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WO2009091889A1 - Traitement de troubles cutanés à l'aide d'inhibiteurs d'egfr - Google Patents

Traitement de troubles cutanés à l'aide d'inhibiteurs d'egfr Download PDF

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WO2009091889A1
WO2009091889A1 PCT/US2009/031101 US2009031101W WO2009091889A1 WO 2009091889 A1 WO2009091889 A1 WO 2009091889A1 US 2009031101 W US2009031101 W US 2009031101W WO 2009091889 A1 WO2009091889 A1 WO 2009091889A1
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cancer
egfr
egfr inhibitor
disorder
disease
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Doru Traian Alexandrescu
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Georgetown University
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Georgetown University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • retinoids which are the most commonly used treatment as they tend to be the most efficacious, often cause undesirable side effects such as erythema (redness), scaling, burning, and/or pruritus (itching) and, in more extreme cases, bone toxicity, especially when they are used long term.
  • compositions, methods, combinations, kits and articles of manufacture are characterized by a variety of component ingredients, steps in treatment, and biophysical, physical, biochemical or chemical parameters. As would be apparent to those of skill in the art, the compositions and methods provided herein include any and all permutations and combinations of the ingredients, steps and/or parameters described below.
  • Provided herein are methods and compositions for treating genetic skin disorders, using one or more epidermal growth factor receptor (EGFR) inhibitors.
  • EGFR epidermal growth factor receptor
  • the genetic skin disorders include keratinization disorders.
  • the genetic skin disorders may be characterized by one or more features selected from among hyperkeratosis, keratinocyte hyperplasia, and ichthyosis.
  • EGFR inhibitor can be any compound that inhibits the signal transduction pathway triggered by EGFR, and the inhibition can occur at any step of the pathway.
  • the EGFR inhibitor can be selected from among an antibody that binds to EGFR, an antisense nucleic acid, a tyrphostin, a quinazolone compound, a quinazoline compound, a quinazolinamine compound, a 2-phenylaminopyrimidine, a quinoxaline, a phenolic stibenoid, a tyrosine metabolite, a flavonoid, an isoflavonoid and methyl-2,5-dihydroxycinnamate.
  • the monogenic keratinization disorder treated using an EGFR inhibitor is Darier's disease.
  • Also provided herein is a method of treating a keratinization disorder by administering to a subject identified as having the keratinization disorder a therapeutically effective amount of an EGFR inhibitor, wherein the EGFR inhibitor is selected from among an antibody that binds to EGFR, an antisense nucleic acid, a quinoxaline, a phenolic stibenoid, a tyrosine metabolite, a flavonoid, an isoflavonoid and methy 1-2 , 5 -dihy droxy cinnamate .
  • an EGFR inhibitor is selected from among an antibody that binds to EGFR, an antisense nucleic acid, a quinoxaline, a phenolic stibenoid, a tyrosine metabolite, a flavonoid, an isoflavonoid and methy 1-2 , 5 -dihy droxy cinnamate .
  • compositions, combinations, kits and articles of manufacture that include an EGFR inhibitor, or an EGFR inhibitor and an anticancer agent, for treating a genetic skin disorder.
  • the article of manufacture optionally includes an EGFR inhibitor adjusted to a dosage suitable for the treatment of a monogenic keratinization disorder, and a carrier for topical administration.
  • the articles of manufacture provided herein can further include a delivery system for the EGFR inhibitor.
  • compositions containing an EGFR inhibitor, an anticancer agent and a carrier selected for topical administration are also provided herein.
  • compositions and methods for treating genetic skin disorders represent a broad class of diseases affecting millions of people, worldwide. To date, over 300 skin conditions have been identified as having a genetic basis. Of these, about 170 disorders are believed to be associated with a single gene that can be inhereited in Mendelian fashion (monogenic diseases).
  • monogenic skin diseases include disorders such as Darier's disease, Hailey-Hailey disease, erythrodermic autosomal recessive lamellar ichthyosis, nonerythrodermic autosomal recessive lamellar ichthyosis, autosomal dominant lamellar ichthyosis, bullous congenital ichthyosiform erythroderma, palmoplantar keratoderma, erythrokeratodermia variabilis, verrucous epidermal nevi, pityriasis rubra pilaris, Netherton syndrome, idiopathic vulgaris, ichthyosis vulgaris, monilethrix, keratosis piliaris, bullous ichthyosiform erythroderma, nonbullous congenital ichthyosis, Sjogreen-Larsson syndrome, erythrokeratodermica variabilis, hyperkeratosisis
  • polygenic genodermatoses are complex diseases requiring interaction of the genetic components with the environment, lifestyle, race, immune system, and other such factors. Examples of polygenic genodermatoses include a spectrum of psoriasis and psoriatic arthritis disorders, vitiligo, alopecia areata, systemic lupus erythematosus, and atopic dermatitis.
  • a comprehensive list of genetic skin disorders, and their associated genes, is set forth in Leech et ah, Br. J.
  • the treatment of any of these disorders is contemplated according to the methods provided herein, and using EGFR inhibitors and compositions thereof as provided herein.
  • a vast majority of genetic skin disorders are characterized by disorders in keratinization; these include mutations in keratin genes, over-production of keratin (hyperkeratosis) and/or keratinocyte hyperplasia.
  • the first human skin disorder gene was identified, the steroid sulfatase (STS) gene on the X-chromosome 9.
  • STS steroid sulfatase
  • the entire STS gene is completely deleted in many males with X-linked ichthyosis, allowing its identification by early molecular genetics techniques.
  • mutations in human keratin genes were linked to a variety of genetic skin disorders (McLean et ah, Ulster Med. J, 76(2):72-82 (2007)).
  • ketain 5 or keratin 14 have been linked to epidermolysis bullosa simplex (EBS) disorders
  • mutations in keratin 1 or keratin 10 have been linked to epidermolytic hyperkeratosis.
  • epidermolytic hyperkeratosis there are a variety of other skin disorders, described and incorporated by reference herein, which are associated with hyperkeratosis; several of these other disorders, however, are caused by genes other than the keratin genes.
  • Darier's disease and Hailey-Hailey disease are autosomal dominant disorders caused by mutations in an ATPase
  • recessive lamellar ichtyosis is an autosomal recessive disorder caused by keratinocyte transglutaminase.
  • Darier's disease Among the methods and compositions provided herein for the treatment of genetic skin disorders, are methods and compositions for treating Darier's disease.
  • the methods and compositions employ EGFR inhibitors that can inhibit any step of the EGFR-mediated signal transduction pathway.
  • Darier's disease is a genetic hyperkeratosis skin disorder characterized by dark crusty patches on the skin, sometimes containing pus. The crusty patches are also known as keratotic papules and also called keratosis follicularis .
  • Darier's disease is an autosomally dominant inherited mutation in the gene ATP2A2, encoding SERCA2 (sarco/endoplasmic reticulum Ca2+-transport ATPase isoform 2).
  • Hailey-Hailey disease in which the ATP2C 1 (the gene encoding the human secretory pathway Ca2+/Mn2+ ATPase (hSPCAl)) is identified as the pathogenic gene that is transmitted in an autosomal dominant fashion.
  • the incidence of the two disorders is similar, 1 :25, 000-1 : 100,000 for Darier's disease, and 1 :50,000 for Hailey-Hailey disease.
  • the penetrance of both these disorders is complete (i.e., all subjects having one mutated allele manifest the symptoms), but expressivity varies significantly among subjects afflicted with the disease.
  • Darier's disease often starts during or later than the teenage years, typically by the third decade.
  • the symptoms of the disease are thought to be caused by an abnormality in the desmosome-keratin filament complex leading to a breakdown in cell adhesion.
  • the disease most commonly affects the chest, neck, back, ears, forehead, and groin, but may involve other body areas.
  • the rash associated with Darier's disease often has a distinct odor, and can be aggravated by heat, humidity, and exposure to sunlight.
  • it is a disease that poses a significant burden to afflicted persons.
  • EGFR inhibitors such as the antibody ERBITUX® (ImClone, New York, New York; also known as cetuximab) and the quinazolone compound erlotinib, are less toxic and better tolerated than the retionoids.
  • the EGFR inhibitors produce a dramatic reduction in skin lesions and other physical manifestations of Darier's disease, relative to the retinoids.
  • the methods can be used to treat Darier's disease or, because of its penetrance at 100%, for reducing the probability of appearance of symptoms prophylactically, prior to their manifestation in a subject identified as carrying the mutant ATP2A2 allele.
  • EGFR Inhibitors The methods and compositions provided herein for the treatment of genetic skin disorders employ the use of EGFR inhibitors. The EGFR inhibitors provided herein can reduce the severity of symptoms/ manifestations of the genetic skin disorders, without triggering unwanted effects.
  • EGFR epidermal growth factor receptor
  • RTKs receptor tyrosine kinases
  • RTKs have a conserved domain structure including an extracellular domain, a membrane-spanning (transmembrane) domain and an intracellular tyrosine kinase domain.
  • the extracellular domain can bind a ligand, such as a polypeptide growth factor or a cell membrane-associated molecule.
  • Some RTKs have been classified as orphan receptors, having no identified ligand.
  • RTKs are classified as constitutive RTKs, active without ligand binding, for example ErbB2 (HER2) does not reqire a ligand for activity.
  • ErbB2 ErbB2
  • RTKs can be homodimers or heterodimers.
  • PDGF is a heterodimer composed of ⁇ and ⁇ subunits.
  • VEGF receptors are homodimers.
  • EGF receptors can be either heterodimers or homodimers.
  • erbB3 in the presence of the ligand heregulin, heterodimerizes with other members of the ErbB family (EGFR family) such as ErbB2 and ErbB3.
  • EGFR family ErbB2 and ErbB3
  • Many RTKs are capable of autophosphorylation when dimerized, such as by transphosphorylation between subunits.
  • Autophosphorylation in the kinase domain maintains the tyrosine kinase domain in an activated state. Autophosphorylation in other regions of the protein can influence interaction of the receptor with other cellular proteins.
  • RTKs interact in signal transduction pathways. For example, RTKs, when activated, can phosphorylate other signaling molecules. RTKs are closely associated with cell growth, proliferation, differentiation and signaling of the immune system.
  • the receptor tyrosine kinases participate in transmembrane signaling, whereas the intracellular tyrosine kinases take part in signal transduction within the cell.
  • EGFR interacts in signal transduction pathways involved in processes including proliferation, dedifferentiation, apoptosis, cell migration and angiogenesis.
  • EGFR family members can recruit signaling molecules through protein:protein interactions; some interactions involve specific binding of signaling molecules to tyrosine phosphorylated sites on the receptor.
  • the Grb2/Sos complex can bind to phosphotyrosine sites on EGFR, in turn activating the Ras/Raf/MAPK signaling cascade, which influences cell proliferation, migration and differentiation.
  • Other exemplary signally molecules include other RTKs, G-coupled receptors, integrins, phospholipase C, Ca2+/calmodulin-dependent kinases, transcriptional activators, cytokines and other kinases.
  • RTKs receptor tyrosine kinases
  • EGFR EGFR is a 170 kDa protein that binds to EGF, a small, 53 amino acid protein- ligand that stimulates the proliferation of epidermal cells and a wide variety of other cell types.
  • EGF receptors are widely expressed in epithelial, mesenchymal and neuronal tissues and play important roles in proliferation and differentiation.
  • EGF receptors are encoded by a family of related genes known also as erbB genes (e.g. erbB2, erbB3, erbB4) and HER genes (e.g. Her-2).
  • the EGF receptor family includes four members, EGF -receptor (HER-I; erbB-1), human epidermal growth factor receptor-2 (HER-2; erbB-2), HER-3 (erbB-3) and HER-4 (erbB-4).
  • EGF -receptor HER-I; erbB-1
  • human epidermal growth factor receptor-2 HER-2; erbB-2
  • HER-3 erbB-3
  • HER-4 erbB-4
  • the ligand for EGFR/HER- 1 is EGF
  • the ligand for HER-2, HER-3 and HER-4 is neuregulin- 1
  • NRG-I preferentially binds to either HER-3 or HER-4 after which the bound receptor subunit heterodimerizes with HER-2.
  • HER-4 also is capable of homodimerization to form an active receptor.
  • Tyrosine kinase inhibitors from the tyrphostin family were found to block EGF-dependent cell proliferation in psoriatic, HPV 16 immortalized and normal keratinocytes.
  • the epidermal growth factor receptor has multiple roles in epidermal biology relating to growth, migration and survival of keratinocytes.
  • overexpression of the EGF receptor (EGFR) kinase is the hallmark of most if not all epithelial cancers.
  • other members of the EGFR family are co-expressed, enabling also the formation of heterodimers necessary for activation of the kinase.
  • the TGF- ⁇ /EGFR system activates in an autocrine manner epidermal keratinocyte proliferation.
  • Misregulation of the ErbB family has been implicated in a number of different types of cancer.
  • overexpression of EGFR is associated with a number of human tumors including, but not limited to, esophageal, stomach, bladder and colon cancers, gliomas and meningiomas, squamous carcinoma of the lungs, and ovarian, cervical and renal carcinomas, squamous cell carcinoma, colorectal cancer, lung cancer, breast cancer, laryngeal cancer, hypopharyngeal cancer, pancreatic cancer, ovarian cancer, gastric cancer and prostate cancer.
  • Overexpression of EGFR is also believed to be associated with other pathological conditions of the skin including psoriasis, keratinocyte proliferation and skin lesions caused or induced by Papilloma virus infection, seborrheic keratoses, acanthosis nigricans, ichthyosis (e.g. ichthyosis vulgaris and congenital ichthyoses), keratodermias, genodermatoses with pathological cornif ⁇ cation disorders (e.g. Darier's disease), further lichen ruber planus, pityriasis rubra pilaris, and skin cancers such as basal cell carcinoma, squamous cell carcinoma and melanoma.
  • EGFR Inhibitors e.g. ichthyosis vulgaris and congenital ichthyoses
  • keratodermias e.g. ichthyosis vulgaris and congenital ichth
  • a wide variety of classes of compounds are known to inhibit EGFR.
  • the inhibitors can act at any step of the EGFR signal transduction pathway.
  • monoclonal antibodies to EGFR inhibit EGFR by preventing the binding of ligands to the receptor binding site.
  • Other classes of compounds, such as the quinazolone compounds act by blocking autophosphorylation (tyrosine kinase activity of EGFR).
  • Any EGFR inhibitor already known to those of skill in the art, or identified by the assays provided herein, can be used in the methods and compositions for treating genetic skin disorders that are provided herein.
  • EGFR is highly expressed in patients with advanced gastric cancer and esophageal cancer.
  • monoclonal antibodies mAbs
  • TKIs low molecular weight tyrosine kinase inhibitors
  • Exemplary cancers that can be treated using EGFR inhibitors include non small cell lung carcinoma, colorectal cancer, squamous cell carcinoma, head and neck cancer, prostate cancer, ovarian cancer and breast cancer.
  • Exemplary EGFR inhibitors include, but are not limited to, natural inhibitors such as genistein, genistin, quercetin, equol, staurosporine, aeroplysinin, indocarbazole, lavendustin, piceatannol, kaempferol, daidzein, erbstatin, isoflavones, and tyrphostins.
  • natural inhibitors such as genistein, genistin, quercetin, equol, staurosporine, aeroplysinin, indocarbazole, lavendustin, piceatannol, kaempferol, daidzein, erbstatin, isoflavones, and tyrphostins.
  • EGFR inhibitors include AG-494 (a member of the tyrphostin family of tyrosine kinase inhibitors), AG-825 (5-[(Benzthiazol-2- yl)thiomethyl]-4-hydroxy-3-methoxybenzylidenecyanoaceta mide), AG-1478 (4-(3- Chloroanilino)-6,7-dimethoxyquinazoline) and 4-aniloquinazoline derivatives (W. A.
  • Tyrphostin 23 (RG-50810), Tyrphostin 25 ([(3 ,4,5-trihydroxyphenyl)-methylene]- propanedinitrile, Gazit et al., J. Med. Chem., 32:2344, 1989; also known as RG- 50875), Tyrphostin 46, Tyrphostin 47 (also known as RG-50864 and AG-213), Tyrphostin 51 , and Tyrphostin 1.
  • Benz Teyrosine Kinase inhibitors Targeted to the Epidermal Growth Factor Receptor Subfamily—Role as Anticancer Agents
  • Drugs 2000 Apr:59(4) (the disclosure of which is incorporated herein by reference) describes various approaches for inhibiting the kinase activity of EGF receptors, including antibodies, immunotoxin conjugates, ligand-binding cytotoxic agents, and small molecule kinase inhibitors.
  • Small nucleotide inhibitors have also been developed for inhibiting EGFR, as well as for such kinases as JNK, MEKK, and others that activate EGFR signalling.
  • Exemplary U.S. Pat. Nos. include 5,914,269 and 6,187,585 for EGFR inhibition, 5,877,309, 6,133,246, and 6,221,850 for JNK inhibition, 6,168,950 for MEKK inhibition, and other such as 6,054,440, 6,159,697, and 6,262,241 (the disicosures of which are all incorporated herein by reference).
  • Antisense compounds that inhibit EGFR are described in U.S. Pat. Nos. 5,914,269 and 6,187,585.
  • antibodies which bind to EGFR include cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, trastuzumab, ABX-EGF and Mab ICR-62, MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507),
  • MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, U.S. Pat. No. 4,943,533, Mendelsohn et al.) and variants thereof, such as chimerized 225 (C225 or Cetuximab; ERBITUX® (ImClone, New York, New York) and reshaped human 225 (H225) (see, WO 96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in U.S.
  • the anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH).
  • EGFR antagonists include small molecules such as compounds described in
  • EGFR antagonists include OSI-774 (CP-358774, TARCEVA® (erlotinib; OSI Pharmaceuticals, Melville, NY); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3- chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quin- azolinyl]-, dihydrochloride, Pfizer Inc.); ZD 1839, gefitinib (IRESSATM) 4-(3'-Chloro-4'- fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoli- ne, AstraZeneca); ZM
  • 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N- 8-(3-chloro-4-fluoro-phenyl)-N-2-(l-methyl-piperidin-4-yl)-pyrimido[5,- A- d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(l- phenylethyl)amino]-lH-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol)- ; (R)-6-(4- hydroxyphenyl)-4-[(l-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimi- dine); CL-
  • tyrosine kinase inhibitors include small molecule HER2 tyrosine kinase inhibitors such as TAKl 65 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GW572016; available from GlaxoSmithKline) an oral HER2 and EGFR tyrosine kinase inhibitor; PKI- 166 (available from Novartis); pan-HER inhibitors such as canertinib (CI- 1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibits Raf-1 signaling; non-HER targeted TK inhibitors such as Imatinib mesylate (GLEEVECTM, Nov
  • EGFR inhibitors include 4-[(3-chloro-4- fluorophenyl)amino]-6- ⁇ [4-(morpholin-4-yl)- 1 -oxo-2-buten- 1 - -yljamino ⁇ -7- cyclopropylmethoxy-quinazoline, 4-[(R)-(I -phenyl-ethyl)amino]-6- ⁇ [4-(morpholin-4- yl)-l -oxo-2-buten- 1-yl] a- mino ⁇ -7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4- fluorophenyl)amino]-6- ⁇ [4-((R)-6-methyl-2-oxo-morpholin-4 ⁇ yl)-
  • EGFR inhibitors Any of the above-mentioned EGFR inhibitors, or EGFR inhibitors identified as inhibiting any step of the EGFR-mediated signal transduction pathway, are contemplated for use in the methods and compositions provided herein.
  • EGFR over-expression is associated with a number of cancers, including several that are of epithelial origin. Therefore, patients susceptible to such cancers often have associated genetic skin disorders. Accordingly, provided herein are methods and compositions for treating cancer patients having a genetic skin disorder, by administering an EGFR inhibitor to treat the skin disorder.
  • the methods and compositions can include additional agents to treat the cancer.
  • agents can include an EGFR inhibitor that is different from the inhibitor that is used to treat the skin disorder, radiation treatment, and a variety of other antineoplastic agents including, but not limited to:
  • Irinotecan cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, leucovorin;
  • Alkylating agents such as Alkyl sulfonates such as Busulfan, Improsulfan and
  • Aziridines such as Benzodepa, Carboquone, Meturedepa and Uredepa; Ethylenimines and methylmelamines such as Altretamine,
  • Triethylenemelamine Triethylenephosphoramide, Triethylenethiophosphoramide and Trimethylolomelamine
  • Nitrogen mustards such as Chlorambucil, Chlornaphazine, Chclophosphamide, Estramustine, Ifosfamide, Mechlorethamine, Mechlorethamine Oxide Hydrochloride, Melphalan, Novembichin, Phenesterine, Prednimustine, Trofosfamide and Uracil Mustard;
  • Nitrosoureas such as Carmustine, Chlorozotocin, Fotemustine, Lomustine, Nimustine and Ranimustine; and others such as Camptothecin, dacarbazine, Mannomustine, Mitobronitol, Mitolactol and Pipobroman;
  • Antibiotics such as Aclacinomycins, Actinomycin Fl, Anthramycin, Azaserine, Bleomycins, Cactinomycin, Carubicin, Carzinophilin, Chromomycins, Dactinomycin, Daunorubicin, 6-Diazo-5-oxo-L-norleucine, Doxorubicin, Epirubicin, Mitomycins, Mycophenolic Acid, Nogalamycin, Olivomycins, Peplomycin, Plicamycin, Porfiromycin, Puromycin, Streptonigrin, Streptozocin, Tubercidin,
  • Antimetabolites including: Folic acid analogs such as Denopterin, Methotrexate, Pteropterin and Trimetrexate;
  • Purine analogs such as Fludarabine, 6-Mercaptopurine, Thiamiprine and Thioguanaine;
  • Pyrimidine analogs such as Ancitabine, Azacitidine, 6-Azauridine, Carmofur, Cytarabine, Doxifluridine, Enocitabine, Floxuridine Fluroouracil and Tegafur;
  • Enzymes such as L- Asparaginase; and others such as Aceglatone, Amsacrine, Bestrabucil, Bisantrene, Bryostatin 1, Carboplatin, Cisplatin, Defofamide, Demecolcine, Diaziquone, Elfornithine, Elliptinium Acetate, Etoglucid, Etoposide,
  • Antineoplastic (hormonal) drugs including: Androgens such as Calusterone, Dromostanolone Propionate, Epitiostanol, Mepitiostane and Testolactone;
  • Antiadrenals such as Aminoglutethimide, Mitotane and Trilostane
  • Antiandrogens such as Flutamide and Nilutamide
  • Antiestrogens such as Tamoxifen and Toremifene
  • Antineoplastic adjuncts including folic acid replenishers such as Frolinic Acid.
  • Patients having any of a variety of cancers can be treated in this manner for any associated genetic skin disease.
  • Such cancers include those of epithelial origin and others including, but not limited to, squamous cell carcinoma, colorectal cancer, lung cancer, esophageal cancer, breast cancer, laryngeal cancer, hypopharyngeal cancer, bladder cancer, pancreatic cancer, ovarian cancer, gastric cancer and prostate cancer.
  • EGFR inhibitors that can be used in the methods and compositions provided herein can be any agents that are known or are identified as inhibiting any step of the signal transduction pathway triggered by EGFR. a. Kinase assays
  • Kinase activity of the EGFR in the presence or absence of the putative inhibitor can be detected and/or measured directly and indirectly.
  • antibodies against phosphotyrosine can be used to detect phosphorylation of the EGFR or of other proteins and signaling molecules in the signal transduction pathway.
  • Activation of tyrosine kinase activity of EGFR can be measured in the presence of a ligand for EGFR.
  • the autophosphorylation detected for example by anti-phosphotyrosine antibodies, can be measured and/or detected in the presence and absence of a putative EGFR inhibitor, thus measuring the ability of the putative inhibitor to effectively reduce EGFR activity.
  • cells expressing EGFR are treated with the putative inhibitor.
  • Cells are lysed and protein extracts (whole cell extracts or fractionated extracts) are loaded onto a polyacrylamide gel, separated by electrophoresis and transferred to membrane, such as used for Western blotting.
  • Immunoprecipitation with anti-EGFR antibodies also can be used to fractionate and isolate EGFr before performing gel electrophoresis and western blotting.
  • the membranes can be probed with anti-phosphotyrosine antibodies to detect phosphorylation.
  • Control cells not treated with the putative inhibitor can be subjected to the same procedures for comparison.
  • Tyrosine phosphorylation also can be measured directly, such as by mass spectroscopy.
  • the EGFR can be isolated from the cells by immunoprecipitation and trypsinized to produce peptide fragments for analysis by mass spectroscopy.
  • Peptide mass spectroscopy is a well-established method for quantitatively determining the extent of tyrosine phosphorylation for proteins; phosphorylation of tyrosine increases the mass of the peptide ion containing the phosphotyrosine, and this peptide is readily separated from the non-phosphorylated peptide by mass spectroscopy.
  • tyrosine-1139 and tyrosine-1248 are known to be autophosphorylated in ErbB-2. Trypsinized peptides can be empirically determined or predicted based on polypeptide sequence, for example by using ExPASy-
  • the extent of phosphorylation of tyrosine-1139 and tyrosine- 1248 can be determined from the mass spectroscopy data of peptides containing these tyrosines. Such assays can be used to assess the extent of autophosphorylation of EGFR in the presence or absence of a putative EGFR inhibitor. b. Complexation
  • Complexation such as dimerization of EGFR
  • a putative EGFR inhibitor can be detected and/or measured in the presence or absence of a putative EGFR inhibitor.
  • Antibodies recognizing EGFR polypeptides can be used to detect the presence of monomers, dimers and other complexed forms.
  • labeled EGFR can be detected in assays that can assess homodimerization or heterodimerization of EGFR in the presence and absence of a putative inhibitor.
  • Ligand binding modulates the activity of EGFR and thus modulates signaling within the signal transduction pathway.
  • Ligand binding to EGFR can be measured in the presence and absence of a putative inhibitor.
  • radiolabeled ligand such as radiolabeled ligand can be added to purified or partially purified EGFR in the presence and absence of the putative inhibitor.
  • Immunoprecipitation and measurement of radioactivity can be used to quantify the amount of ligand bound to EGFR in the presence and absence of the putative inhibitor.
  • Cell Proliferation assays EGFR is known to play a role in cell proliferation. Therefore, the effects of a putative EGFR inhibitor on cell proliferation can be measured.
  • ligand can be added to cells expressing EGFR.
  • a putative EGFR inhibitor can be added to such cells before, concurrently or after ligand addition and effects on cell proliferation measured.
  • the cells are incubated at standard growth temperature (e.g. 37 0 C) for several days. Cells are trypsinized, stained with trypan blue and viable cells are counted. Cells not exposed to the putative inhibitor are used as controls for comparison. e. Cell disease model assays
  • Cells from a disease or condition or which can be modulated to mimic a disease or condition, such as a variety of cancers that over-express EGFR, can be used to measure and/or detect the effect of a putative inhibitor on EGFR.
  • a putative EGFR inhibitor is added to such cells and a phenotype is measured or detected in comparison to cells not exposed to the putative inhibitor.
  • Such assays can be used to measure effects including effects on cell proliferation, metastasis, inflammation, angiogenesis, pathogen infection and bone resorption. f. Animal models
  • Animal models can be used to assess the effect of a putative inhibitor on EGFR.
  • cancer cells such as ovarian cancer cells are exposed to a putative EGFR inhibitor. After a culturing period in vitro, cells are trypsinized, suspended in a suitable buffer and injected into mice (e.g., into flanks and shoulders of model mice such as Balb/c nude mice). Tumor growth is monitored over time. Control cells, not exposed to a putative EGFR inhibitor, can be injected into mice for comparison. Similar assays can be performed with other cell types and animal models, for example, murine lung carcinoma (LLC) cells and C57BL/6 mice and SCID mice. 5. Assessing the efficacy of EGFR inhibitors in treating genetic skin disorders
  • Efficacy of the EGFR inhibitors in ameliorating the symptoms/manifestations of a genetic skin disorder can be assessed by measuring in subjects, before and after treatment, a number of parameters including, but not limited to, the extent of lesions, lesion thickness, mean rating of severity, and global examination by a physician. This is exemplified in Examples 1 and 2.
  • a canine genetic model of Darier's disease exhibits a phenotype similar to Darier's disease, including skin lesions histologically similar to Darier's disease and depleted sarcoplasmic/endoplasmic reticulum-gated calcium stores in keratinocytes.
  • a model could be used to test the efficacy of EGFR inhibitors in reducing the severity of the lesions and/or replenishing the keratinocyte calcium stores (Byrne C.R., J.
  • a mouse model of Darier's disease characterized by mutations in the ATP2A2 gene, exhibits perturbations in Ca 2+ homeostatis and a high incidence of squamous cell carcinomas and papillomas in keratinized epithelial cells, the same cell type affected in human Darier disease (Liu et al, J. Biol. Chem., 276(29):26737-26740 (2001)).
  • the efficacy of EGFR inhibitors can be tested by observing whether treatment with EGFR inhibitors affords a reduction in symptoms associated with the phenotype.
  • the disorders can be autosomal dominant or autosomal recessive and may further be characterized by hyperkeratosis or ichthyosis.
  • the keratinization disorders can be selected from among over 300 genetic skin disorders as provided or incorporated by reference herein.
  • the keratinization disorder can be selected from among Darier's disease, Hailey-Hailey disease, erythrodermic autosomal recessive lamellar ichthyosis, nonerythrodermic autosomal recessive lamellar ichthyosis, autosomal dominant lamellar ichthyosis, bullous congenital ichthyosiform erythroderma, palmoplantar keratoderma, erythrokeratodermia variabilis, verrucous epidermal nevi, pityriasis rubra pilaris, Netherton syndrome, idiopathic vulgaris, ichthyosis vulgaris, monilethrix, keratosis piliaris, bullous ichthyosiform erythroderma, nonbullous congenital ichthyosis, Sjogren-Larsson syndrome, erythrokeratodermica variabilis, hyperkerato
  • the EGFR inhibitors used in the methods provided herein can belong to any one of a number of different types of compounds that inhibit the signal transduction pathway triggered by EGFR.
  • the inhibition can occur at any step of the signal transduction pathway.
  • the EGFR inhibitor can be a monoclonal antibody that inhibits EGFR activity by binding to EGFR in a manner that prevents binding of a ligand, such as epidermal growth factor (EGF), which ordinarily would trigger the EGFR-mediated signal transduction pathway.
  • the EGFR inhibitor can be a quinazolone compound that inhibits EGFR-mediated signalling by binding to adenosine triphosphate (ATP) and preventing autophosphorylation of EGFR.
  • ATP adenosine triphosphate
  • the EGFR inhibitor can be a known agent as provided herein.
  • the EGFR inhibitor can be one that is identified as having EGFR inhibitory activity by conducting assays, as provided herein and as known to those of skill in the art, on a test agent heretofore unidentified as being an
  • the EGFR inhibitor can be selected from among quinazolone compounds.
  • a quinazolone compound used as an EGFR inhibitor can be selected from among those provided herein, or a heretofore unknown quinazolone EGFR inhibitor can be identified as having EGFR inhibitory activity by performing assays as provided herein and as known to those of skill in the art.
  • the quinazoline compound is selected from among erlotinib, gefitinib and lapatinib. In one example, the quinazoline compound is erlotinib.
  • EGFR inhibitor(s) for treatment of the skin disorder in combination with a therapeutically effective amount of one or more anticancer agents.
  • the anticancer agent can be an EGFR inhibitor that is different from the one used to treat the genetic skin disorder, or it can be selected from among other anticancer agents as provided and incorporated by reference herein.
  • exemplary anticancer agents include irinotecan, cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, leucovorin and radiation treatment.
  • the anticancer agent is radiation treatment.
  • the anticancer agent is irinotecan.
  • the cancer is squamous cell carcinoma and the anticancer agent is radiation treatment, or the cancer is colorectal cancer and the anticancer agent is irinotecan.
  • the monogenic inherited keratinization disorder treated using an EGFR inhibitor can be Darier's disease.
  • the EGFR inhibitor used to treat Darier's disease can be selected from among the various classes of EGFR inhibitors as provided herein, or an agent that is identified as an EGFR inhibitor by one or more of the assays as provided herein and as known to those of skill in the art. For example, the
  • EGFR inhibitor is an antibody that binds to EGFR.
  • exemplary antibodies include, but are not limited to, cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, trastuzumab, ABX-EGF and Mab ICR-62.
  • the monoclonal antibody is cetuximab.
  • the EGFR inhibitor used to treat Darier's disease can also a quinazoline compound such as, for example, erlotinib.
  • the subject identified as having Darier's disease can further be identified as having cancer.
  • the cancer can be selected from among squamous cell carcinoma, colorectal cancer, lung cancer, esophageal cancer, breast cancer, laryngeal cancer, hypopharyngeal cancer, bladder cancer, pancreatic cancer, ovarian cancer, gastric cancer and prostate cancer.
  • the cancer is squamous cell carcinoma.
  • the methods can further include the administration of a therapeutically effective amount of one or more anticancer agent(s).
  • the anticancer agents that is/are administered to the patient identified as having Darier's disease and cancer may be EGFR inhibitor(s), or they may not be EGFR inhibitors.
  • the anticancer agent can be selected from among those that are provided herein and known to those of skill in the art.
  • Exemplary anticancer agents include, but are not limited to, irinotecan, cisplatin, carboplatin, oxaliplatin, 5- fluorouracil, leucovorin and radiation treatment.
  • the patient identified as having Darier's disease is further identified as having squamous cell carcinoma.
  • an exemplary treatment can include treating the Darier's disease with an EGFR inhibitor and the squamous cell carcinoma with radiation as the anticancer agent.
  • the patient identified as having Darier's disease is further identified as having colorectal cancer.
  • the Darier's disease can be treated with an EGFR inhibitor and the colorectal cancer can be treated using irinotecan as the anticancer agent.
  • Also provided herein is a method of treating a keratinization disorder by administering to a subject identified as having the keratinization disorder a therapeutically effective amount of an EGFR inhibitor, wherein the EGFR inhibitor is selected from among an antibody that binds to EGFR, an antisense nucleic acid, a quinoxaline, a phenolic stibenoid, a tyrosine metabolite, a flavonoid, an isoflavonoid and methyl-2,5-dihydroxycinnamate.
  • the keratinization disorder can be monogenic or polygenic.
  • the keratinization disorder may be a complex disorder.
  • any genetic skin disorder including keratinization disorders, may be treated by administration of an EGFR inhibitor that is an antibody that binds to EGFR.
  • the antibody can be a polyclonal antibody, or it can be a monoclonal antibody.
  • the monoclonal antibody can be selected from among a variety of antibodies as provided herein and as known to those of skill in the art. Exemplary monoclonal antibodies include, but are not limited to, cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, trastuzumab, ABX-EGF and Mab ICR-62. In one example, the monoclonal antibody is cetuximab.
  • the methods provided herein can further include a step of administering one or more additional agents for treating keratinization disorders.
  • the additional agent(s) can be selected from among a number of agents, exemplary of which are an EGFR inhibitor that is different from the EGFR inhibitor administered as the first agent for treatment of the keratinization disorder, a retinoid, a corticosteroid, cyclosporin, an alpha-hydroxy acid, a beta-hydroxy acid, benzoyl peroxide, tazarotene, bexarotene, adapalene and a laser treatment.
  • agents exemplary of which are an EGFR inhibitor that is different from the EGFR inhibitor administered as the first agent for treatment of the keratinization disorder, a retinoid, a corticosteroid, cyclosporin, an alpha-hydroxy acid, a beta-hydroxy acid, benzoyl peroxide, tazarotene, bexarotene, adapalene and a laser
  • compositions, combinations, kits and articles of manufacture that include an EGFR inhibitor, or an EGFR inhibitor and an anticancer agent, for treating a genetic skin disorder.
  • the compositions, combinations and articles of manufacture can be administered using a variety of routes such as intravenous or other systemic route, topical application, subcutaneous or transdermal application.
  • an article of manufacture that includes an EGFR inhibitor, an anticancer compound and a carrier for topical administration, for treating a genetic skin disorder.
  • an article of manufacture that includes an EGFR inhibitor adjusted to a dosage suitable for the treatment of a monogenic keratinization disorder, and a carrier for topical administration.
  • the article of manufacture can, by way of example, contain exclusively an EGFR inhibitor adjusted to a dosage suitable for the treatment of a monogenic keratinization disorder, and a carrier for topical administration.
  • the monogenic keratinization disorder may, for example, be Darier's disease.
  • the articles of manufacture provided herein can further contain a label indicating that the composition is for treating Darier's disease or other skin disorder as provided herein.
  • the EGFR inhibitor contained in the articles of manufacture may be an antibody that binds to EGFR.
  • the antibody can be a polyclonal antibody, or a monoclonal antibody.
  • the antibody can be a monoclonal antibody selected from among cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, trastuzumab, ABX-EGF and Mab ICR-62.
  • the monoclonal antibody is cetuximab.
  • the EGFR inhibitor contained in the articles of manufacture can, in some examples, be a quinazolone compound.
  • the quinazoline compound can be selected from among those provided and incorporated by reference herein.
  • the quinazolone compound is selected from among erlotinib, gef ⁇ tinib and lapatinib.
  • the quinazolone compound is erlotinib.
  • the articles of manufacture provided herein can further include a delivery system for the EGFR inhibitor.
  • the delivery system can be selected from among a variety of vehicles for administering therapeutic agents, as known to those of skill in the art.
  • the delivery system can be selected from among a transdermal patch, a lotion, a cream, a syringe, an intravenous drip, an intravenous tube, a tablet or a feeding tube.
  • compositions containing an EGFR inhibitor, an anticancer agent and a carrier selected for topical administration are also provided herein.
  • the EGFR inhibitor and the anticancer agent can be selected from among any of those provided herein, incorporated by reference herein, identified by assays as provided herein, or known to those of skill in the art.
  • Therapeutically effective concentrations (for amelioration of the symptoms manifested by the genetic skin disorder) of one or more EGFR inhibitors or pharmaceutically acceptable derivatives thereof are mixed with a suitable pharmaceutical carrier or vehicle for oral, subcutaneous, transdermal, intravenous, intramuscular, ophthalmic or other routes.
  • the EGFR inhibitors are included in an amount effective for reducing the genetic skin disorder for which treatment is contemplated.
  • concentration of active compound (EGFR inhibitor) in the composition will depend on absorption, inactivation, excretion rates of the active compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.
  • the dosages will be lower, typically at least about or at 5 to 10 fold lower but up to about or at 15, 20, 25, 30, 35, 40, 50, 100, 200 or 500-fold lower, than the amount of EGFR inhibitor administered for the treatment of cancer.
  • the period of administration of the EGFR inhibitor for the treatment of the skin disorder will generally be longer than when administered for the treatment of cancer, because the symptoms of genetic skin disorders generally recur in the absence of treatment.
  • the dosages and period of administration may be empirically determined.
  • Exemplary dosages of an EGFR inhibitor that is an antibody administered as an intravenous infusion can be in the range of from about or at 20 mg/m 2 to about or at 500 mg/m 2 ; about or at 40 mg/m 2 to about or at 500 mg/m 2 ; about or at 50 mg/m 2 to about or at 400 mg/m 2 ; about or at 100 mg/m 2 to about or at
  • 400 mg/m 2 about or at 200 mg/m 2 to about or at 300 mg/m 2 ; about or at 200 mg/m 2 to about or at 250 mg/m 2 .
  • Exemplary dosages of an EGFR inhibitor administered orally, such as a quinazolone compound can be in the range of from about or at 0.1, 0.2, 0.5, 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 115, 125,
  • the frequency of dosage can be determined empirically; exemplary frequencies are twice daily, daily, weekly, bi-weekly or monthly. Dosage frequencies can be gradually attenuated over time and maintained at a steady dose suitable for long-term - six months, 1 year, 5 years, 10 years or more, up to lifelong administration to control the symtoms of the skin disorder. For example, dosage administration can begin at from three or more times a day, to two times a day, to once a day, to two times a week, to once a week, to once every two weeks or less frequent than once every two weeks.
  • compositions suitable for administration of the compounds and for the methods provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
  • the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients, such as anticancer agents as provided herein.
  • a therapeutically effective dosage is formulated to contain a concentration (by weight) of at least about 0.1% up to about 50% or more, and all combinations and subcombinations of ranges therein.
  • compositions can be formulated to contain the EGFR inhibitor or inhibitor(s) in a concentration of from about 0.1 to less than about 50%, for example, about 49, 48, 47, 46, 45, 44, 43, 42, 41 or 40%, with concentrations of from greater than about 0.1%, for example, about 0.2, 0.3, 0.4 or 0.5%, to less than about 40%, for example, about 39, 38, 37, 36, 35, 34, 33, 32, 31 or 30%.
  • compositions may contain from about 0.5% to less than about 30%, for example, about 29, 28, 27, 26, 25, 25, 24, 23, 22, 21 or 20%, with concentrations of from greater than about 0.5%, for example, about 0.6, 0.7, 0.8, 0.9 or 1%, to less than about 20%, for example, about 19, 18, 17, 1 6, 1 5, 14, 13, 12, 11 or 10%.
  • the compositions can contain from greater than about 1% for example, about 2%, to less than about 10%, for example about 9 or 8%, including concentrations of greater than about 2%, for example, about 3 or 4%, to less than about 8%, for example, about 7 or 6%.
  • the active agent can, for example, be present in a concentration of about 5%. In all cases, amounts may be adjusted to compensenate for differences in amounts of active ingredients actually delivered to the treated tissue.
  • the active ingredient such as the EGFR inhibitor or the EGFR inhibitor combined with an anticancer agent may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the tissue being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that, for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only.
  • the form and mode of administration of the resulting composition depends upon a number of factors, including the intended application, the subject (whether afflicted with only a genetic skin disorder or a genetic skin disorder and cancer), and the solubility of the active agent(s) in the selected carrier or vehicle.
  • the effective concentration is sufficient for ameliorating the manifestations of the genetic skin disorder, and may be empirically determined.
  • compositions may be a solution, suspension, emulsion or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, injectable solutions, or any other formulation suitable for topical or intravenous or other systemic administration.
  • compositions suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
  • the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients, such as anticancer agents.
  • the active compound(s) is included in the carrier in an amount sufficient to exert a therapeutically useful effect [i.e., amelioration of the symptoms of the genetic skin disorder, or both the skin disorder and cancer, in the case of cancer patients], with minimal or no toxicity or other side effects.
  • the compounds may be formulated in compositions in the form of gels, creams, lotions, solids, solutions or suspensions, or aerosols.
  • emollient or lubricating vehicles that help hydrate the skin are more preferred than volatile vehicles, such as ethanol, that dry the skin.
  • suitable bases or vehicles for preparing compositions for use with human skin are petrolatum, petrolatum plus volatile silicones, lanolin, cold cream and hydrophilic ointment.
  • Suitable pharmaceutically and dermatologically acceptable vehicles for topical application include those suited for use include lotions, creams, solutions, gels, tapes and the like.
  • the vehicle is either organic in nature or an aqueous emulsion and capable of having the selected compound or compounds, which may be micronized, dispersed, suspended or dissolved therein.
  • the vehicle may include pharmaceutically-acceptable emollients, moisterizers, including lactic acid, ammonium lactate and urea, skin penetration enhancers, coloring agents, fragrances, emulsifiers, thickening agents, and solvents.
  • the compounds can be formulated and used as tablets, capsules or elixirs for oral administration; salves or ointments for topical application; suppositories for rectal administration; sterile solutions, suspensions, and the like for injection.
  • injectables can also be prepared in conventional forms either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like.
  • the injectable pharmaceutical compositions can contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents and the like.
  • kits containing the combinations optionally including instructions for administration are provided.
  • the combinations include, for example, the compositions as provided herein containing one or more EGFR inhibitors, optionally one or more anticancer agents, and reagents or solutions for diluting the compositions to a desired concentration for administration to a host subject, including human beings.
  • compositions provided herein can be packaged as articles of manufacture containing packaging material, a composition provided herein, and a label that indicates that the composition is for treating a genetic skin disorder, such as Darier's disease, and is formulated for oral delivery, intravenous delivery, or other form of delivery as described herein.
  • a genetic skin disorder such as Darier's disease
  • packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. See, e.g., U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252.
  • Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. D. Definitions
  • a “genetic skin disorder” is any skin disease whose occurrence can be attributed to a defective or abnormal gene or genes.
  • defective or abnormal used interchangeably herein, is meant gene(s) that is/are mutated, i.e., point mutations, insertions, deletions, or whose expression is de-regulated, i.e., down- regulated or up-regulated relative to normal expression levels.
  • Exemplary genetic skin disorders include, but are not limited to, Darier's disease, Hailey-Hailey disease, erythrodermic autosomal recessive lamellar ichthyosis, nonerythrodermic autosomal recessive lamellar ichthyosis, autosomal dominant lamellar ichthyosis, bullous congenital ichthyosiform erythroderma, palmoplantar keratoderma, erythrokeratodermia variabilis, verrucous epidermal nevi, pityriasis rubra pilaris, Netherton syndrome, idiopathic vulgaris, ichthyosis vulgaris, monilethrix, keratosis piliaris, bullous ichthyosiform erythroderma, nonbullous congenital ichthyosis, Sjogren-Larsson syndrome, erythrokeratodermica variabilis, hyperkera
  • an "inherited skin disorder” is one that is caused by a defective gene or genes that are transmitted from generation to generation in an autosomal dominant, autosomal recessive, or partially or completely co-dominant fashion.
  • An “autosomal dominant” disease is one where the phenotype of the disease can be manifested when one defective allele is present.
  • An “autosomal recessive” disease is one where both alleles must be defective for the disease phenotype to become manifest.
  • a "co-dominant” disease is one where a defective allele and a normal (wild-type) allele combine to produce a phenotype that is intermediate between the normal gene phenotype and the defective gene phenotype.
  • penetrance is a measure of the likelihood that a person carrying a disease gene will manifest symptoms of the disease.
  • the penetrance of Darier's disease is 100% or complete, which means that every person carrying the mutant allele will exhibit symptoms of the disease, although the degree of severity will vary.
  • a penetrance of 30% means that only 30% of the subjects carrying the mutant allele in an autosomal dominant disorder, or 30% of subjects carrying both defective alleles in an autosomal recessive disorder, will exhibit symptoms of the disorder.
  • a "monogenic" skin disorder is one whose cause is attributable to a single gene.
  • An example of a monogenic skin disorder is Darier's disease, an autosomal dominant skin disorder caused by a mutation in the ATP2A2 (an ATPase) gene.
  • a monogenic skin disorder is characterized by the feature of being able to confirm the diagnosis of the disorder (manifested or as a carrier), based on mutations in a single gene.
  • a monogenic skin disorder as used herein can be caused by mutations in more than one alternate gene.
  • the skin disorder epidermolytic hyperkeratosis is caused by mutations in the keratin 1 gene or the keratin 10 gene.
  • a "polygenic" skin disorder is one whose manifestation is attributable to more than one gene. Manifestation of the disease involves the interplay of more than one gene, each of which predisposes the person to the disorder.
  • Examples of polygenic diseases are psoriasis and psoriatic arthritis.
  • Polygenic diseases such as a spectrum of psoriasis disorders often are characterized as "complex" diseases which, as used herein, means that the defective genes are involved in a complex interplay with one or more other factors including other genes, lifestyle, environmental factors and immune responses.
  • the term "keratinization disorder” refers to a defect in keratin metabolism. Some keratinization disorders are caused by mutations in keratin genes.
  • a keratinization disorder In the context of skin diseases, a keratinization disorder usually results in the appearance of scaly and/or thickened skin.
  • Skin keratinization disorders generally are characterized by "hyperkeratosis,” which as used herein means the over-production of keratin, and/or “keratinocyte hyperplasia,” which as used herein means the generation of a larger than normal number of keratinocytes.
  • ichthyosis disorder refers to a family of genetic dermatological conditions seen in humans and domestic animals. The word comes from the Greek term for "forming fish," as people or animals with ichthyosis have scaly skin which can vaguely resemble the scales of a fish. While ichthyosis acquisita is acquired (as its name indicates), most forms of ichthyosis are considered congenital.
  • Ichthyosis vulgaris X-linked ichthyosis
  • Ichthyosis lamellaris Epidermolytic hyperkeratosis
  • Harlequin type ichthyosis Netherton's syndrome
  • Sj ⁇ gren-Larsson syndrome Sj ⁇ gren-Larsson syndrome
  • a "receptor tyrosine kinase (RTK)” refers to a protein, typically a glycoprotein, that is a member of the growth factor receptor family of proteins. Growth factor receptors are typically involved in cellular processes including cell growth, cell division, differentiation, metabolism and cell migration. RTKs also are known to be involved in cell proliferation, differentiation and determination of cell fate as well as tumor growth. RTKs have a conserved domain structure including an extracellular domain, a membrane-spanning (transmembrane) domain and an intracellular tyrosine kinase domain. Typically, the extracellular domain binds a polypeptide growth factor or a cell membrane-associated molecule.
  • an RTK does not bind a ligand, and/or is active independently from ligand binding; for example HER2 is active without ligand binding and a ligand binding HER2 has not been identified.
  • the tyrosine kinase domain is involved in positive and negative regulation of the receptor.
  • ErbB3 kinase activity is not present in the receptor alone.
  • Receptor tyrosine kinases have been grouped into families based on, for example, structural arrangements of sequence motifs in their extracellular domains. For example, structural motifs such as, immunoglobulin, fibronectin, cadherin, epidermal growth factor and kringle repeats.
  • RTKs include, but are not limited to, erythropoietin-producing hepatocellular (EPH) receptors, epidermal growth factor (EGF) receptors, fibroblast growth factor (FGF) receptors, platelet-derived growth factor (PDGF) receptors, vascular endothelial growth factor (VEGF) receptor, cell adhesion RTKs (CAKs), Tie/Tek receptors, insulin-like growth factor (IGF) receptors, and insulin receptor related (IRR) receptors.
  • EPH erythropoietin-producing hepatocellular
  • EGF epidermal growth factor
  • FGF fibroblast growth factor
  • PDGF platelet-derived growth factor
  • VEGF vascular endothelial growth factor
  • CAKs cell adhesion RTKs
  • Tie/Tek receptors insulin-like growth factor (IGF) receptors
  • IRR insulin receptor related
  • RTKs include, but are not limited to, ERBB2, ERBB3, DDRl, DDR2, TKT, EGFR, EPHAl, EPHA8, FGFR2, FGFR4, FLTl (also known as VEGFR-I), FLKl (also known as VEGFR-2) MET, PDGFRA,
  • PDGFRB PDGFRB
  • TEK also known as TIE-2
  • modulate and modulation refer to a change of an activity of a molecule, such as a protein. Activities include, but are not limited to biological activities, such as signal transduction. Modulation can include an increase in the activity (i.e., up-regulation of agonist activity), a decrease in activity (i.e., down- regulation or inhibition) or any other alteration in an activity (such as periodicity, frequency, duration, kinetics). Modulation can be context-dependent and typically modulation is compared to a designated state, for example, the wildtype protein, the protein in a constitutive state, or the protein as expressed in a designated cell type or condition.
  • inhibitor and “inhibition” refer to a reduction in a biological activity
  • inhibitor refers to a molecule that effects the reduction in biological activity.
  • the reduction in activity generally contemplated herein is anywhere from about or at 10% reduction of the normal biological activity to about or at 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%,
  • inhibitors refer to any of a large class of compounds capable of modulating tyrosine kinase signal transduction.
  • the inhibitors can include molecules such as antibodies that compete for binding of the ligand (EGF, TGF- ⁇ ) to EGFR, or they can include molecules such as quinazolones that bind to ATP and inhibit autophosphorylation of EGFR, or they can include any inhibitor that blocks the signal transduction pathway mediated by the interaction of EGF with EGFR.
  • tyrosine kinase inhibitors and molecules capable of modulating tyrosine kinase signal transduction include, but are not limited to, 4-aminopyrrolo[2,3-d]pyrimidines (see for example, U.S. Pat. No. 5,639,757), and quinazoline compounds and compositions (e.g., U.S. Pat. No. 5,792,771).
  • a variety of EGFR inhibitors are listed, for example, in U.S.
  • Exemplary of these inhibitors are antibodies that bind to EGFR, antisense nucleic acids, tyrphostins, quinazolone compounds, 2-phenylaminopyrimidines, quinoxalines, phenolic stibenoids, tyrosine metabolites, flavonoids, isoflavonoids and methy 1-2 , 5 -dihy droxy cinnamate .
  • composition refers to any mixture. It can be a solution, a suspension, liquid, powder, a paste, aqueous, non-aqueous or any combination thereof.
  • a “combination” refers to any association between or among two or more items.
  • the combination can be two or more separate items, such as two compositions or two collections, can be a mixture thereof, such as a single mixture of the two or more items, or any variation thereof.
  • a “pharmaceutical effect” refers to an effect observed upon administration of an agent intended for treatment of a disease or disorder or for amelioration of the symptoms thereof.
  • treatment means any manner in which the symptoms of a condition, disorder or disease or other indication, are ameliorated or otherwise beneficially altered.
  • therapeutic effect means an effect resulting from treatment of a subject that alters and typically improves or ameliorates the symptoms of a disease or condition or that cures or prevents a disease or condition.
  • a therapeutically effective amount refers to the amount of a composition, molecule or compound which results in a therapeutic effect following administration to a subject.
  • prevention means that the statistical likelihood of manifestation of the disease in the presence of the preventative (drug or prophylactic, e.g., an EGFR inhibitor) is less than the statistical likelihood of occurrence of the disease in the absence of the preventative.
  • Prevention as used herein can also mean there is a delay in the onset of symptoms of the disease. The reduction in likelihood of occurrence, or the delay in onset of symptoms of the disease, can be anywhere from a factor of about or at 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,
  • the term "subject" refers to animals, including mammals, such as human beings. As used herein, a patient refers to a human subject.
  • a biological activity refers to a function of a polypeptide including but not limited to complexation, dimerization, multimerization, phosphorylation, dephosphorylation, autophosphorylation, ability to form complexes with other molecules, ligand binding, catalytic or enzymatic activity, activation including auto-activation and activation of other polypeptides, inhibition or modulation of another molecule's function, stimulation or inhibition of signal transduction and/or cellular responses such as cell proliferation, migration, differentiation, and growth, degradation, membrane localization, membrane binding, and oncogenesis.
  • a biological activity can be assessed by assays described herein and by standard assays known in the art, including but not limited to, in vitro assays, cell- based assays, in vivo assays, animal models and other known biological models.
  • assays described herein including but not limited to, in vitro assays, cell- based assays, in vivo assays, animal models and other known biological models.
  • the terms "activity” or "function" are interchangeable with
  • biological activity and refer to the in vivo activities of a compound, such as a protein, vitamin, mineral or drug, or physiological responses that result upon in vivo administration of a compound, composition or other mixture. Activity, thus, encompasses therapeutic effects and pharmaceutical activity of compounds, compositions and mixtures. Biological activities also can be observed in in vitro systems designed to test or use such activities.
  • a “kit” refers to a combination in which components are packaged optionally with instructions for use and/or reagents and apparatus for use with the combination.
  • polypeptide means at least two amino acids, or amino acid derivatives, including mass modified amino acids and amino acid analogs, that are linked by a peptide bond, which can be a modified peptide bond.
  • the terms "polypeptide,” “peptide” and “protein” are used synonymously herein.
  • a polypeptide can be associated with one or more functional activities including, but not limited to, a nutrient to provide amino acid building blocks, an antioxidant, an enzyme, an antibody, a regulator of gene expression, a scaffold, etc.
  • therapeutically effective amount refers to an amount of the active agent for a desired therapeutic, prophylactic, or other biological effect or response when a composition is administered to a subject in a single or multiple dosage form.
  • the particular amount of active agent in a dosage will vary widely according to conditions such as the nature of the active agent, the nature of the condition being treated, the age and size of the subject.
  • pharmaceutically acceptable derivatives of a compound include salts, esters, enol ethers, enol esters, acids, bases, solvates, hydrates or prodrugs thereof.
  • Such derivatives can be readily prepared by those of skill in this art using known methods for such derivatization.
  • the compounds produced can be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs.
  • salts include, but are not limited to, amine salts, such as but not limited to N 5 N'- dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, 1 -para-chlorobenzyl-2-pyrrolidin- 1 '-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydro
  • esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulf ⁇ nic acids and boronic acids.
  • ACCUTANE® Hoffman-La Roche, Nutley, New Jersey
  • SORIATANE® Hoffman-La Roche, Nutley, New Jersey
  • a patient with stage IV squamous cell carcinoma and a long-standing history of Darier's disease was examined for a clinical update and possible options for further treatments.
  • the patient had recently completed a treatment often weekly infusions of cetuximab (as described in Example 1), as adjuvant therapy for the metastatic squamous cell carcinoma.
  • the cetuximab had shown dramatic effects in reducing the lesions associated with Darier's disease.
  • the patient had taken ACCUTANE® and SORIATANE® (retinoids) in the past, for treating Darier's disease, and neither of the treatments had shown a good response.
  • TARCEVA® erlotinib
  • OSI Pharmaceuticals Melville, NY
  • 150 mg orally per day as adjuvant therapy for the metastatic squamous cell carcinoma.
  • the patient tolerated treatment with TARCEVA® well, with no side effects or other complications. Treatment led to a significant reduction in severity of the Darier's lesions.
  • the patient had been off TARCEVA® for five weeks, and the Darier's lesions had deteriorated at all sites.
  • Treatment with TARCEVA® was resumed on the day of examination as adjuvant therapy for the metastatic squamous cell carcinoma.
  • the treatment for over six months was very well-tolerated by the patient, and resulted in a dramatic reduction of the severity of Darier's lesions.
  • the lesions associated with the disease had almost cleared, relative to the period when the patient had been off TARCEVA®.

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Abstract

La présente invention concerne des procédés et des compositions utiles dans le traitement de troubles cutanés (troubles cutanés génétiques, par exemple). Lesdits procédés et lesdites compositions incluent un inhibiteur d'EGFR. Pour des troubles cutanés génétiques qui présentent un pourcentage élevé de pénétrance, ou une pénétrance totale, tels que la maladie de Darier, les procédés et les compositions décrites ici peuvent être utilisées en vue d'empêcher ou de réduire la manifestation des symptômes de ladite maladie.
PCT/US2009/031101 2008-01-18 2009-01-15 Traitement de troubles cutanés à l'aide d'inhibiteurs d'egfr Ceased WO2009091889A1 (fr)

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WO2019234418A1 (fr) 2018-06-06 2019-12-12 The Institute Of Cancer Research: Royal Cancer Hospital Dérivés d'hexahydropyrrolo[3,4-c]pyrrole utiles en tant qu'inhibiteurs de lox
WO2020099886A1 (fr) 2018-11-16 2020-05-22 The Institute Of Cancer Research: Royal Cancer Hospital Inhibiteurs de lox
WO2020136650A1 (fr) * 2018-12-25 2020-07-02 Sol-Gel Technologies Ltd. Traitement de troubles cutanés avec des compositions comprenant un inhibiteur d'egfr
WO2021014447A1 (fr) * 2019-07-24 2021-01-28 Sol-Gel Technologies Ltd. Traitement de troubles cutanés à l'aide de compositions à usage topique à base de tapinarof-inhibiteur d'egfr
WO2021090322A1 (fr) * 2019-11-06 2021-05-14 Sol-Gel Technologies Ltd. Procédé de traitement du kératoderme palmoplantaire
CN113194954A (zh) * 2018-10-04 2021-07-30 国家医疗保健研究所 用于治疗角皮病的egfr抑制剂
WO2021204843A1 (fr) 2020-04-07 2021-10-14 Laboratoires C.T.R.S. Utilisation topique d'erlotinib pour le traitement de kératodermies chez les enfants
US11633399B2 (en) 2018-12-25 2023-04-25 Sol-Gel Technologies Ltd. Treatment of skin disorders with compositions comprising an EGFR inhibitor
CN118787745A (zh) * 2024-06-05 2024-10-18 南方医科大学 泛jak抑制剂在治疗家族性良性慢性天疱疮中的应用
US12491186B2 (en) 2018-10-04 2025-12-09 INSERM (Institut National de la Santé et de la Recherche Médicale) EGFR inhibitors for treating keratodermas

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Cited By (18)

* Cited by examiner, † Cited by third party
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US12018029B2 (en) 2018-06-06 2024-06-25 The Institute Of Cancer Research: Royal Cancer Hospital Hexahydropyrrolo[3,4-c]pyrrole derivatives useful as LOX inhibitors
WO2019234418A1 (fr) 2018-06-06 2019-12-12 The Institute Of Cancer Research: Royal Cancer Hospital Dérivés d'hexahydropyrrolo[3,4-c]pyrrole utiles en tant qu'inhibiteurs de lox
EP3860608A1 (fr) * 2018-10-04 2021-08-11 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de l'egfr pour traiter les kératodermies
US12491186B2 (en) 2018-10-04 2025-12-09 INSERM (Institut National de la Santé et de la Recherche Médicale) EGFR inhibitors for treating keratodermas
CN113194954A (zh) * 2018-10-04 2021-07-30 国家医疗保健研究所 用于治疗角皮病的egfr抑制剂
WO2020099886A1 (fr) 2018-11-16 2020-05-22 The Institute Of Cancer Research: Royal Cancer Hospital Inhibiteurs de lox
US11633399B2 (en) 2018-12-25 2023-04-25 Sol-Gel Technologies Ltd. Treatment of skin disorders with compositions comprising an EGFR inhibitor
JP2022515256A (ja) * 2018-12-25 2022-02-17 ソル － ゲル テクノロジーズ リミテッド Ｅｇｆｒ阻害剤を含む組成物による皮膚障害の治療
WO2020136650A1 (fr) * 2018-12-25 2020-07-02 Sol-Gel Technologies Ltd. Traitement de troubles cutanés avec des compositions comprenant un inhibiteur d'egfr
CN114206315A (zh) * 2019-07-24 2022-03-18 索尔-格尔科技有限公司 用局部他匹那洛夫-egfr抑制剂组合物治疗皮肤病
WO2021014447A1 (fr) * 2019-07-24 2021-01-28 Sol-Gel Technologies Ltd. Traitement de troubles cutanés à l'aide de compositions à usage topique à base de tapinarof-inhibiteur d'egfr
US20220062285A1 (en) * 2019-11-06 2022-03-03 Sol-Gel Technologies Ltd. Method of treating a skin disorder with egfr inhibitor
WO2021090322A1 (fr) * 2019-11-06 2021-05-14 Sol-Gel Technologies Ltd. Procédé de traitement du kératoderme palmoplantaire
WO2023084515A1 (fr) * 2019-11-06 2023-05-19 Sol-Gel Technologies Ltd. Procédé de traitement d'un trouble cutané avec un inhibiteur de l'egfr
EP4054526A4 (fr) * 2019-11-06 2023-05-24 Sol-Gel Technologies Ltd. Procédé de traitement du kératoderme palmoplantaire
WO2021204843A1 (fr) 2020-04-07 2021-10-14 Laboratoires C.T.R.S. Utilisation topique d'erlotinib pour le traitement de kératodermies chez les enfants
CN115803007A (zh) * 2020-04-07 2023-03-14 C.T.R.S.实验室公司 厄洛替尼在治疗儿童角化病中的局部应用
CN118787745A (zh) * 2024-06-05 2024-10-18 南方医科大学 泛jak抑制剂在治疗家族性良性慢性天疱疮中的应用

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