Co-administration of astemizole and an anticancer agent to treat cancer

Abstract

In accordance with the purpose(s) of the disclosure, as embodied and broadly described herein, the disclosure, in an aspect, relates to the treatment of a disorder of uncontrolled cellular proliferation in a mammal comprising the step of administering to the mammal a therapeutically effective amount of astemizole and an anticancer agent. In one aspect, the methods described herein inhibiting ANGPTL4 activity in a mammal. In another aspect, the methods described herein inhibit metastasis in a mammal

Description

CO-ADMINISTRATION OF ASTEMIZOLE AND AN ANTICANCER AGENT TO TREAT CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to co-pending U.S. Provisional Patent Application No. 63 / 581 ,018, filed on September 7, 2023, the contents of which are incorporated by reference herein in their entireties.BACKGROUND

[0002] Currently, chemotherapy and radiation therapy remain the most common methods for cancer treatment. These treatments were based on targeting proliferating cells rather than cancer cells only, which is also a factor in detrimental side effects from these treatments. Targeted therapy, a new generation of cancer treatment, targets cancer-specific changes of molecules and signaling pathways to inhibit cellular proliferation or induce cancer cell death, but with limited side effects on normal cells. Considerable effort has been made in finding the targets and the ways of affecting the targets inside the cells as a treatment, in particular for targets associated with difficult to treat cancers such as pancreatic cancer. For example, pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly cancers with an average survival of 3.5 months for non- resectable tumors. Gemcitabine is the primary prescribed chemotherapy drug for PDAC, but with only limited success.

[0003] Angiopoietin Like 4 (ANGPTL4) expression has been implicated in many cancer types and other diseases both as pathogenic and beneficial. It is known to occur in at least three isoforms, each with different functions. Previous work (Kirby, M.K., et al., 2016, Molecular Oncology, 10(8): 1169-1182), has shown varying gene expression levels for PDAC tumors correlating with survival outcomes. This study assessed RNA sequencing data from 119 patient tumor tissues, and 323 survival-correlated transcripts were identified. Further analysis revealed a 19-transcript predictive model for survival rates. In vitro patient tumor cell studies revealed a subset of these transcripts, which correlated with resistance to gemcitabine.

[0004] Despite advances in research directed towards improving outcomes with cancer, there is still a scarcity of compounds that are both potent, efficacious, and selective modulators of targets in cancer cells, such as ANGPTL4. These needs and other needs are satisfied by thepresent disclosure.SUMMARY

[0005] In accordance with the purpose(s) of the disclosure, as embodied and broadly described herein, the disclosure, in an aspect, relates to the treatment of a disorder of uncontrolled cellular proliferation in a mammal comprising the step of administering to the mammal a therapeutically effective amount of astemizole and an anticancer agent. In one aspect, the methods described herein inhibiting ANGPTL4 activity in a mammal. In another aspect, the methods described herein inhibit metastasis in a mammal.

[0006] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views.

[0008] FIG. 1 shows that astemizole / gemcitabine 1 pM provided significant reduction in viability in MIA PaCa-2 cells overexpressing ANGPTL4 versus gemcitabine or astemizole alone (MP2= MIA PaCa-2 cells; OE = over expression of ANGPTL4 from plasmid.)DESCRIPTION

[0009] Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0010] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0011] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0012] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0013] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0014] While aspects of the present disclosure can be described and claimed in a particularstatutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

[0015] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0016] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.Definitions

[0017] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of.

[0018] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an excipient” include, but are not limited to, mixtures or combinations of two or more such excipients, and the like.

[0019] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each ofthe ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0020] When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and 'about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0021] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1 % to 5%” should be interpreted to include not only the explicitly recited values of about 0.1 % to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range. Thus, for example, if a component is in an amount of about 1%, 2%, 3%, 4%, or 5%, where any value can be a lower and upper endpoint of a range, then any range is contemplated between 1% and 5% (e.g., 1 % to 3%, 2% to 4%, etc.).

[0022] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially”mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0023] As used herein, nomenclature for compounds, including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. When one or more stereochemical features are present, Cahn-lngold-Prelog rules for stereochemistry can be employed to designate stereochemical priority, EIZ specification, and the like. One of skill in the art can readily ascertain the structure of a compound if given a name, either by systemic reduction of the compound structure using naming conventions, or by commercially available software, such as ChemDraw® (PerkinElmer, Inc., Waltham, Massachusetts).

[0024] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0025] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0026] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible nonexpress basis for interpretation, including: matters of logic with respect to arrangement of stepsor operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0027] As used herein, “ANGPTL4,” “Angiopoietin-related protein 4,” or “Angiopoietin Like 4” refer to a protein encoded by a human gene located at chromosomal location 19p13.2. The terms are also inclusive of protein homologues of the human protein. The human gene encodes three isoforms which are generated by alternative mRNA splice variants. The three protein isoforms are designated in the UniProtKB / Swiss-Prot database with the identifiers: Q9BY76-1 , Q9BY76-2, and Q9BY76-3. The canonical protein sequence is associated with UniProtKB / Swiss-Prot database with the identifiers, Q9BY76-1 , which is a 406 amino acid protein with a molecular weight of 45,214 kD. The ANGPTL4 protein is a glycosylated, secreted protein containing a C- terminal fibrinogen domain. The secreted protein circulates as a homooligomer.

[0028] The homooligomer undergoes proteolytic processing to release its carboxyl fibrinogen- like domain, which circulates as a monomer. The C-terminal domain may be proteolytically- cleaved from the full-length secreted protein in vivo. The C-terminal domain is referred to as CANGPTL4. The natural cleavage site in vivo can occur between amino acids 162-229 of the canonical sequence.

[0029] As used herein, the term “CANGPTL4” refers to a C-terminal fragment of the canonical ANGPTL4 human protein sequence beginning at any amino acid position between 162-229, or homologues thereof. In an aspect, the terminal fragment, CANGPTL4, comprises amino acid residues 179-406 of the canonical ANGPTL4 human protein sequence, or homologues thereof. In an aspect, the terminal fragment, CANGPTL4, comprises amino acid residues 184-406 of the canonical ANGPTL4 human protein sequence, or homologues thereof. Unless specified otherwise, the use of “ANGPTL4” is inclusive of reference to both ANGPTL4 and CANGPTL4.

[0030] As used herein, the term “ANGPTL4 modulator” or “modulator of ANGPTL4” refers to a compound or agent that directly or indirectly modulates the activity of ANGPTL4, as an isolated protein, in a cell or in an animal, in particular a mammal, for example a human. For example, an ANGPTL4 modulator can alter the basal activity level of isolated ANGPTL4 in vitro or the activity of ANGPTL4 in a cell, in vivo or in vitro. In an aspect, an ANGPTL4 modulator can inhibit the activity of ANGPTL4 in a cell. The cell can be a mammalian cell line transfected with human ANGPTL4. The cell can be a mammalian cell line transfected with a rodent, e.g., rat, ANGPTL4. The cell can be a mammalian cell line transfected with a mammalian ANGPTL4. The cell can bea cancer cell-line such as PANC-1 , ASPC 1 , BXPC-3, or MIA-PaCa-2 cells.

[0031] As used herein, the term “modulation of ANGPTL4 activity” refers to modulation of either ANGPTL4 or CANGPTL4 activity or both, unless otherwise specified. Modulation of activity, as understood herein, is altering the activity of ANGPTL4 from a baseline level of activity, e.g., inhibition of a baseline or basal activity level. Accordingly, in some aspects, modulation can be inhibition of ANGPTL4 activity. The modulation, for example, inhibition, of ANGPTL4 activity in a cell can result in cell death or inhibition of cellular proliferation.

[0032] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.). The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In an aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects. In an aspect of a disclosed method, the subject has been diagnosed with a need for treatment of one or more disorders of uncontrolled cellular proliferation associated with an ANGPTL4 dysfunction, e.g., aberrant expression of ANGPTL4. In an aspect of a disclosed method, the subject has been diagnosed with a need for modulation of ANGPTL4 activity. In an aspect of a disclosed method, the subject has been diagnosed with a disorder of uncontrolled cellular proliferation, e g. cancer. In an aspect of a disclosed method, the subject has been identified with a disorder treatable by modulation of ANGPTL4 activity. In an aspect, a subject can be treated prophylactically with a compound or composition disclosed herein. In an aspect, the subject is a mammal such as a primate. In an aspect, the subject is a human.

[0033] As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. Treatment includes active treatment, that is, treatment directed specifically toward the improvement of the health of a subject with a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, treatment includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of thedisease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, treatment includes any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease.

[0034] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein. For example, “diagnosed with a disorder treatable by modulation of ANGPTL4 activity” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by a compound or composition that can modulate ANGPTL4 activity.

[0035] As used herein, the phrase “identified to be in need of treatment for a disorder,” or the like, refers to selection of a subject based upon need for treatment of the disorder. For example, a subject can be identified as having a need for treatment of a disorder (e.g., a disorder related to ANGPTL4 activity) based upon an earlier diagnosis by a person of skill and thereafter subjected to treatment for the disorder. It is contemplated that the identification can, in an aspect, be performed by a person different from the person making the diagnosis. It is also contemplated, in an aspect, that the administration can be performed by one who subsequently performed the administration.

[0036] As used herein, the terms “administering” and “administration” refer to any method or route of administration of a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdemnal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administrationcan be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.

[0037] The term “contacting” as used herein refers to bringing a disclosed compound and a cell, a target (e.g. ANGPTL4), or other biological entity together in such a manner that the compound can affect the activity of the target, either directly; i.e. , by interacting with the target itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the target is dependent.

[0038] As used herein, the terms “effective amount" and "amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a "prophylactically effective amount"; that is, an amount effective for prevention of a disease or condition.

[0039] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprisingan instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0040] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0041] As used herein, the terms “therapeutic agent” include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and / or physiologic effect by local and / or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term "therapeutic agent" includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants,antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or prodrugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0042] As used herein, “IC50,” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% modulation of a biological process, or component of a process. For example, IC50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay. For example, an IC50 for ANGPTL4 can be determined in an in vitro using purified or isolated ANGPTL4, or alternatively in an in vitro cellbased assay system. Frequently, assays, including suitable assays for ANGPTL4 modulation, make use of a suitable cell-line, e.g. a cell line that either expresses endogenously a target of interest, has been transfected with a suitable expression vector that directs expression of a recombinant form of the target such as ANGPTL4, or is a cell-line derived from a cancer that can be associated with ANGPTL4 over-expression. For example, the IC50 for ANGPTL4 can be determined using cell-lines such as PANC-1 , ASPC 1 , BXPC-3, or MIA-PaCa-2 cells, and determined the effect of a compound on cell proliferation using an assay for cellular proliferation, e.g., a luminescent-based assay such as the Cell Titer-Gio® (Promega Corporation, Madison, Wisconsin).

[0043] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effectsor interacting in a deleterious manner.

[0044] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0045] As used herein, “astemizole” refers to a compound having a structure represented by the formula:Pharmaceutically acceptable salts astemizole can also be used in the methods described herein.

[0046] As used herein, the term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When a compound is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (-ic and -ous), ferric, ferrous, lithium, magnesium, manganese (-ic and -ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0047] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry,(John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0048] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible nonexpress basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0049] Disclosed are the components to be used to prepare the compositions of the disclosure as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the disclosure. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the disclosure.

[0050] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures will typically achieve the same result.

[0051] In an aspect, the disclosure pertains to compounds useful as inhibitors of ANGPTL4. In an aspect, the compounds of the disclosure are useful in the treatment of disorders of uncontrolled cellular proliferation, e.g., a cancer, associated with an ANGPTL4 dysfunction, e.g., aberrant expression levels of ANGPTL4, and other diseases in which an ANGPTL4 dysfunction is involved.

[0052] It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the disclosure. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that disclosed compounds can be employed in the disclosed methods of using.Co-Administration of Astemizole with an Anticancer Agent

[0053] The methods described herein are useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders associated with uncontrolled cellular proliferation. For example, a treatment can include modulation of ANGPTL4 to an extent effective to a cancer. Thus, a disorder can be associated with ANGPTL4 activity. Thus, provided are methods of treating or preventing a disorder in a subject comprising the step of administering to the subject astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent

[0054] in a dosage and amount effective to treat the disorder in the subject.

[0055] In one aspect, the disclosure pertains to a method for the treatment of a disorder of uncontrolled cellular proliferation, e.g., a cancer, in a mammal comprising the step of administering to the mammal astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent.

[0056] In another aspect, the disclosure pertains to a method for the treatment of a gemcitabine-resistant cancer, in a mammal comprising the step of administering to the mammal astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent.

[0057] Also provided is a method for the treatment of one or more disorders, e.g., a cancer, associated with ANGPTL4 activity in a subject comprising the step of administering to the subject astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent; or a disclosedmedicament in a dosage and amount effective to treat the disorder in the subject.

[0058] In another aspect, the disclosure pertains to a method for modulation of ANGPTL4 activity in a mammal comprising the step of administering to the mammal an effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent

[0059] In another aspect, the disclosure pertains to a method for modulation of ANGPTL4 activity in at least one cell, comprising the step of contacting the at least one cell with an effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent in a dosage and amount effective to inhibit ANGPTL4 activity in the at least one cell.

[0060] In another aspect, the disclosure pertains to a method for inhibiting metastasis in a mammal comprising the step of administering to the mammal a therapeutically effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent.

[0061] In another aspect, the methods described herein have utility in treating a variety of cancers, e.g., a cancer associated with ANGPTL4 activity, including one or more of the following conditions or diseases: a pancreatic cancer, breast cancer, renal cancer, gastric cancer, colorectal cancer, lymphoma, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, pancreatic cancer, and malignant melanoma. In an aspect, the methods described herein have utility in treating a pancreatic cancer.

[0062] In another aspect, the methods described herein have utility in treating a variety of gemcitabine-resistant cancers, e.g., a cancer associated with ANGPTL4 activity, including one or more of the following gemcitabine-resistant cancers: gemcitabine-resistant pancreatic cancer, gemcitabine-resistant breast cancer, gemcitabine-resistant renal cancer, gemcitabine-resistant gastric cancer, gemcitabine-resistant colorectal cancer, gemcitabine-resistant lymphoma, gemcitabine-resistant cancers of the brain, gemcitabine-resistant genitourinary tract cancer, gemcitabine-resistant lymphatic system cancer, gemcitabine-resistant stomach cancer, gemcitabine-resistant larynx cancer, gemcitabine-resistant lung cancer, and gemcitabineresistant melanoma. In another aspect, the methods described herein have utility in treating a pancreatic cancer. In another aspect, the methods described herein have utility in treating a gemcitabine-resistant pancreatic cancer.

[0063] In another aspect, the cell is mammalian, for example, human. In an aspect, the cell has been isolated from a subject prior to the contacting step. In an aspect, contacting is viaadministration to a subject. In aspect, modulation is inhibition of ANGPTL4 activity.

[0064] In another aspect, the disclosure pertains to a method for modulation of ANGPTL4 activity in a subject comprising the step of administering to the subject astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent in a dosage and amount effective to inhibit ANGPTL4 activity in the subject. In an aspect, the subject is mammalian, for example, human. In an aspect, the mammal has been diagnosed with a need for modulation of ANGPTL4 activity prior to the administering step. In an aspect, the mammal has been diagnosed with a need for modulation of ANGPTL4 activity prior to the administering step. In an aspect, the method further comprises the step of identifying a subject in need of modulation of ANGPTL4 activity.

[0065] In another aspect, the disclosure pertains to a method for the treatment of a cancer associated with an ANGPTL4 dysfunction, for example, a cancer associated with increased ANGPTL4 expression, in a mammal comprising the step of administering to the mammal astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent in a dosage and amount effective to treat the disorder in the mammal. In an aspect, the mammal is a human. In an aspect, the mammal has been diagnosed with a need for treatment for the disorder prior to the administering step. In an aspect, the method further comprises the step of identifying a subject in need of treatment for the disorder.

[0066] Disclosed methods comprise treating a subject by coadministering astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent. In an aspect, “coadministered” can be administration of a fixed dosage form combination astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent. In an aspect, “coadministered” can be administration of separate dosage forms, e.g., astemizole or a pharmaceutically acceptable salt thereof as a solid oral dosage form and the anticancer drug as an intravenous dosage form. Astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent can be administered separately or in conjunction with each other. In addition, the administration of astemizole or a pharmaceutically acceptable salt thereof can be prior to, concurrent to, or subsequent to the administration the anticancer agent. Astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent can be coadministered, either in concomitant therapy or in a fixed combination.

[0067] When astemizole or a pharmaceutically acceptable salt thereof and an anticanceragent are used contemporaneously, a pharmaceutical composition in unit dosage form containing astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent can be used. However, the combination therapy can also include therapies in which astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent are administered on different overlapping schedules. It is also contemplated that when used in combination, astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent can be used in lower doses than when each is used singly.

[0068] In one aspect, astemizole or a pharmaceutically acceptable salt thereof is administered to the mammal prior to the administration of the anticancer agent. In another aspect, astemizole or a pharmaceutically acceptable salt thereof is administered to mammal at least 12 hours prior to the administration of the anticancer agent. In another aspect, astemizole or a pharmaceutically acceptable salt thereof is administered to mammal at least 12 hours to up to 96 hours prior to the administration of the anticancer agent, or 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 84 hours, or 96 hours, where any value can be a lower or upper endpoint of a range (e.g., 24 hours to 72 hours).

[0069] In one aspect, the methods described herein can be administered in conjunction with the use of physical methods such as with radiation therapy or surgery.

[0070] In an aspect, astemizole or a pharmaceutically acceptable salt thereof and anticancer agent can be coadministered in the disclosed methods with a hormone therapy agent. In a still further aspect, the hormone therapy agent leuprolide, tamoxifen, raloxifene, megestrol, fulvestrant, triptorelin, medroxyprogesterone, letrozole, anastrozole, exemestane, bicalutamide, goserelin, histrelin, fluoxymesterone, estramustine, flutamide, toremifene, degarelix, nilutamide, abarelix, or testolactone, or a pharmaceutically acceptable salt thereof, or combinations thereof.

[0071] In an aspect, astemizole or a pharmaceutically acceptable salt thereof can be coadministered in the disclosed methods with a chemotherapeutic agent. In a still further aspect, the chemotherapeutic agent coadministered in the disclosed methods is selected from one or more of the group consisting of an alkylating-like agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, an mTor inhibitor agent or another chemotherapeutic agent, or combinations thereof.

[0072] In an aspect, astemizole or a pharmaceutically acceptable salt thereof can be coadministered in the disclosed methods with an antineoplastic antibiotic agent such asdoxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, or valrubicin, or a pharmaceutically acceptable salt thereof, or combinations thereof.

[0073] In an aspect, astemizole or a pharmaceutically acceptable salt thereof can be coadministered in the disclosed methods with an antimetabolite agent such as gemcitabine, 5- fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, or thioguanine, or a pharmaceutically acceptable salt thereof, or combinations thereof.

[0074] In an aspect, astemizole or a pharmaceutically acceptable salt thereof can be coadministered in the disclosed methods with an alkylating-like agent such as carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, or streptozocin, or a pharmaceutically acceptable salt thereof, or combinations thereof.

[0075] In an aspect, astemizole or a pharmaceutically acceptable salt thereof can be coadministered in the disclosed methods with a mitotic inhibitor agent such as etopside, vincristine, ixabepilone, vinorelbine, vinblastine, or teniposide, or a pharmaceutically acceptable salt thereof, or combinations thereof.

[0076] In an aspect, astemizole or a pharmaceutically acceptable salt thereof can be coadministered in the disclosed methods with a mTor inhibitor agent such as everolimus, siroliumus, or temsirolimus, or a pharmaceutically acceptable salt thereof, or combinations thereof.

[0077] The weight ratio of astemizole or a pharmaceutically acceptable salt thereof to the anticancer agent can be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, the weight ratio of astemizole or a pharmaceutically acceptable salt thereof to the anticancer agent will generally range from about 1000:1 to about 1 ;1000, preferably about 200:1 to about 1 :200. Combinations of astemizole or a pharmaceutically acceptable salt thereof and the anticancer agent will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

[0078] In the treatment of conditions such as cancer, an appropriate dosage level ofastemizole or a pharmaceutically acceptable salt thereof can be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level can be about 0.1 to about 250 mg / kg per day; more preferably about 0.5 to about 100 mg / kg per day. A suitable dosage level can be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15. 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. Astemizole or a pharmaceutically acceptable salt thereof and the anticancer agent can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen can be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient can be varied and will depend upon a variety of factors including the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0079] In an aspect of a disclosed method, the subject has been diagnosed with a need for treatment prior to the administering step. In an aspect of a disclosed method, the subject has been diagnosed with a disorder treatable by modulation of ANGPTL4 activity and / or a need for modulation of ANGPTL4 activity prior to the administering step. In an aspect of a disclosed method, the subject has been diagnosed with a disorder of uncontrolled cellular proliferation prior to the administering step. In an aspect, a subject can be treated prophylactically with astemizole or a pharmaceutically acceptable salt thereof and the anticancer agent.

[0080] In an aspect, the methods described herein exhibit modulation of ANGPTL4 activity with an ICso of less than about 50 pM. In an aspect, the methods described herein exhibit modulation of ANGPTL4 activity with an ICso of less than about 25 pM. In an aspect, the methods described herein exhibit modulation of ANGPTL4 activity with an ICso of less than about 10 pM. In an aspect, the methods described herein exhibit modulation of ANGPTL4 activity with an ICso of less than about 5 pM. In an aspect, the methods described herein exhibit modulation of ANGPTL4 activity with an ICso of less than about 500 nM. In an aspect, the methods described herein exhibit modulation of ANGPTL4 activity with an ICso of less than about 250 nM. In an aspect, the methods described herein exhibit modulation of ANGPTL4 activity with an ICso of lessthan about 100 nM. In an aspect, the methods described herein exhibit modulation of ANGPTL4 activity with an IC50 of less than about 50 nM. In an aspect, the methods described herein exhibit modulation of ANGPTL4 activity with an IC50 of less than about 10 nM.

[0081] In an aspect, the methods described herein exhibit modulation of ANGPTL4 activity with an IC50 of between from about 1 nM to about 50 pM. In an aspect, the methods described herein exhibit modulation of ANGPTL4 activity with an IC50 of between from about 1 nM to about 25 pM. In an aspect, the methods described herein exhibit modulation of ANGPTL4 activity with an IC50 of between from about 1 nM to about 10 pM. In an aspect, the methods described herein exhibit modulation of ANGPTL4 activity with an IC50 of between from about 1 nM to about 5 pM. In an aspect, the methods described herein exhibit modulation of ANGPTL4 activity with an IC50 of between from about 1 nM to about 1 pM.

[0082] In an aspect, the methods described herein exhibit inhibition of cellular proliferation with an IC50 of less than about 50 pM. In an aspect, the methods described herein exhibit inhibition of cellular proliferation with an IC50 of less than about 25 pM. In an aspect, the methods described herein exhibit inhibition of cellular proliferation with an IC50 of less than about 10 pM. In an aspect, the methods described herein exhibit inhibition of cellular proliferation with an IC50 of less than about 5 pM. In an aspect, the methods described herein exhibit inhibition of cellular proliferation with an IC50 of less than about 500 nM. In an aspect, the methods described herein exhibit inhibition of cellular proliferation with an IC50 of less than about 250 nM. In an aspect, the methods described herein exhibit inhibition of cellular proliferation with an IC50 of less than about 100 nM. In an aspect, the methods described herein exhibit inhibition of cellular proliferation with an IC50 of less than about 50 nM. In an aspect, the methods described herein exhibit inhibition of cellular proliferation with an IC50 of less than about 10 nM.

[0083] In an aspect, the methods described herein exhibit inhibition of cellular proliferation with an IC50 of between from about 1 nM to about 50 pM. In an aspect, the methods described herein exhibit inhibition of cellular proliferation with an IC50 of between from about 1 nM to about 25 pM. In an aspect, the methods described herein exhibit inhibition of cellular proliferation with an IC50 of between from about 1 nM to about 10 pM. In an aspect, the methods described herein exhibit inhibition of cellular proliferation with an IC50 of between from about 1 nM to about 5 pM. In an aspect, the methods described herein exhibit inhibition of cellular proliferation with an IC50 of between from about 1 nM to about 1 pM.

[0084] In one aspect, astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compounds of the disclosure, and / or pharmaceutically acceptable salt(s) thereof, can also be administered by controlled release means and / or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

[0085] Thus, the pharmaceutical compositions of this disclosure can include a pharmaceutically acceptable carrier and astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent. In the alternative, astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent can be formulated independently with a pharmaceutically acceptable carrier.

[0086] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0087] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of theirease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques

[0088] A tablet containing astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0089] In one aspect, the pharmaceutical compositions of the present disclosure comprise astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0090] Pharmaceutical compositions of the present disclosure suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0091] Pharmaceutical compositions of the present disclosure suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion mediumcontaining, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0092] Pharmaceutical compositions of the present disclosure can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the disclosure, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[0093] Pharmaceutical compositions of this disclosure can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

[0094] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the disclosure, and / or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[0095] In the treatment conditions which require modulation of ANGPTL4 activity, an appropriate dosage level of astemizole will generally be about 0.01 to 500 mg per kg patient body weight per day and can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg / kg per day; more preferably 0.5 to 100 mg / kg per day. A suitable dosage level can be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0 to 50 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 milligrams of theactive ingredient for the symptomatic adjustment of the dosage of the patient to be treated. Astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosing regimen can be adjusted to provide the optimal therapeutic response.

[0096] It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors. Such factors include the age, body weight, general health, sex, and diet of the patient. Other factors include the time and route of administration, rate of excretion, drug combination, and the type and severity of the particular disease undergoing therapy.

[0097] The present disclosure is further directed to a method for the manufacture of a medicament for modulating ANGPTL4 activity (e.g., treatment of one or more disorder of uncontrolled cellular proliferation associated with ANGPTL4 dysfunction) in mammals (e.g., humans) comprising combining astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent with a pharmaceutically acceptable carrier or diluent.

[0098] It is understood that the disclosed pharmaceutical compositions can be prepared from disclosed compounds. It is also understood that the disclosed pharmaceutical compositions can be employed in the disclosed methods of using.Kits

[0099] In an aspect, the disclosure pertains to kits comprising astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent and instructions for administering the compound in connection with treating a disorder of uncontrolled cellular proliferation.

[0100] In an aspect, astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent are co-formulated. In another aspect, astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent are independently formulated with a pharmaceutically acceptable carrier, where astemizole or a pharmaceutically acceptable salt thereof and the anticancer agent are in separate containers.

[0101] The kits can also include astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and / or product and another component fordelivery to a patient.

[0102] In an aspect, the kit further comprises instructions to provide and administer astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent in connection with surgery. In an aspect, the kit further comprises instructions to provide and administer astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent in connection with surgery, wherein the instructions provide that surgery is performed prior to the administering of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent. In an aspect, the kit further comprises instructions to provide and administer astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent in connection with surgery, wherein the instructions provide that surgery is performed after the administering astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent. In an aspect, the kit further comprises instructions to provide and administer astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent in connection with surgery, wherein the instructions provide that surgery is performed after the administering astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent, and wherein the instructions provide that the administering astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent is to effect presurgical debulking of a tumor. In an aspect, the kit further comprises instructions to provide and administer astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent in connection with surgery, wherein the instructions provide that surgery is performed after the administering and administer astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent, and wherein the instructions provide that surgery is performed at about the same time as the administering and administer astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent.

[0103] In an aspect, the kit further comprises instructions to provide and administer astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent in connection with radiotherapy. In an aspect, the kit further comprises instructions to provide and administer astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent in connection with radiotherapy, wherein the instructions provide that radiotherapy is performed prior to the administering of and administer astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent. In an aspect, the kit further comprises instructions to provide and administer astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent in connection with radiotherapy, wherein the instructions provide that radiotherapy is performed after the step of the administering of and administer astemizole or a pharmaceutically acceptable salt thereofand an anticancer agent. In an aspect, the kit further comprises instructions to provide and administer astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent in connection with radiotherapy, wherein the instructions provide that radiotherapy is performed at about the same time as the step of the administering of and administer astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent.

[0104] In an aspect, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises a therapeutically effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent. In an aspect, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises a therapeutically effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent, and wherein each dose of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent are coformulated. In an aspect, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises a therapeutically effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent, and wherein each dose of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent are co-packaged.

[0105] In an aspect, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises a therapeutically effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent, and wherein the dosage forms are formulated for oral administration and / or intravenous administration. In an aspect, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises a therapeutically effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent, and wherein the dosage forms are formulated for oral administration. In an aspect, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises a therapeutically effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent, and wherein the dosage forms are formulated for intravenous administration.

[0106] In an aspect, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises a therapeutically effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent; and wherein the dosage form for the compound is formulated for oral administration and the dosage form forthe at least one agent is formulated for intravenous administration. In an aspect, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises a therapeutically effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent; and wherein the dosage form for astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent is formulated for intravenous administration and the dosage form for the at least one agent is formulated for oral administration.

[0107] In an aspect, the instructions for treating a disorder of uncontrolled cellular proliferation provide instructions for treating a cancer. It is understood that the disclosed kits can be prepared from astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using.Aspects

[0108] Aspect 1. A method for the treatment of a disorder of uncontrolled cellular proliferation in a mammal comprising the step of administering to the mammal a therapeutically effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent.

[0109] Aspect 2. The method of Aspect 1 , wherein the mammal is a human.

[0110] Aspect 3. The method of Aspect 1 or 2, wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step.

[0111] Aspect 4. The method of any one of Aspects 1-3, further comprising the step of identifying a mammal in need of treatment of the disorder.

[0112] Aspect 5. The method of any one of Aspects 1-4, wherein the disorder is associated with ANGPTL4 expression.

[0113] Aspect 6. The method of any one of Aspects 1-4, wherein the disorder is a cancer.

[0114] Aspect 7. The method of Aspect 6, wherein the cancer is pancreatic cancer, oral, thyroid, ovarian, breast cancer, renal cancer, gastric cancer, colorectal cancer, lymphoma, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, and malignant melanoma.

[0115] Aspect 8. The method of Aspect 6, wherein the cancer is pancreatic cancer.

[0116] Aspect 9. The method of Aspect 8, wherein the pancreatic cancer is a gemcitabineresistant pancreatic cancer.

[0117] Aspect 10. A method for inhibiting ANGPTL4 activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent.

[0118] Aspect 11. A method for inhibiting metastasis in a mammal comprising the step of administering to the mammal a therapeutically effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent.

[0119] Aspect 12. The method of any one of Aspects 1-11 , wherein the anticancer agent comprises a chemotherapeutic agent, an antineoplastic antibiotic agent, an antimetabolite agent, an alkylating agent, a mitotic inhibitor agent, or a mTor inhibitor agent.

[0120] Aspect 13. The method of any one of Aspects 1-11, wherein the anticancer agent is gemcitabine.

[0121] Aspect 14. The method of any one of Aspects 1-13, wherein astemizole is administered to the mammal prior to the administration of the anticancer agent.

[0122] Aspect 15. The method of any one of Aspects 1-13, wherein astemizole is administered to mammal at least 12 hours prior to the administration of the anticancer agent.

[0123] Aspect 16. The method of any one of Aspects 1-13, wherein astemizole is administered to the mammal after the administration of the anticancer agent.

[0124] Aspect 17. The method of any one of Aspects 1-13, wherein astemizole is coadministered to the mammal with the administration of the anticancer agent.EXAMPLES

[0125] EXAMPLE 1

[0126] MIA PaCa-2 cells from ATCC were grown in ATCC-formulated Dulbecco's Modified Eagle's Medium, Catalog No. 30-2002 with 10% fetal bovine serum in 96-well plates seeded with 10,000 cells per well. Cells were treated with 1 uM astemizole and 1 to 8 pM gemcitabine for 24 hours. Viability was measured using the Cell Titer Gio luminescence kit from Promega. FIG. 1shows that astemizole / gemcitabine 1 pM provided significant reduction in viability in MIA PaCa-2 cells overexpressing ANGPTL4 versus gemcitabine or astemizole alone (MP2= MIA PaCa-2 cells; OE = over expression of ANGPTL4 from plasmid.)

[0127] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[0128] It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope or spirit of the disclosure. Other embodiments of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims.

Claims

CLAIMS1. A method for the treatment of a disorder of uncontrolled cellular proliferation in a mammal comprising the step of administering to the mammal a therapeutically effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent.

2. The method of claim 1 , wherein the mammal is a human.

3. The method of claim 1 , wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step.

4. The method of claim 1 , further comprising the step of identifying a mammal in need of treatment of the disorder.

5. The method of claim 1 , wherein the disorder is associated with ANGPTL4 expression.

6. The method of claim 1 , wherein the disorder is a cancer.

7. The method of claim 6, wherein the cancer is pancreatic cancer, oral, thyroid, ovarian, breast cancer, renal cancer, gastric cancer, colorectal cancer, lymphoma, cancers of the brain, genitourinary tract cancer, lymphatic system cancer, stomach cancer, larynx cancer, lung, and malignant melanoma.

8. The method of claim 6, wherein the cancer is pancreatic cancer.

9. The method of claim 8, wherein the pancreatic cancer is a gemcitabine-resistant pancreatic cancer.

10. A method for inhibiting ANGPTL4 activity in a mammal comprising the step of administering to the mammal a therapeutically effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent.

11. A method for inhibiting metastasis in a mammal comprising the step of administering to the mammal a therapeutically effective amount of astemizole or a pharmaceutically acceptable salt thereof and an anticancer agent.

12. The method of any one of claims 1-11 , wherein the anticancer agent comprises a chemotherapeutic agent, an antineoplastic antibiotic agent, an antimetabolite agent, an alkylating agent, a mitotic inhibitor agent, or a mTor inhibitor agent.

13. The method of any one of claims 1-11 , wherein the anticancer agent is gemcitabine.

14. The method of any one of claims 1-11 , wherein astemizole is administered to the mammal prior to the administration of the anticancer agent.

15. The method of any one of claims 1-11, wherein astemizole is administered to mammal at least 12 hours prior to the administration of the anticancer agent.

16. The method of any one of claims 1-1 T wherein astemizole is administered to the mammal after the administration of the anticancer agent.

17. The method of any one of claims 1-11. wherein astemizole is coadministered to the mammal with the administration of the anticancer agent.

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