The mice are anesthetized using ketamine/zylazine on a warming plate to maintain core body temperature. Once anesthetized the scalp is swabbed with chlorohexidine and a sagittal incision is made over the parieto-occipital bone about 1 cm long on the left side. The exposed skull is cleaned using a cotton swab with 3% hydrogen peroxide. Xenograft cells are provided at a concentration of 300.000-500.000 cells in 3uL serum-free media, and this cell suspension is drawn into a syringe and injected at a depth of 3mm into the cortical tissue.
The injection is carried out slow ly over a period of one minute to localize the xenografted cells focally to specific brain region and prevent dissemination of the cells into the ventricles and spinal cord. After injection the skull is cleaned with 3% hydrogen peroxide and sterile bone wax is to the incised skull defect. The scalp is drawn over the skull and stapled closed. Buprenorphine is optionally administered for post-operative pain relief, and recovery time is about 30 minutes.
One week after injection the study subjects arc divided into 4 groups and
bioluminescent monitoring of the xenografts begins. Group 1 mice receive placebo saline for the duration of the experiment. Group 2 receives 20mg/kg/day TMZ. Group 3 receives 5 or l Omg/kg/day PMP depending on what dose produces a partial effect in monotherapy experiments. Group 4 is a combination group that receives both the TMZ and PMP treatments. Mice are bioluminescent monitored every 4 days during the study, for example using D-luciferin and an in vivo imaging system such as 1VIS-200 (PerkinElmer. Inc,
Norwalk Connecticut) to measure bioluminescent photon release as a quantitative indicator of tumor growth.
These and related studies will demonstrate that PMP and other anti-cancer effective AMPAR antagonists according to the teachings herein potently prevent and treat AMPAR positive CNS cancers, including GBM. in mammalian subjects. Particular results will demonstrate a dose-dependent reduction in overall luminescence over an effective course of AMPAR antagonist treatment, correlated w ith reduced tumor size, reduced tumor cell number and/or reduced xenograft proliferative and/or metastatic capacity mediated by the anti-cancer AMPAR antagonist for example PMP. PMP and other selected AMPAR antagonist will also significantly decrease tumor cell survival, viability and proliferation, and increase correlated indicia including time to tumor doubling and tripling, as well as subject survival (e.g.. by time and/or numbers of subjects), in addition to mediating significant therapeutic benefits corresponding to all other anti-cancer activity indicators described herein above
In more detailed in vivo protocols, PMP will exhibit significant inhibitory activity against GBM xenograft cell viability, proliferative capacity, tumor growth and metastases at concentrations of 1 -1 OuM or greater, i.e., at plasma levels that are safe and effective for cancer chemotherapy.
In other detailed aspects. PMP will be shown to be combinatorially effective to complement anti-GBM effects of secondary anti-cancer drugs and treatments, for example temozolomide (TMZ). In certain embodiments. PMP will complement, potentiate or even synergistically enhance anti-cancer activities of other drugs, for example to significantly increase overall anti-cancer effects in combination with TMZ, compared to anti-cancer effects mediated by TMZ alone. In these embodiments the combinatorial use of PMP and TMZ, e.g.. at therapeutic dosage levels of PMP between about 30uM- 100uM. provides for enhanced efficac of TMZ and lower TMZ dosages with reduced TMZ-associated side effects, an exemplary model of coordinate treatment that will be demonstrable across a range of combinations of AMPAR antagonists and secondary/adjunctive anti-cancer agents and therapies.
In related illustrative protocols the efficacy of anti-cancer AMPAR antagonists such as PMP is demonstrated in combinatorial usage with a PRMT5 inhibitor, such as RPZO 15666. As recently reported by Braun et al (201 7). high grade gliomas may be dependent on deletion of detained introns of oncogenic transcripts for sustained growth and survival. PRMT5 ensures proper splicing of these introns to become mature transcripts useful for production of various oncogenic proteins. Inhibition of PRMT5 with EPZO 15666 reportedly mediates oncostatic effects against GBM. In one illustrative study here, the foregoing intracranial xenograft study design is adapted to include one individual test group of 6 mice receiving 100mg/kg/day EPZO 15666. one group treated with l Omg/kg/day PMP, and a combinatorial group treated with both EPZO 1 5666 and PMP. Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that PMP is anti-cancer effective alone, and combinatorially effective (e.g.. complementary, additive potentiating or synergistic) in coordinate administration with EPZO 15666.
In other illustrative protocols of the invention the efficacy of anti-cancer AMPAR antagonists such as PMP is demonstrated in combinatorial methods with tumor treating fields. Recent studies report that electrical fields using insulated electrodes applying frequencies of 200kHz can inhibit cell cycle progression in GBM cells (see, e.g., Kirson et al, 2007; and Stupp et al, 2015). In an exemplary study here the intracranial xenograft protocol is adapted to include one individual test group of 6 mice receiving an external insulated electrode closest to the area of the xenograft applying a 200kl Iz current for the duration of the study, one group treated with l Omg/kg/day PMP. and a combinatorial group treated with both therapies. Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that PMP is anti-cancer effective alone and combinatorially effective in coordinate administration with tumor treating fields.
In other exemplary protocols of the invention the efficacy of anti-cancer AMPAR antagonists such as PMP is demonstrated in combinatorial therapies employing proteins that interfere with telomere function of tumors, for example the TRE I inhibitor ETP-47037. Due to rapid proliferation of most tumors, tumor cells are particularly vulnerable to DNA damage that can result in cell death. Telomeres are the caps of chromosomes made of repetitive DNA. which serve to prevent protein-coding DNA loss or damage during cell division. Several proteins are implicated in maintaining telomeres, one of which is a protein designated TRE E Recent studies report that pharmacological or genetic ablation of this TRF 1 reduces tumor formation and growth in animal models (see, e.g.. Bejarano et al, 2017). In one report, 75mg/kg of ETP-47037 prevented tumor growth in mice. In an illustrative protocol here, the intracranial xenograft protocol above is adapted to include one test group of mice receiving a therapeutic dosage of 75mg/kg of ETP-47037. one group treated with l Omg/kg/day PMP. and a combinatorial group treated with both therapies. Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that PMP is anti-cancer effective alone and combinatorial!}' effective in coordinate administration with ETP-47037. Additional studies are contemplated to show that combinatorial treatment w ith PMP provides for lower dosing of the ETP-47037 to achieve the same or greater clinical benefits with fewer side effects (e.g., wherein a comparable, partial anti-cancer effect as exhibited by 75mg/kg is observed in combination with PMP at reduced effective dosages of H I P-47037 of 25-50mg/kg or lower).
In another exemplary combination treatment model of the invention, the efficacy of anti-cancer AMPAR antagonists such as PMP is demonstrated in coordinate protocols with a transcription inhibitor, such as terameprocol. Terameprocol is a global transcription inhibitor that affects proliferation, apoptosis and drug resistance, currently being clinically evaluated for treatment of GBM (Grossman et al. 2012). In one representative study the intracranial xenograft study includes one test group of mice treated with 20mg/kg/day Terameprocol, one group treated ith l Omg/kg/day PMP. and a combinatorial group treated with both therapies. Bioluminescent imaging and other measures of anti-cancer efficacy will demonstrate that PMP is anti-cancer effective alone and combinatorially effective in coordinate administration with Terameprocol. Additional studies will show that combinatorial treatment with PMP provides for low er dosing of Terameprocol to achieve the same or greater clinical benefits, with fewer side effects.
In yet additional combinatorial treatment methods of the invention, the efficacy of anti-cancer AMPAR antagonists such as PMP is demonstrated in coordinate protocols with NEK2 inhibitors. Recent studies report that EZH2 is vital for maintaining glioma stem cells, a subset of glioma cells that are responsible for chemo- and radiotherapy resistance due to their ability to regenerate new tumor cells after existing tumor cells are destroyed. NEK2 is responsible for guarding EZH2 against premature breakdown, allow ing EZH2 to exert a longer and more robust oncogenic effect. Recent studies report that an inhibitor of NEK2, Cmp3a. exerts anti-cancer effects as demonstrated by prolongation of cancer survival time in mice (Wang et al. 201 7). According to the modified study protocol here one group of mice receives l Omg kg /day Cmp3a. one group received l Omg/kg/day PMP. and a combinatorial group is treated with both therapies. Bioluminescent imaging and other measures of anti cancer efficacy w ill demonstrate that PMP is anti-cancer effective alone and combinatorially effecti\ e in coordinate administration with NEK2 inhibitors such as Cmp3a. Additional studies will show' that combinatorial treatment with PMP provides for lower dosing of NEK3 inhibitors to achieve the same or greater clinical benefits, with fewer side effects. Example H I
Anti-Cancer Activity of AMPAR Antagonists In Combination with
Standard Of Care Glioma Treatment
Figure imgf000038_0001
In exemplary clinical protocols of the invention anti-cancer effective AMPAR antagonist treatment will be combined with secondary anti-cancer therapy comprising standard of care (SOC) glioma treatments. In one illustrative example, patients are initially treated with SOC maximal safe surgical resection, followed by an aggressive SOC chemoradiation protocol. For the first 6 weeks of treatment, patients receive 75mg/m2/day of Temozolomide (Temodar) starting one hour prior to radiation treatment. Patients additionally receive 200cGy focal radiation per day for the first five days of the week over a 6 week timespan (30 fractions) lor a total of 60Gy radiation. Radiation targets the tumor area as well as surrounding edema plus a 1 cm margin. 1 month after the last radiation treatment, patients are administered 150-200mg/m2/day temozolomide for the first 5 days of every month followed by 3 weeks rest as well as antiemetic prophylaxis treatment as needed.
Treatments are stopped if platelet count drops belo 100.000/uL. or if there is evidence of disease progression or severe treatment-related toxicity (Grossman et al, 2009). In combination with the SOC glioma treatment outlined above, patients receive 8mg peramplanel orally 1 hour prior to the first radiation session. Perampanel is further administered once per day, and weekly titrated up 2 mg/day until patients receive the maximally tolerated approved dose (MTD) of 12 mg (Gidal et al, 2015) (though this range can be adjusted up or dow n based on patient-specific tolerance and other clinical factors determined by the managing physician). Within illustrative methods for treating GBM, patients receive the M FD throughout an initial 6-week treatment period, during the 1 month SOC rest period, and w hile patients are taking maintenance Temodar. Patients are maintained on perampanel treatment as determined by the managing physician, unless disease progression or evidence of pcramplanel-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-glioma therapy.
Example IV
Anti-Cancer Activity of AMPAR Antagonists In Combination with
Eevetiracetain Co-Treatment In additional clinical examples patients are treated concomitantly with an AMPAR antagonist such as peramplanel and Levetiracetam (Keppra). which has been shown to augment temozolomide efficacy (Bobustuc et al. 2010) and reduce aggression-related adverse events in patients taking perampanel (Kanemura et al. 2019; Kim et al. 2015). Patients are administered perampanel as described above along with 500mg levetiracetam 1 hour prior to the first radiation session. Levetiracetam is administered twice a day. the second time being at night before bed. Within illustrative methods lor treating GBM, patients receive 200- 500mg levetiracetam twice a day throughout the first 6-week treatment period, during the 1 month rest period and while patients are taking maintenance Temodar. Patients continue to receive levetiracetam and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will sho substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Hxample V
Anti-Cancer Activity of AMPAR Antagonists In Combination with
NMDA Receptor Anta onist Co-Treatment
In other clinical protocols useful w ithin the invention patients are treated
concomitantly with an N-methyl-D-aspartate (NMDA) receptor antagonist, such as memantine. Memantine has been reported to exert anti-cancer effects, possibly by abrogating constitutive!}' active growth pathways in cancer (Stepulak et al, 2005; Maraka et al, 2019). Patients receive perampanel along w ith 5-20mg memantine orally prior to the first radiation session. Within illustrative methods for treating GBM. perampanel and memantine are administered once a day throughout the first 6-week treatment period during the 1 month rest period and while patients are taking maintenance Temodar. Patients are maintained on memantine and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy. In addition to memantine ketamine an NMDA-antagonist used in the setting of pharmacoresistant depression may also be used. Ketamine is given at doses ranging from 5-500mg/day and started prior to the first radiation session. Ketamine and its active metabolite
hydroxynorketamine (Zanos et al. 2016) may provide anti-cancer benefits (Malsy et al,
2015). and will be a beneficial adjunct within the methods of the invention for example to complement standard of care + perampanel treatments. Example VI
Anti-Cancer Activity of AMPAR Antagonists In Combination with
Riluzole/Troriluzole Co-T re atment
Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with Ri!uzole/ troriluzole (see, e.g., Khan et al, 2019). Patients receive perampanel as above in coordinate treatment with with 20-50mg
Riluzole/troriluzole orally prior to the first radiation session. Within illustrative methods for treating GBM. perampanel and Riluzole/troriluzole arc administered once a day throughout the first 6-week treatment period during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on Riluzole/troriluzole and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example VI 1
Anti-Cancer Activity of AMPAR Antagonists In Combination w ith
CSF 1 R Inhibitors
Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with a colony stimulating factor 1 receptor (CSF 1 R) inhibitor such as PLX3397 (plexidartinib) or PEX5562 (see, e.g., Yan et al, 2017; Butowski et al, 2016). Patients are administered perampanel as above in coordinate treatment with 100- 1000 mg PLX3397 orally prior to the first radiation session. Within illustrative methods for treating GBM. perampanel and PLX3397 are administered together or separately once a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on PLX3397 and perampanel unless disease progression or ev idence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy. While CSF 1 R inhibition is reported to provide pre-clinical anti-cancer benefitsresults (Patwardhan et al, 2014: Yan et al. 2017: Quail et al. 2016). most pre-clinical models of different types of cancer demonstrate acquired resistance throughout this treatment (Patwardhan et al, 2014; Quail et al. 2016). In particular, for brain cancer, it has been shown that insulin-like growth factor 1 (IGF 1 ) induces glioma rebound in CSF 1 R inhibitor-treated mice (Quail et al, 2016). Surprisingly, AMPA-glutamate antagonism according to the methods described here w ill negate oncogenic effects of IGF 1. and AMPA-glutamate antagonism w ill complement with CSF 1 R inhibition to lower tumor burden in co-treated subjects. In more detailed aspects of the invention, it is noted that PLX3397 may inhibit PDGFRB signaling in cancer
(Patwardhan et al. 2014). and that PDGFRB reportedly coordinates an anti-oxidant program in cancer through NRF2 transcription (Yang et al, 201 8; Nanjaiah et al, 2019). On this basis, according to the teachings herein, PLX3397 will be beneficially combined with glutamate antagonists like memantine, within AMPAR antagonist methods of the invention, to bolster combined efficacy by suppressing an anti-oxidant program, e.g., in glioma cells.
Example VIII
Anti-Cancer Activity of AMPAR Antagonists In Combination with
Anti-Malarial Drugs
Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinate!} administered w ith one or more anti-malarial drugs such as chloroquine, hydroxychloroquine, primaquine and mefloquine (see. e.g., Johnson et al, 2015; Liu et al, 2016; Maraka et al, 2019). In exemplary protocols, patients receive perampanel as above along with 250mg mefloquine orally prior to the first radiation session. Within illustrative methods for treating GBM. Mefloquine is administered once every two days throughout the first 6-week treatment period, during the I month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the anti-malarial and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol w ill show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example V1X
Anti-Cancer Activity of AMPAR Antagonists In Combination with
Metforinin/Phenformin
Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with metformin (see, e.g., Benjamin et al, 2016: Maraka et al, 2019). Patients receive perampanel as above along with 500-2000mg metformin orally prior to the first radiation session. In exemplary protocols for treating GBM. perampanel and metformin are administered once a day throughout the first 6-week treatment period during the 1 month rest period and while patients are taking maintenance Temodar. Patients are maintained on the metformin and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example X
Anti-Cancer Activity of AMPAR Antagonists In Combination with
PD- 1 Inhibitor Treatment
Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinate!) administered with anti-cancer biologies including programmed cell death protein 1 (PD- 1 ) inhibitors such as pembrolizumab or nivolumab (see, e.g., Nghiem et al. 2016; Motzer et al, 201 5). Resistance to PD- 1 antagonism has been attributed to TNF-a production in the tumor microenvironment (Neubert et al, 2018). Since Ampa-glutamate antagonism has been shown to reduce TNF-a secretion in a model of intraventricular hemorrhage (Dohare et al. 2016), AMPAR antagonist treatment according to the invention will augment the efficacy of PD- 1 inhibitors. In exemplary protocols, patients are administered perampanel as above in conjunction with l -3mg/kg pembrolizumab/nivolumab intravenously prior to the first radiation session. Within illustrative methods for treating GBM. patients then receive pembrolizumab/nivolumab every 2 weeks throughout the first 6- week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Treatment is continued thusly unless disease progression or evidence of drug-related toxicity appears. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti cancer therapy.
Example XI
Anti-Cancer Activity of AMPAR Antagonists In Combination with
PD- 1 Inhibitor + CSF 1 R Inhibitor Treatment
Within more detailed examples, AMPAR antagonists such as perampanel are coordinately administered with PD- 1 inhibitors, and also with CSF 1 R inhibitors. Notably, while PD- 1 inhibitors reported!) exhibit robust efficacy in some patients, they appear to have little to no therapeutic effects in other patients. Recently it has been suggested that CSF 1 and TNF-a secretion by tumor cells may stanch the efficacy of PD- 1 therapy (Neubert et al, 2018). As disclosed herein, patients be treated with a combination of AMPAR antagonists PD- 1 inhibitors and CSF 1 R inhibitors (e.g.. with perampanel. pembrolizumab, and PLX3397) will benefit by reduced CSF I signaling in the tumor microenvironment, combined with ampa-glutamate antagonist repression of TNF signaling (see, e.g., Dohare et al, 2016).
negating PD- 1 inhibitor resistance to yield enhanced clinical benefits over SOC or other conventional anti-cancer therapy.
Example XII
Anti-Cancer Activity of AMPAR Antagonists In Combination with
Clemastine Fumarate Co-Treatment
Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinated administered with clemastine fumarate (see, e.g., Dobbeling et al, 2013; Le Joncour et al. 2019). Patients are administered perampanel as above along with 0.5- 2.68mg clemastine fumarate orally prior to the first radiation session. In illustrative protocols for treating GBM, perampanel and clemastine are taken once a day throughout the first 6- week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the clemastine fumarate and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol w ill show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
Example XIII
Anti-Cancer Activity of AMPAR Antagonists In Combination with
SSRI Co-Treatment
Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinated administered with one or more selective serotonin reuptake inhibitors (SSRIs) ( see. e.g.. Sun et al. 201 8; Huang et al. 201 1 ; Lin et al. 2010; Liu et al, 201 5; Yuan et al. 2018; Raabe & Gentile. 2008). In exemplary protocols for treating GBM, patients are administered perampanel along with the SSRI(s) orally prior to the first radiation session, then once a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the SSR1 and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy. fxample XIV
Anti-Cancer Activity of AMPAR Antagonists In Combination with
TCA Co-Treatment
Additional clinical methods of the invention employ an AMPAR antagonist such as peram panel coordinately administered with one or more tricyclic antidepressants (TCAs) (see, e.g.. Jahchan et al, 2013; Jeon et al. 201 1 ; Raabc & Gentile, 2008; Reynolds & Miller, 1988: Sernagor et al. 1989; Stoll et al. 2007). Patients receive perampanel along with the TCA(s) orally prior to the first radiation session. In exemplary protocols for treating GBM, the perampanel and TCA are then each administered once a day throughout the first 6-week treatment period, during the I month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the TCA and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this
combinatorial protocol will sho substantially improved clinical benefits over SOC or other conventional anti-cancer therapy. fxample XV
Anti-Cancer Activity of AMPAR Antagonists In Combination with
Ampakine Co-Treatment
Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with one or more positive allosteric AMPA receptor modulators (Ampakines). In exemplary protocols, patients are administered perampanenl in combination with one or more ampakines, such as 2.3.6a.7.8.9-hexahydro- l 1 H- 1 ,4- dioxino[2,3-g]pyrrolo[2.1 -b][ 1.3 ]benzoxazine- l 1 -one ( CX614") (see. e.g., Radin et al,
2018). Though ampakines are thought to augment AMPA-mediated currents in neurons, they have also been reported to induce AMPA receptor desensitization and down regulation via endocytosis and degradation after prolonged treatment (Jourdi et al. 2005). whereby they may serve as functional antagonists. Within illustrative methods for treating GBM, patients are administered perampanel along with CX614 or another amplakine orally prior to the first radiation session then once a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the ampakine(s) and perampanel unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti cancer therapy.
Example XVI
Anti-Cancer Activity of AMPAR Antagonists In Combination with
Can n a binoid Co-Treatm e n t
Additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with one or more cannabinoids, for example tetrahydrocannabinol ( I I 1C) and/or cannabidiol (CBD) (see. e.g.. Scott et al, 2014; Marcu et al. 2010; Shrivastava et al. 201 I ). In exemplary protocols for treating GBM, patients are administered perampanel along ith 100-600mg CBD and 1 - I OOmg THC prior to the first radiation session, then once a day throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the cannabinoid and perampanel therapy unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this
combinatorial protocol will show substantially improved clinical benefits over SOC or other conventional anti-cancer therapy. For treatment of GBM. cannabinoids have been reported to potent effects on glioma stem cells (Lopez-Valero et al. 201 8). Considering that AMPA receptors are overexpressed on glioma stem cells (Oh et al. 2012), the combinatorial treatment methods and compositions described here w ill sensitize resistant tumor cells to the DNA-damaging effects of Temodar and radiation therapy (McLendon et al. 2006; Chen et al, 2012) and thereby enhance clinical benefits. Further, cannabinoids reportedly exert oncolytic effects through induction of harmful reactive oxygen species (Shrivastava et al, 201 1 ;
Nanjaiah et al, 2019). w hereby the methods and compositions of the invention combining cannabinoids w ith glutamate antagonists will negate antioxidant defenses in cancer cells and enhance clinical benefits particularly in glioma patients.
Example XVI
Anti-Cancer Activity of AMPAR Antagonists In Combination with
Disulfiram Co-Treatment Yet additional clinical methods of the invention employ an AMPAR antagonist such as perampanel coordinately administered with disulfiram (see, e.g., Lun et al, 2016; Triscott et al, 2012). Disulfiram targets cancer stem cells and reportedly inhibits MGMT to boost efficacy of Temodar (Paranjpe et al, 2014). Within the methods of the invention, both disulfiram and perampanel augment Temodar s efficacy and refine targeting of cancer cells, yielding surprisingly enhanced benefits for treating SOC treatment-resistant cancers. Within exemplary methods for treating GBM. patients are administered perampanel along with 50- 500mg disulfiram orally prior to the first radiation session, then once daily throughout the first 6-week treatment period, during the 1 month rest period, and while patients are taking maintenance Temodar. Patients are maintained on the perampanel and disulfiram unless disease progression or evidence of drug-related toxicity is observed. Subjects treated according to this combinatorial protocol will show' substantially improved clinical benefits over SOC or other conventional anti-cancer therapy.
The instant description and examples are provided for illustration, and those skilled in the art will realize that the invention extends to additional embodiments and aspects following the teachings herein and is therefore not limited except as by the appended claims.
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Claims

What is Claimed:
1. A method for treating an AMPA Receptor (AM PAR) positive cancer in a mammalian subject comprising administering an anti-cancer effective amount of an AMPAR antagonist compound to said subject.
2. The method of claim 1. wherein the AMPAR antagonist compound is an allosteric AMPAR antagonist compound.
3. The method of claim I . wherein the AMPAR antagonist compound is a Perampanel (PMP) compound.
4. The method of claim 3, wherein the PMP compound is an anti-cancer effective analog or derivative of PMP.
5. The method of claim 1 , wherein the AMPA Receptor (AMPAR) positive cancer is selected from an AMPA Receptor (AMPAR) positive brain cancer, lung cancer, prostate cancer, breast cancer; skin cancer liver cancer, thyroid cancer, esophageal cancer sarcoma colorectal cancer, bladder cancer gall bladder cancer, stomach cancer, renal cancer ovarian cancer uterine cancer cervical cancer, non-Hodgkin's lymphoma; acute myelogenous leukemia (AML), acute lymphocytic leukemia, chronic lymphocytic leukemia (CI .L). myeloma mesothelioma pancreatic cancer, Hodgkin's disease, testicular cancer. Waldenstrom's disease head/neck cancer, tongue cancer or viral-induced cancer.
6. The method of claim 1 , w'herein the AMPA Receptor (AMPAR) positive cancer is selected from an AMPA Receptor (AMPAR) positive glioblastoma (GBM), or cancer of the breast pancreas lung or kidney.
7. The method of claim 1. wherein the AMPA Receptor (AMPAR) positive cancer is an AMPA Receptor (AMPAR) positive glioblastoma (GBM).
8. The method of claim 1 , w'herein the AMPAR positive cancer is a glioblastoma
(GBM).
9. The method of claim 1. wherein the AMPAR antagonist compound is Perampanel (PMP) formulated in an aqueous carrier for parenteral or intravenous administration.
10. T he method of claim 1. wherein the AMPAR antagonist compound is Perampanel (PMP) formulated in an oral dosage form.
1 1 . The method of claim 1 , wherein the AMPAR antagonist compound mediates a greater than 20% increase in cancer free survival for treated subjects compared to control subjects.
12. The method of claim 1 , wherein the AMPAR antagonist compound mediates a 20- 50% or greater increase in cancer free survival for subjects compared to control subjects.
13. The method of claim 1 , wherein the AMPAR antagonist compound mediates at least a 20% decrease in average size or number of primary tumors or metastases in treated subjects compared to control subjects.
14. The method of claim 1. wherein the AMPAR antagonist compound mediates a 20- 50% or larger decrease in average size or number of primary tumors or metastases in treated subjects compared to control subjects.
1 5. The method of claim I . wherein the AMPAR antagonist compound is Perampanel (PMP) or an anti-cancer effective prodrug, metabolite, analog or derivative of PMP.
16. The method of claim 1 , further comprising coordinately administering a secondary anti-cancer agent or therapy to the subject.
17. The method of claim 16, wherein the secondary anti-cancer agent or therapy is
selected from tubulin depolymerizing agents. DNA damaging agents, inhibitors of DNA synthesis, anti-metabolics, anti-angiogenic agents, vascular disrupting agents (VDAs), anti-cancer antibodies, endocrine cancer therapies, immuno-modulators, histone deacetylase inhibitors, inhibitors of signal transduction, inhibitors of heat shock proteins, retinoids, growth factors, growth factor receptor modulators, anti mitotic compounds anti-inflammatory drugs, and cell cycle regulators.
1 8. The method of claim 16, wherein the secondary anti-cancer agent or therapy is
selected from anti-cancer chemotherapy surgery and radiation.
19. The method of claim 16. further comprising coordinately administering one or more secondary anti-cancer, chemotherapeutic agent(s) selected from azacitidine, bevacizumab. bortezomib. capecitabine. cetuximab, clofarabine, dasatinib, decitabine, docetaxel, emend, erlotinib hydrochloride, exemestane, fulvestrant, gefltinib, gemcitabine hydrochloride, imatinib mesylate, imiquimod, lenalidomide, letrozole . nelarabine. oxaliplatin, paclitaxel, docetaxel, palifermin, panitumumab, pegaspargase, pemetrexed disodium, rituximab, sorafenib tosylate, sunitinib malate, tamoxifen citrate, targretin. temozolomide. thalidomide, and/or topotecan hydrochloride.
20. The method of claim 16. further comprising coordinately administering one or more secondary anti-cancer agents selected from an interleukin, interferon, filgrasten, G- CSF. epoetin alia, erythropoietin and/or an anti-cancer antibody or antibody fragment.
21. The method of claim 16, wherein the AMPAR antagonist compound is Perampanel (PMP) or an anti-cancer effective prodrug, metabolite, analog or derivative of PMP, and the secondary anti-cancer agent is selected from temozolomide (TMZ), a transcription inhibitor, a telomere disrupting agent an inhibitor of a gene splicing protein, an indoleamine 2, 3. dioxegenase (IDO) inhibitor, a lapatinib ditosylate enzyme blocker, and an anti-cancer antibody or antibody fragment.
22. The method of claim 16. wherein the AMPAR antagonist compound is Perampanel (PMP) or an anti-cancer effective prodrug metabolite analog or derivative of PMP, and the secondary anti-cancer therapy employs tumor treating fields or radiation.
23. A pharmaceutical composition comprising an anti-cancer effective amount of an AMPAR antagonist compound and a secondary anti-cancer agent selected from a tubulin depolymerizing agent a DNA damaging agents, an inhibitor of DNA synthesis, an anti-metabolic drug, an anti-angiogenic agent a vascular disrupting agent (VDAs), and anti-cancer antibody or antibody fragment, an anti-cancer cytokine, an anti-cancer hormone, a histone deacetylase inhibitor, a retinoid, a growth factor, a growth factor receptor modulator, an anti-mitotic compound, or a cell cycle regulator compound.
24. The pharmaceutical composition of claim 23. wherein the secondary anti-cancer agent is selected from temozolomide (TMZ). a transcription inhibitor a telomere disrupting agent, an inhibitor of a gene splicing protein an indoleamine 2, 3, dioxegenase (IDO) inhibitor a lapatinib ditosylate enzyme blocker and an anti-cancer antibody or antibody fragment.
25. The method of claim 1 , further comprising coordinately administering a secondary therapeutic agent or method to the subject selected from NMDA antagonists; anti PD- 1 /PDL-l therapy; CSF 1 R inhibitors; cannabinoid drugs; anti-malarials;
Riluzole/troriluzole treatment; antihistamines; biguanides: anti-cancer biologies; SSRIs; TCAs; Ampakines: levetiracetam, or a combination thereof.
26. The pharmaceutical composition of claim 23 comprising an anti-cancer effective amount of an AMPAR antagonist compound and a secondary therapeutic agent selected from NMDA antagonists; anti PD- l /PDL- 1 drugs; CSF 1 R inhibitors;
cannabinoid drugs; anti-malarials; Riluzole/troriluzole; antihistamines; biguanides; anti-cancer biologies; SSRIs; TCAs: Ampakines; levetiracetam, or a combination thereof.
PCT/US2019/043525 2018-07-27 2019-07-25 Clinical methods and pharmaceutical compositions employing ampa receptor antagonists to treat glioblastoma and other cancers WO2020023800A1 (en)

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