EGFR inhibitors for treating keratoderma

Abstract

To provide a method of treating a keratoderma.SOLUTION: The present invention provides a method of treating a keratoderma in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an EGFR inhibitor. Preferably, the EGFR inhibitor is selected from the group consisting of brigatinib, erlotinib, gefitinib, icotinib, lapatinib, sapitinib, vandetanib, varlitinib, afatinib, canertinib, dacomitinib, neratinib, osimertinib, pelitinib, and rociletinib.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the use of EGFR inhibitors or inhibitors of the EGFR activation and signaling pathway for keratodermas.

[0002] Background technology: "Keratoderma" is a term that refers to a marked thickening of the skin. Keratoderma may be inherited (hereditary). In particular, Olmsted syndrome (OS) is a rare genodermatosis that is classically characterized by a combination of bilateral, segmental, transgredient palmoplantar keratoses (PPKs) on the dorsum of the hands and feet, and keratotic macules around the mouth, but which shows considerable clinical heterogeneity. The disease usually presents at birth or in early childhood. OS is observed in both sexes, but males are more frequently affected. The most suggestive symptoms associate PPKs with pseudo-eyelum and keratotic macules around the mouth. Frequent associated features include hair and nail abnormalities, white keratosis, corneal default, and recurrent infections. Pain and pruritus at the site of hyperkeratosis are variable but may be severe. Most reported cases of OS are sporadic, but familial cases with different inheritance patterns have also been reported. Current treatments for hyperkeratosis, topical or systemic (mainly emollients, keratolytics, retinoids, or corticosteroids), are symptomatic and provide only temporary partial relief. Specific management of pain and pruritus is important to reduce disease morbidity. The disease is a debilitating and progressive keratoderma, and spontaneous amputation of the digits can prevent patients from grasping and walking, and may render them wheelchair-bound. Therefore, new treatment options are crucial and are expected from a better understanding of the disease mechanism.

[0003] Since 2012, gain-of-function mutations in the TRPV3 (transient receptor potential vanilloid-3) gene have been reported as a cause of OS (Wilson, Neil J., et al. "Expanding the phenotypic spectrum of Olmsted syndrome." The Journal of investigative dermatology 135.11 (2015): 2879.). Although the association between TRPV3 mutations and clinical symptoms had not been established, a study by Cheng et al. (Cheng, Xiping, et al. "TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation." Cell 141.2 (2010): 331-343.) demonstrated that TRPV3 signaling, which operates as a Ca2+-permeable nonselective cation channel, is mediated by EGFR transactivation in mouse and human keratinocytes and amplified by positive feedback. The process of TRPV3 transactivation of EGFR involves activation of the membrane protease ADAM17, also called TACE, which cleaves the membrane precursor of the EGFR ligand TGF-α, leading to activation of EGFR. A hint at this discovery was the phenotype of non-conditional or keratinocyte-targeted TRPV3 knockout mice, which exhibited a curly beard and perm hair phenotype similar to the waved-1 and waved-2 mutants previously shown to be caused by hypomorphic mutations of TGF-α and EGFR (Schneider, Marlon R., et al. "Beyond wavy hairs: the epidermal growth factor receptor and its ligands in skin biology and pathology." The American journal of pathology 173.1 (2008): 14-24.).Although the role of EGFR in skin biology is complex, the phenotype observed in EGFR and TGF-α transgenic mice indicates that EGFR plays an important role in keratinocyte proliferation and differentiation, and more generally in skin homeostasis (Schneider, Marlon R., et al., "Beyond wavy hairs: the epidermal growth factor receptor and its ligands in skin biology and pathology." The American journal of pathology 173.1 (2008): 14-24.).

[0004] Summary of the invention: The present invention relates to the use of EGFR inhibitors for keratodermas. In particular, the invention is defined by the claims.

[0005] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A first object of the present invention relates to a method for treating keratoderma in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of an EGFR inhibitor.

[0006] As used herein, the term "keratoderma" has its common meaning in the art and is a term that refers to a marked thickening of the skin. The classification of keratoderma depends on whether it is hereditary and its clinical characteristics. Diffuse keratoderma affects most of the palms and soles. Focal keratoderma affects mainly pressure areas. Punctate keratoderma causes small bumps on the palms and soles. In most cases, the abnormal skin is only on the palms and soles (without extending to the dorsum of the hands and feet), but sometimes it can extend to the tops of the hands and feet (with extension to the dorsum of the hands and feet).

[0007] In some embodiments, the keratoderma is palmoplantar keratosis. The term "palmoplantar keratosis" or "PPK" refers to any form of persistent thickening of the epidermis of the palms and soles, and includes inherited and acquired conditions. PPK represents a large and diverse group of conditions that differ widely in terms of symptoms and clinical findings. PPK may be acquired in inflammatory skin diseases such as eczema, psoriasis, and lichen planus, and has been reported as a paraneoplastic phenomenon. Genetically determined PPK is a heterogeneous group of individual rare disorders that are inherited by various mechanisms or occur sporadically.

[0008] In some embodiments, the congenital keratosis is a diffuse palmoplantar keratosis (e.g., diffuse epidermolytic palmoplantar keratosis, diffuse non-epidermolytic palmoplantar keratosis, Meleda's disease), a localized palmoplantar keratosis (e.g., linear palmoplantar keratosis), a punctate palmoplantar keratosis (e.g., keratosis punctata palmaris et al ... plantaris), squamous keratosis, focal acral hyperkeratosis), diffuse palmoplantar keratosis (e.g., fluctuating erythrokeratoderma, Sybert palmoplantar keratosis, Olmsted syndrome, and Naegeli-Franceschetti-Jadassohn syndrome), focal palmoplantar keratosis (e.g., Papillon-Lefèvre syndrome, pachyonychia congenita type I, pachyonychia congenita type II, focal palmoplantar keratosis with oral mucosal hyperkeratosis, and Kamisa disease), ectodermal dysplasia (Clauston syndrome), ectopic keratoses (e.g., hidrotic ectodermal dysplasia, acral keratoderma, and reticular pigmented dermatosis), syndromic keratoses (e.g., Vorwinkel syndrome, palmoplantar keratoderma associated with esophageal cancer, palmoplantar keratoderma and spastic paraplegia, Naxos disease, linear palmoplantar keratoderma, trichotillomania, as well as left ventricular dilated cardiomyopathy, keratitis-ichthyosis-deafness syndrome, Corneodermatosseous syndrome, Huriez syndrome, oculocutaneous tyrosinemia, cardio-facio-cutaneous syndrome, and Schepf-Schultz-Passarge syndrome).

[0009] In some embodiments, acquired keratodermas include AIDS-associated keratoderma, arsenical keratoderma, callus cutis, menopausal keratoderma, corns, eczema, human papilloma virus, pyorrhagic keratoderma, lichen planus, Norwegian scabies, paraneoplastic keratoderma, psoriasis, reactive arthritis, secondary syphilis, athlete's foot, Sezary syndrome, and cutaneous verrucous tuberculosis drug-induced keratoderma.

[0010] In some embodiments, the patient suffers from Olmsted syndrome. As used herein, the term "Olmsted syndrome" or "OS" has its general meaning in the art and refers to a hereditary palmoplantar keratosis characterized by bilateral segmental palmoplantar keratosis extending over the dorsum of the hands and feet in combination with periorificial keratotic plaques. The term is also known as segmental palmoplantar keratosis with periorificial keratotic plaques (PPK). The disease usually begins at birth, during the neonatal period, or in infancy, when the child begins to walk and grasp, and worsens over time. The disease has a slow but progressive course.

[0011] In some embodiments, the patient has a TRPV3 mutation. As used herein, the term "TRPV3" has its general meaning in the art and refers to transient receptor potential cation channel subfamily V member 3. The human amino acid sequence of TRPV3 is represented by SEQ ID NO:1. [ka]

[0012] TRPV3 mutations associated with OS are known in the art and include missense mutations such as p.G568C, p.G573S, p.G573C, p.L673F, P.W692G, and recessive mutations such as p.Gln216_Gly262del. Mutations in the TRPV3 gene can be identified by any suitable method in the art, but in certain embodiments, the mutations are identified by one or more of polymerase chain reaction (PCR) or sequencing.

[0013] In some embodiments, the patient is under the age of 20. In some embodiments, the patient is under the age of 18. In some embodiments, the patient is under the age of 15. In some embodiments, the patient is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, or 18 years old.

[0014] In some embodiments, the patient also suffers from erythromelalgia. As used herein, the term "erythromelalgia" has its usual meaning in the art and refers to a rare condition that affects primarily the feet and, less frequently, the hands (extremities). It is characterized by intense, burning pain, severe redness (erythema), and elevated skin temperature in the affected extremities, which can be sudden or nearly constant in nature.

[0015] As used herein, the term "treatment" or "treating" refers to both prophylactic or preventative treatment and curative or disease-modifying treatment, including treatment of patients at risk of or suspected of having a disease, as well as patients who are ill or have been diagnosed with a disease or condition, and includes the suppression of clinical recurrence. Treatment may be administered to a subject who has a medical disorder or who may eventually develop a disorder to prevent, cure, delay onset, reduce severity, or ameliorate one or more symptoms of the disorder or recurrent disorder, or to extend the subject's survival beyond the expected survival in the absence of such treatment. "Treatment regimen" refers to a pattern of treatment of a disease, e.g., a dosing pattern used during treatment. A treatment regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a treatment regimen (or a portion of a treatment regimen) used for the initial treatment of a disease. The general purpose of an induction regimen is to provide a high level of drug to the patient during the initial period of the treatment regimen. The induction regimen may use (partially or entirely) a "loading regimen" which may include administering a higher dose of drug than the doctor would use during a maintenance regimen, administering a drug more frequently than the doctor would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a treatment regimen (or a portion of a treatment regimen) used to maintain a patient during disease treatment, for example, to keep the patient in remission for an extended period of time (months or years). A maintenance regimen may use continuous therapy (e.g., administering a drug at regular intervals such as weekly, monthly, yearly, etc.) or intermittent therapy (e.g., intermittent treatment, intermittent treatment, treatment upon relapse, or treatment upon certain predetermined criteria (e.g., disease manifestation, etc.) are met).

[0016] In particular, EGFR inhibitors are particularly suitable for alleviating pain, especially pain associated with areas of hyperkeratosis. EGFR inhibitors are also suitable for treating anorexia and insomnia, as well as inducing complete disappearance of hyperkeratosis.

[0017] As used herein, the term "EGFR" has its general meaning in the art and is intended herein to mean according to its usual meaning in the art, i.e., epidermal growth factor receptor or ErbB-1 (HER1 in humans). It is a member of the ErbB family of receptors. Naturally occurring EGFR is expressed on the cell surface and is activated by binding of specific ligands, including epidermal growth factor (EGF) and transforming growth factor alpha (TGFα). Upon activation by its growth factor ligand, EGFR transitions from an inactive monomeric form to an active homodimer. EGFR can also pair with other members of the ErbB receptor family, such as ErbB2 / Her2 / neu, to give rise to activated heterodimers and / or to form clusters of activated forms of EGFR.

[0018] As used herein, the term "EGFR inhibitor" refers to any EGFR inhibitor currently known in the art or to be identified in the future, and includes any chemical entity that, when administered to a patient, inhibits biological activities associated with EGFR activation in a patient, including any downstream biological effects resulting from the binding of a natural ligand to EGFR. Such EGFR inhibitors include any agent capable of blocking EGFR activation or any downstream biological effects of EGFR activation. Such inhibitors can act by directly binding to the intracellular domain of the receptor and inhibiting its kinase activity. Alternatively, such inhibitors may act by occupying the ligand-binding site or a portion thereof of the EGFR receptor, thereby rendering the receptor inaccessible to its natural ligand and thereby preventing or reducing its normal biological activity. Alternatively, such inhibitors may act by modulating the dimerization of EGFR polypeptides or the interaction of EGFR polypeptides with other proteins. EGFR inhibitors also include inhibitors of the EGFR activation and signaling pathway, and in particular include inhibitors of ADAM17 and TGFβ, since these proteins act as components of the EGFR (trans)activation pathway.

[0019] EGFR inhibitors are well known in the art and include, for example, quinazoline EGFR inhibitors, pyrido-pyrimidine EGFR inhibitors, pyrimido-pyrimidine EGFR inhibitors, pyrrolo-pyrimidine EGFR inhibitors, pyrazolo-pyrimidine EGFR inhibitors, phenylamino-pyrimidine EGFR inhibitors, oxindole EGFR inhibitors, indolocarbazole EGFR inhibitors, phthalazine EGFR inhibitors, isoforms, Flavone EGFR inhibitors, quinalone EGFR inhibitors, and tyrphostin EGFR inhibitors, including those described in the following patent publications, and all pharma- ceutically acceptable salts and solvates of said EGFR inhibitors: WO 96 / 33980, WO 96 / 30347, WO 97 / 30034, WO 97 / 30044, WO 97 / 38994, WO 97 / 49688, WO 98 / 02434, WO 97 / 38983, WO 97 / 38984, WO 97 / 38995, WO 97 / 49688, WO 98 / 02434, WO 97 / 38985, WO 97 / 38986, WO 97 / 38988, WO 97 / 38989, WO 97 / 38999, WO 97 / 49688, WO 98 / 02434, WO 97 / 38983, WO 97 / 38987, WO 97 / 389 ... 95 / 19774, 95 / 19970, 97 / 13771, 98 / 02437, 98 / 02438, 97 / 32881, 98 / 33798, 97 / 32880, 97 / 3288, 97 / 02266, 97 / 27199, 98 / 07726, 97 / 34895, 96 / 31510, 98 / 14449, 98 / 14450, 98 / 14451, 95 / 0984 7, 97 / 19065, 98 / 17662, 99 / 35146, 99 / 35132, 99 / 07701, and 92 / 20642; European Patent Applications Nos. 520722, 566226, 787772, 837063, and 682027; U.S. Patent Nos. 5,747,498, 5,789,427, 5,650,415, and 5,656,643; and German Patent Application No. 19629652. Additional non-limiting examples of low molecular weight EGFR inhibitors include any of the EGFR inhibitors described in Traxler, P (1998) and Al-Obeidi FA et al. (2000).

[0020] In some embodiments, the EGFR inhibitor of the present invention is selected from the group consisting of brigatinib, erlotinib, gefitinib, icotinib, lapatinib, sapitinib, vandetanib, varlitinib, afatinib, canertinib, dacomitinib, neratinib, osimertinib, pelitinib, and rociletinib.

[0021] In some embodiments, the EGFR inhibitor of the present invention is erlotinib (6,7-bis(2-methoxyethoxy)-4-quinazolin-4-yl]-(3-ethynylphenyl)amine) (U.S. Pat. No. 5,747,498; WO 01 / 34574, and Moyer JD. et al. (1997)). Erlotinib has the formula: [ka] It has the structure:

[0022] In some embodiments, the EGFR inhibitor of the present invention is gefitinib (also known as ZD1839 or IRESSA®; Astrazeneca) (Woodburn et al., 1997, Proc. Am. Assoc. Cancer Res. 38:633). The compound disclosed in WO 96 / 33980 (Example 1) has the formula: [ka] It has the structure:

[0023] In another embodiment, the EGFR inhibitor may consist of an antibody or antibody fragment capable of partially or completely blocking EGFR activation by HB-EGF. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253;Teramoto, T., et al., 1996, Cancer 77:639-645;Goldstein et al., 1995, Clin.Cancer Res. 1:1311-1318;Huang, SM, et al., 1999, Cancer Res. 15:59(8):1935-40;and Yang, X., et al., 1999, Cancer Res.59:1236-1243. Thus, the EGFR inhibitor may be the monoclonal antibody Mab E7.6.3 (Yang, XD et al. (1999)) or Mab C225 (ATCC Accession No. HB-8508, U.S. Patent No. 4,943,533), or an antibody or antibody fragment having these binding specificities. Suitable monoclonal antibody EGFR inhibitors include, but are not limited to, IMC-C225 (also known as cetuximab or ERBITUX™; Imclone Systems), ABX-EGF (Abgenix), EMD 72000 (Merck KgaA, Darmstadt), RH3 (York Medical Bioscience Inc), and MDX-447 (Medarex / Merck KgaA).

[0024] As used herein, the term "ADAM17" or "TACE" has its general meaning in the art and refers to a protein having an amino acid sequence substantially identical to any of the representative TACE sequences in GenBank Accession Nos. NP_003174.3 (human), NP_033745.4 (mouse), and NP_064702.1 (rat). Suitable cDNAs encoding TACE are provided in GenBank Accession Nos. NM_003183.4 (human), NM_009615.5 (mouse), and NM_020306.1 (rat).ADAM17 inhibitors are well known in the art and are typically described in WO2012005229, WO0012467, WO0012478, WO035885, WO044709, WO0044710, WO0044711, WO044713, WO044716, WO044723, WO044730, WO044740, WO044749, WO046189, WO046221, WO056704, WO059285, WO069812, WO00 No. 69819, No. 0069821, No. 0069822, No. 0069827, No. 0069839, No. 0071514, No. 0075108, No. 0112592, No. 0122952, No. 0130360, No. 0144189, No. 01551 No. 12, No. 0160820, No. 0162733, No. 0162742, No. 0162750, No. 0162751, No. 0 No. 170673, No. 0170734, No. 0185680, No. 0187870, No. 0187883, No. 0204416 , No. 0206215, No. 9005719, No. 9402447, No. 9504715, No. 9506031, No. 9633 No. 166, No. 9633167, No. 9633968, No. 9702239, No. 9718188, No. 9718207, No. 9719050, 9719053, 9720824, 9724117, 9742168, 9743249 No. 9743250, No. 9749674, No. 9807742, No. 9816503, No. 9816506, No. 981 6514, 9816520, 9830541, 9830551, 9832748, 9837877, 9838163, 9838179, 9839326, 9843963, 9851665, 9855449, 9902510, 9903878, 9906410, 9918076, 9931052, 9937625, 9910080, 9942436, 9958531, and 9961412.

[0025] In some embodiments, the ADAM17 inhibitor is selected from the group consisting of W-3646, Ro-32-7315, GW-3333, aplatastat, or (3S)-N-hydroxy-4[[4[(4-hydroxybut-2-ynyl)oxy]phenyl]sulfonyl]-2,2-dimethylthiomorpholine-3-carboxamide, GW-4459, CGS-33090A, DPC-333, TNF-484, WTACE2, SP-057, SL-422, FYK-1388, and KB-R7785. Also of advantage are the following ADAM17 inhibitors: 3-[3-[N-isopropyl-N-(4-methoxyphenylsulfonyl)amino]phenyl]-3-(3-pyridyl)-2(E)-propenohydroxamic acid, (2R,3S)-3-(formylhydroxyamino)-4-methyl-2-(2-methylpropyl)-N-[(1S,2S)-2-methyl-1-[(2-pyridinylamino)carbonyl]butyl]pentanamide, (2R,3S)-3-(formylhydroxyamino)-N-[(1S) -4-[[imino(nitroamino)methyl]amino]-1-[(2-thiazolylamino)carbonyl]butyl]-2-(2-methylpropyl)hexanamide, (αR,1α,4β)-α-[[(4-ethoxyphenyl)sulfonyl](4-pyridinylmethyl)amino]-N-hydroxy-4-propoxycyclohexaneacetamide, and (αR)-N-hydroxy-α,3-dimethyl-2-oxo-3-[4-(2-methyl-4-quinolinylmethoxy)phenyl]-1-pyrrolidineacetamide. Another example includes BMS566394.

[0026] By "therapeutically effective amount" is meant an amount of EGFR inhibitor sufficient to treat Olmsted syndrome at a reasonable benefit / risk ratio applicable to any medical treatment. It will be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex, and diet of the subject; the time of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or simultaneously with the specific polypeptide used; and similar factors well known in the medical art. For example, it is well within the skill of the art to start with a dose of the compound at a level lower than that required to achieve the desired therapeutic effect, and then gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the product may vary over a wide range, from 0.01 to 1,000 mg per adult per day. Typically, the composition contains 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250, and 500 mg of the agent, so that the dosage for the subject being treated can be symptomatically adjusted. The medicament typically contains about 0.01 mg to about 500 mg of the agent, preferably 1 mg to about 100 mg of the agent. An effective amount of the drug is usually supplied at a dosage level of about 0.0002 mg / kg (body weight) to about 20 mg / kg (body weight) per day, particularly about 0.001 mg / kg (body weight) to 7 mg / kg (body weight) per day.

[0027] Typically, the EGFR inhibitors of the present invention are combined with pharma- ceutically acceptable excipients and, optionally, sustained release matrices such as biodegradable polymers to form pharmaceutical compositions. The term "pharmaceutical" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to mammals, particularly humans, as appropriate. A pharma- ceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation auxiliary of any kind. The carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils.

[0028] In some embodiments, it may be desirable to administer the EGFR inhibitor of the present invention in a topical formulation. As used herein, the term "topical formulation" refers to a formulation that can be applied to the skin. Topical formulations can be used for both topical and transdermal administration of a substance. As used herein, "topical administration" is used in its conventional sense to mean delivery of a substance, such as a therapeutically active agent, to a localized area of ​​the skin or body of a subject. As used herein, "transdermal administration" refers to administration through the skin. Transdermal administration is often applied when systemic delivery of an active substance is desired, but is also useful for delivering active substances to tissues underlying the skin with minimal systemic absorption. Typically, a topical pharmacologic acceptable carrier is any substantially non-toxic carrier that can be conventionally used for topical administration of pharmaceuticals, in which the EGFR inhibitor of the present invention remains stable and bioavailable when applied directly to the skin surface. For example, carriers such as those known in the art that are effective in penetrating the keratin layer of the skin to the stratum corneum may be useful for delivering the EGFR inhibitor of the present invention to the area of ​​interest. Such carriers include liposomes. The EGFR inhibitors of the present invention can be dispersed or emulsified in a medium in a conventional manner to form liquid preparations, or can be mixed with semi-solid (gel) or solid carriers to form pastes, powders, ointments, creams, lotions, etc. Suitable topical pharmacopoeia acceptable carriers include water, buffered saline, petroleum jelly (petrolatum), petrolatum, mineral oil, vegetable oil, animal oil, organic and inorganic waxes, such as microcrystalline, paraffin, and ozokerite wax, natural polymers, such as xanthan, gelatin, cellulose, collagen, starch, or gum arabic, synthetic polymers, alcohols, polyols, etc. The carrier can be a water-miscible carrier composition. Such water-miscible topical pharmacopoeia acceptable carrier compositions can include those that are made with one or more suitable components at the start of treatment. An acceptable carrier for topical use is any substantially non-toxic carrier that can be conventionally used for topical administration in which the EGFR inhibitors of the present invention remain stable and bioavailable when applied directly to the skin surface.Suitable cosmetically acceptable carriers are known to those skilled in the art and include, but are not limited to, cosmetically acceptable liquids, creams, oils, lotions, ointments, gels, or solids, such as conventional cosmetic night creams, foundation creams, tanning lotions, sunscreens, hand lotions, make-up and make-up bases, masks, etc. Any suitable carrier or vehicle effective for topical administration to a patient as known in the art can be used, such as cream bases, creams, liniments, gels, lotions, ointments, foams, solutions, suspensions, emulsions, pastes, aqueous mixtures, sprays, aerosolized mixtures, oils such as Crisco®, soft soaps, and any other preparations pharma- ceutical suitable for topical administration to a body surface of a human and / or animal, such as the skin or mucous membranes. The topical acceptable carrier may have similar or identical properties to the topical pharma- ceutical acceptable carriers described above. To increase the contact time of the EGFR inhibitor of the present invention on the skin, it may be desirable to have a delivery system that controls the release of the EGFR inhibitor of the present invention on the skin and adheres to or maintains itself on the skin for an extended period of time. The sustained or delayed release of the EGFR inhibitor of the present invention provides more efficient administration, reducing the frequency and / or dosage of the EGFR inhibitor of the present invention, and provides better patient compliance. Examples of carriers suitable for sustained or delayed release in moist environments include gelatin, gum arabic, and xanthan polymers. Pharmaceutical carriers capable of releasing the EGFR inhibitors of the present invention upon exposure to any oily, greasy, waxy, or moist environment in the area to be treated include thermoplastic or flexible thermoset resins or elastomers including thermoplastic resins such as polyvinylhalides, polyvinyl esters, polyvinylidene halides, and halogenated polyolefins, elastomers such as brasiliensis, polydienes, and halogenated natural and synthetic rubbers, and flexible thermoset resins such as polyurethanes, epoxy resins, and the like.Controlled delivery systems are described, for example, in U.S. Patent No. 5,427,778, which provides gel formulations and viscous solutions for delivering the EGFR inhibitors of the present invention to skin sites. Gels have the advantages of having a high water content to keep the skin moist, having the ability to absorb skin exudates, being easy to apply, and being easily removed by washing. Preferably, the sustained or delayed release carrier is a gel, a liposome, a microsponge, or a microsphere. The EGFR inhibitors of the present invention can also be administered in combination with other pharma- ceutically active agents, including, but not limited to, antibiotics, other skin healing agents, and antioxidants. In some embodiments, the topical formulations of the present invention include a penetration enhancer. As used herein, "penetration enhancer" refers to an agent that improves the transport of molecules, such as active agents (e.g., drugs), into or through the skin. A variety of pathological conditions can occur at different sites in the body, either within the skin or subcutaneously, creating a need to target the delivery of compounds. Thus, "penetration enhancers" can be used to aid in the delivery of an active agent directly to the skin or underlying tissue, or indirectly to the site of a disease or symptom thereof via systemic distribution. Penetration enhancers may be pure substances or may comprise mixtures of different chemical entities.

[0029] The present invention is further illustrated by the following figures and examples, which should not, however, be construed as limiting the scope of the present invention in any manner.

[0030] Working Example: Olmsted syndrome (OS) is a heterogeneous genetic dermatosis characterized primarily by palmoplantar keratosis (PPK) accompanied by additional features such as severe pain at the sites of hyperkeratosis. Since 2012, gain-of-function mutations in the TRPV3 (transient receptor potential vanilloid-3) gene have been reported as the cause of OS (Wilson, Neil J., et al. "Expanding the phenotypic spectrum of Olmsted syndrome." The Journal of investigative dermatology 135.11 (2015): 2879.). Although the association between TRPV3 mutations and clinical symptoms had not been established, a study by Cheng et al. (Cheng, Xiping, et al. "TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation." Cell 141.2 (2010): 331-343.) demonstrated that TRPV3 signaling, which operates as a Ca2+-permeable nonselective cation channel, is mediated by EGFR transactivation in mouse and human keratinocytes and amplified by positive feedback. A clue to this discovery was the phenotype of non-conditional or keratinocyte-targeted TRPV3 knockout mice, which display a curly beard and perm hair phenotype similar to waved-1 and waved-2 mutants that have previously been shown to result from hypomorphic mutations in TGF-α and EGFR (Schneider, Marlon R., et al. "Beyond wavy hairs: the epidermal growth factor receptor and its ligands in skin biology and pathology." The American journal of pathology 173.1 (2008): 14-24.).Although the role of EGFR in skin biology is complex, the phenotype observed in EGFR and TGF-α transgenic mice indicates that EGFR plays an important role in keratinocyte proliferation and differentiation and, more generally, in skin homeostasis (Schneider, Marlon R., et al. "Beyond wavy hairs: the epidermal growth factor receptor and its ligands in skin biology and pathology." The American journal of pathology 173.1 (2008): 14-24.). Indeed, pathological examination of skin biopsies from OS patients showed that all epidermal cell compartments were amplified and that EGFR expression expanded with thickening of the stratum corneum, consistent with a role for EGFR in stimulating transglutaminase in suprabasal cells. This led us to propose the use of the EGFR inhibitor erlotinib for the treatment of three OS patients already reported to have clinical symptoms and TRPV3 mutations, with the aim of breaking the vicious cycle initiated by constitutive activation of TRPV3.

[0031] Patients 1 and 2 are two siblings, aged 18 and 15, with the recessive mutations p.Gly568Cys and p.Gln216_Gly262del (Duchatelet, Sabine, et al. "Olmsted syndrome with erythromelalgia caused by recessive transient receptor potential vanilloid 3 mutations." British Journal of Dermatology 171.3 (2014): 675-678), and patient 3 is a 14-year-old girl with the dominant heterozygous missense mutation p.Leu673Phe (Duchatelet, Sabine, et al. "A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia." JAMA dermatology 150.3 (2014): 303-306.). Patients 1 and 3 had severe asymmetric PPK (only the plantar part in patient 1) with erythrodynia refractory to analgesics and had used cooling techniques such as ice application and prolonged foot immersion in cold water to relieve symptoms, resulting in immersion injury with ulceration and infection due to maceration of the skin. The combination of skin symptoms and progressive foot deformity had rendered the patient wheelchair-bound since the age of 3. Patient 2 had mild PPK with less severe erythrodynia.

[0032] Erlotinib was started at 100 mg in patients 1 and 2 and 50 mg in patient 3, depending on weight and height. The dose was immediately reduced to 50 mg in patient 2 because of abdominal pain and nausea. The dose was adjusted on days 30 and 60 in relation to plasma concentration, tolerability, and efficacy. Rapid pain relief was observed within a few days in patients 1 and 2, and later in patient 3, and was completely resolved after 3 months, and analgesics were spontaneously discontinued. The keratoderma gradually disappeared, and regression was complete by day 30 in patient 2 and by day 90 in patients 1 and 3. The pain relief associated with the areas of hyperkeratosis suggests that mediators secreted by abnormal keratinocytes may trigger nociceptive neuronal receptors present in the skin, the nature of which has not yet been identified. The only persistent side effect of erlotinib was a moderate acne reaction in patient 1.

[0033] Patients must be maintained on erlotinib treatment continuously, but not at the lowest dose that maintains remission, as its long-term effects, especially in developing children, are not well understood. Because the biology of abnormal keratinocytes differs from that of malignant cells, which usually result from aggressive growth characteristics and the accumulation of mutations that endow cells with defects in DNA repair and apoptosis, resistance to treatment as observed in oncology is not expected to occur in these patients.

[0034] In conclusion, the dramatic improvements in three patients demonstrate that erlotinib is a first-line, efficient treatment for OS and support the hypothesis that EGFR signaling is a key mediator of symptoms caused by gain-of-function mutations in TRPV3.

[0035] References: Throughout this application, various references describe the state of the art to which this invention pertains, the disclosures of which are incorporated by reference into this disclosure.

Claims

1. 20. A method of treating keratoderma in a patient in need thereof comprising administering to the patient a therapeutically effective amount of an EGFR inhibitor.

2. The method of claim 1 , wherein the patient is suffering from palmoplantar keratosis.

3. The patient has diffuse palmoplantar keratosis (e.g., diffuse epidermolytic palmoplantar keratosis, diffuse non-epidermolytic palmoplantar keratosis, Meleda's disease), localized palmoplantar keratosis (e.g., linear palmoplantar keratosis), punctate palmoplantar keratosis (e.g., KPPP (keratosis punctata palmaris et al. plantaris), squamous keratosis, focal acral hyperkeratosis), diffuse palmoplantar keratosis (e.g., fluctuating erythrokeratoderma, Sybert palmoplantar keratosis, Olmsted syndrome, and Naegeli-Franceschetti-Jadassohn syndrome), focal palmoplantar keratosis (e.g., Papillon-Lefevre syndrome, pachyonychia congenita type I, pachyonychia congenita type II, focal palmoplantar keratosis with oral mucosal hyperkeratosis, and Kamisa disease), ectodermal dysplasia (Clauston's hidrotic ectodermal dysplasia, acral keratosis, and reticular pigmented dermatosis), syndromic keratosis (e.g., Vorwinkel's syndrome, palmoplantar keratosis associated with esophageal cancer, palmoplantar keratosis and spastic paraplegia, Naxos disease, linear palmoplantar keratosis, trichotillomania, and left ventricular dilated cardiomyopathy, keratitis-ichthyosis-deafness syndrome, Corneodermatosseoous syndrome, Huriez syndrome, oculocutaneous tyrosinemia, cardio-facio-cutaneous syndrome, and Schepf-Schultz-Passalge syndrome).

4. The method of claim 1 , wherein the patient is suffering from Olmsted Syndrome.

5. 2. The method of claim 1, wherein the patient has at least one TRPV3 mutation, such as p. G568C, p. G573S, p. G573C, p. L673F, p. W692G, and a recessive mutation, such as p. Gln216_Gly262del.

6. 2. The method of claim 1, wherein the patient is under 20 years of age, or under 18 years of age, or under 15 years of age.

7. The method of claim 1 , wherein the patient is also suffering from erythromelalgia.

8. 2. The method of claim 1, wherein the EGFR inhibitor is selected from the group consisting of brigatinib, erlotinib, gefitinib, icotinib, lapatinib, sapitinib, vandetanib, varlitinib, afatinib, canertinib, dacomitinib, neratinib, osimertinib, pelitinib, and rociletinib.

9. The method of claim 1 , wherein the EGFR inhibitor is erlotinib.

10. The method of claim 1 , wherein the EGFR inhibitor is an inhibitor of the EGFR activation and signaling pathway.

11. The method of claim 10, wherein the inhibitor of the EGFR activation and signaling pathway is selected from an ADAM17 inhibitor or a TGFα inhibitor.

12. The method of claim 1 , wherein the EGFR inhibitor is administered to the patient in a topical formulation.

Images