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WO2025101692A1 - Méthodes et compositions pour le traitement d'anomalies vasculaires - Google Patents

Méthodes et compositions pour le traitement d'anomalies vasculaires Download PDF

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WO2025101692A1
WO2025101692A1 PCT/US2024/054845 US2024054845W WO2025101692A1 WO 2025101692 A1 WO2025101692 A1 WO 2025101692A1 US 2024054845 W US2024054845 W US 2024054845W WO 2025101692 A1 WO2025101692 A1 WO 2025101692A1
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inhibitor
composition
subject
kit
combination
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Joyce E. Bischoff
Annegret HOLM
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Boston Childrens Hospital
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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

Definitions

  • the technology described herein relates to the treatment of vascular anomalies, e.g., infantile hemangioma.
  • Vascular anomalies can result in malformed vasculature or proliferation of vascular tumors, sometimes causing a serious threat to a patient’s health, as well as aesthetic concerns dependent upon location.
  • infantile hemangioma IH is a common childhood tumor composed of disorganized blood vessels and immature cells. IH results from a disruption of neonatal vasculogenesis, de novo formation of vessels from progenitor cells, angiogenesis, and a sprouting of new vessels from pre-existing vasculature.
  • IH infantile hemangioma
  • Propranolol was introduced as atreatment for IH (Leaute- Labreze et al., NEJM 2008 358:2649-2651; Siegfried et al., NEJM 2008 359:2846; and Leaute-Labreze et al., NEJM 2015 372:735-46 (PMID 25693013)).
  • IH Leaute- Labreze et al., NEJM 2008 358:2649-2651; Siegfried et al., NEJM 2008 359:2846; and Leaute-Labreze et al., NEJM 2015 372:735-46 (PMID 25693013).
  • Concerning side effects of propranolol are due to its antagonistic effect on [3-adrenergic receptors and include sleep
  • the technology described herein is directed to methods and compositions relating to the treatment of vascaular anomalies, e.g. hemangiomas. Aspects of the technology described herein are based on the inventors’ discovery that famesyltransferase and/or geranylgeranyltransferas inhibitors target pathways controlling the differentiation of hemangioma-derived stem cells. [0006] In one aspect of any of the embodiments, described herein is a method of treating a vascular anomaly in a subject in need thereof, the method comprising administering a composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor to the subject.
  • a combination or kit comprising: at least one famesyltransferase inhibitor and/or at least one geranylgeranyltransferase inhibitor; and at least one statin; beta-blocker, mTOR inhibitor, and/or steroid.
  • a combination or kit comprising: at least one famesyltransferase inhibitor and/or at least one geranylgeranyltransferase inhibitor; and at least one statin, beta-blocker, mTOR inhibitor, and/or steroid; for use in treating a vascular anomaly.
  • composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyltranserase inhibitor, for use in treating a vascular anomaly.
  • the famesyltransferase inhibitor is selected from the group consisting of: tipifamib; lonafamib; LNK-754; chaetomellic acid; clarvaric acid; FPT Inhibitor I (sc-221625); FPT Inhibitor II (sc-221626); FPT Inhibitor III (sc-221627); FTase Inhibitor I (sc-221632); FTase Inhibitor II (sc-221633), FTI-276; FTI-277; FGTI-2734; GGTI-297; L-744,832; manumycin A; gingerol; gliotoxin; and alpha-hydrozy famesyl phosphonic acid.
  • the famesyltransferase inhibitor is tipifamib. In some embodiments of any of the aspects, the famesyltransferase inhibitor is lonfamib. In some embodiments of any of the aspects, the geranylgeranyltransferase inhibitor is selected from the group consisting of: GGTI-2418; and FGTI- 2734.
  • the vascular anomaly is selected from the group consisting of: infantile hemangioma, congenital hemangioma, pyogenic granuloma, tufted angioma, kaposiform hemangioendothelioma, epitheloid hemangioendothelioma (EHE), capillary malformations, arteriovenous malformations, venous malformations, lymphatic malformations, complex lymphatic malformations, generalized lymphatic anomaly, central conducting lymphatic anomaly, kaposiform lymphangiomatosis, and Gorham-Stout disease.
  • the vascular anomaly is infantile hemangioma.
  • the subject is further administered at least one statin, beta-blocker, mTOR inhibitor, and/or steroid.
  • the statin is selected from the group consisting of: simvastatin; atorvastatin; cerivastatin; fluvastatin; lovastatin; mevastatin; pitavastatin; pravastatin; and rosuvastatin.
  • the statin is simvastatin.
  • the statin is atorvastatin.
  • the beta-blocker is selected from the group consisting of: R+ atenolol; atenolol; nadolol; propranolol; R+propranolol; and timolol.
  • the beta-blocker is selected from the group consisting of: R+ atenolol; atenolol; propranolol; R+propranolol, and timolol. In some embodiments of any of the aspects, the beta-blocker is selected from the group consisting of: R+ atenolol; atenolol; propranolol; and R+propranolol. In some embodiments of any of the aspects, the beta-blocker is R+ propranolol. In some embodiments of any of the aspects, the mTOR inhibitor is selected from the group consisting of: sirolimus; everolimus; temisrolimus; and rapamycin.
  • the mTOR inhibitor is rapamycin.
  • the steroid is a corticosteroid.
  • the corticosteroid is selected from the group consisting of: dexamethasone; prednisone; prednisolone; triamcinolone; clobetasol propionate; betamethasone valerate; betamethasone dipropionate; and mometasone furoate.
  • the combination, kit, or composition of one of the preceding claims is formulated for oral administration. In some embodiments of any of the aspects, the combination, kit, or composition of one of the preceding claims is a syrup or suspension.
  • Figs. 1A-1D demonstrate that tipifamib inhibits vessel formation in a murine xenograft model for infantile hemangioma.
  • Hemangioma-derived stem cells designated as HemSC 149 were pretreated with 100 nM tipifamib or 0.0025% DMSO in PBS for 24 hours, suspended in Matrigel with 50 nM tipifamib and an equivalent DMSO concentration (0.005%) and injected into nude mice with 2 implants/mouse. The mice were treated with 0.4, 2, 10, and 50 mg/kg/d tipifamib with a maximum concentration of 6.2% DMSO twice a day for 7 days as depicted in the schematic.
  • Fig. 1A Hemangioma-derived stem cells
  • Fig. ID Schematic of the mevalonate pathway and its inhibitors, statins and tipifamib (gray).
  • Figs. 1E-1J demonstrate that the prenylation inhibitors Tipifamib (famesyltransferase inhibitor) and GTI-2418 (geranylgeranyltransferase inhibitor) inhibit blood vessel formation in a xenograft model of infantile hemangioma (IH).
  • Fig. IE depicts a schematic of infantile hemangioma (IH) xenograft model.
  • HemSC isolated from IH patient were pre-treated with 100 nM tipifamib or GGTI-2418 or vehicle (0.001% DMSO), suspended in Matrigel with 50 nM tipifamib or GGTI-2418 (0.0005% DMSO), and injected subcutaneously into nude mice, with 2 implants/mouse. Mice were treated with 0.001 - 10 mg/kg/d tipifamib or GGTI-2418 twice a day via intraperitoneal injections.
  • Fig. IF depicts Matrigel implants harvested after 7 days of tipifamib treatment (top right) compared to vehicle treatment (top left). H&E staining indicates reduction of blood vessels in Tipifamib treated (middle right) compared to control mice (middle left). Immunofluore scent antihuman CD31 staining (dark gray) confirmed reduced human vessel formation in tipifamib-treated mice (bottom right) compared to controls (bottom left). Images from the GGTI-2418 -treated mice were similar (data not shown). Cell nuclei were stained with DAPI (light gray). Scale bars 100 pm.
  • Fig. 1G shows quantification of human CD31 positive vessels/mm2 in a dose response experiment ranging from 0.001 - 10 mg/kg/d.
  • the results show a significant reduction in vessel density in the implants of tipifamib-treated mice compared to control mice. Tipifamib achieved a significant inhibition of vessel formation at 0.001 mg/kg/day.
  • P values were calculated using one-way ANOVA and the Tukey’s multiple comparison test. Data are shown as mean ⁇ SD.
  • Fig. 1H shows quantification of human CD31 positive vessels/mm2 in a dose response experiment ranging from 0.001 - 10 mg/kg/d.
  • the results show a significant reduction in vessel density in the implants of GGTI-2418-treated mice compared to control mice.
  • GGTI-2418 achieved a significant inhibition of vessel formation at of 0.001 mg/kg/day.
  • P values were calculated using oneway ANOVA and the Tukey’s multiple comparison test. Data are shown as mean ⁇ SD.
  • Fig. II depicts the body weight change in percent versus day of treatment at all drug doses of Tipifamib compared to the control (vehicle).
  • Fig. 1 J depicts the body weight change in percent versus day of treatment at all drug doses of GTI-2418 compared to the control (vehicle).
  • famesyltransferase inhibitors and geranylgeranyl inhibitors are surprisingly efficacious in blocking hemangioma vessel formation. This finding was demonstrated in infantile hemangioma, but the inventors pose that famesyltransferase inhibitors and geranylgeranyl inhibitors will provide therapeutic effect in other types of vascular anomalies in which activation of proteins by prenylation, such as Ras family of small GTPases, is involved.
  • a method of treating a vascular anomaly in a subject in need thereof comprising administering a composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor to the subject.
  • a composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor to the subject.
  • at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor for use in a method of treating a vascular anomaly.
  • Vascular anomalies comprise a wide spectrum of rare disorders that are attributed to focal disruption in vascular development processes and are classified according to the International Society for the Study of Vascular Anomalies (ISSVA). See, e.g., the ISSVA Classification of Vascular Anomalies 2018 International Society for the Study of Vascular Anomalies Available on the world wide web at issva.org/classification; which is incorporated by reference herein in its entirety.
  • ISSVA International Society for the Study of Vascular Anomalies
  • Two distinct entities are differentiated: vascular tumors and vascular malformations.
  • Vascular tumors are further subdivided into benign, locally aggressive, and malignant tumors.
  • Vascular malformations can occur in each vessel type and are thus classified into capillary, venous, arteriovenous, and lymphatic malformations.
  • vascular anomalies include, but are not limited to infantile hemangioma, congenital hemangioma, pyogenic granuloma, tufted angioma, kaposiform hemangioendothelioma, epitheloid hemangioendothelioma (EHE), capillary malformations, arteriovenous malformations, venous malformations, lymphatic malformations, and complex lymphatic malformations (generalized lymphatic anomaly, central conducting lymphatic anomaly, kaposiform lymphangiomatosis and Gorham-Stout disease).
  • EHE epitheloid hemangioendothelioma
  • capillary malformations arteriovenous malformations, venous malformations, lymphatic malformations, and complex lymphatic malformations (generalized lymphatic anomaly, central conducting lymphatic anomaly, kaposiform lymphangiomatosis and Gorham-Stout disease).
  • the diagnosis and biology of hemangiomas are well known
  • vascular anomalies are vacular tumors or vascular malformations.
  • Vascular malformations are disorders in which the vasculature is improperly formed, resulting in discolored areas, lesions, masses and benign growths that can be locally aggressive (e.g., arteriovenous malformations) or even malignant (e.g., angiosarcoma), and lesions.
  • vascular malformations can be proliferative vascular disorders.
  • Non-limiting examples of vascular malformations include slow-flow vascular malformations (e.g. capillary malformation, venous malformation, and lymphatic malformation), fast-flow vascular malformations (e.g.
  • vascular anomalies are often treated with targeted medical therapy (ideally based on genetic results of an underlying mutation - “theranostics”), surgical reduction, sclerotherapy and laser, alone or in combination.
  • vascular anomalies can be a hemangioma or vascular tumor.
  • hemangioma refers to a benign, usually self-involuting tumor of the endothelial cells of blood vessels.
  • a hemangioma can comprise an increased number of blood vessels and/or capillaries.
  • the vessels and/or capillaries can comprise blood and be connected to the circulatory system.
  • Hemangiomas can occur anywhere in the body, but are typically found in or on the skin, particularly on the face and neck, or in the liver. Hemangiomas can form in utero (e.g. congenital hemangioma) or after birth. Most hemangiomas appear within a few months of birth.
  • hemangioma examples include, but are not limited to: infantile hemangioma, congenital hemangioma, kaposiform hemangioendothelioma, infant syndromed hemangioma (“strawberry naevus”), senile hemangioma (“cherry hemangioma”), arteriovenous hemangioma (“cirsoid aneurysm”), and verrucous hemangioma.
  • the diagnosis and treatment of hemangiomas is well known in the art and has been described, for example, in Mulliken, JB; Glowacki, J. Plastic and reconstructive surgery 1982 69 (3): 412-22; Greene, AK.
  • Hemangiomas affecting the skin can be diagnosed by visual examination.
  • Other approaches that can aid a physician in detecting and/or diagnosing hemangioma can include ultrasound, MRI, and/or a biopsy.
  • Hemangiomas can be distinguished from numerous similar conditions by immunohistochemical staining for, e.g. GLUT-1.
  • Markers and symptoms of proliferative vascular disorders, e.g. hemangioma can include, but are not limited to tumors of the endothelial cells of blood vessels; an increased number of blood vessels and/or capillaries; discoloration of the skin; GLUT-1 expression; hemosiderin pigmentation; ulceration; and bleeding.
  • hemangiomas While many hemangiomas will regress without medical intervention, the location and extent of some cases can be harmful or dangerous to the subject’s health, e.g. interfere with breathing or vision, or induce bone erosion, high-output heart failure, ulceration, and/or raise the possibility of significant cosmetic injury.
  • Symptoms and complications of hemangioma can include, but are not limited to, ulcerations (break down of the hemangioma), bleeding, occlusion, amblyopia (if the hemangioma is near or in the eye), psychosocial complications, alteration of the subject’s appearance, attention and malicious reactions from others, and PHACES syndrome (in the case of segmented hemangiomas of the head and neck).
  • Treatments for hemangioma can include, but are not limited to, oral or topical beta blockers as first line therapy, oral corticosteroid or sirolimus therapy, and surgical removal as well as laser therapy.
  • Hemangiomas of the vertebrae are typically treated with radiation, surgical removal, and/or embolization.
  • the methods and compositions described herein can be combined with any known treatment for hemangioma.
  • FPP famesyl pyrophosphate
  • FTase famesyltransferase
  • Exemplary famesyltransferase inhibitors include tipifamib; lonafamib; LNK-754; chaetomellic acid; clarvaric acid; FPT Inhibitor I (sc-221625); FPT Inhibitor II (sc-221626); FPT Inhibitor III (sc-221627); FTase Inhibitor I (sc-221632); FTase Inhibitor II (sc-221633), FTI-276; FTI-277; FGTI-2734; GGTI-297; L-744,832; manumycin A; gingerol; gliotoxin; and alpha-hydrozy famesyl phosphonic acid.
  • the famesyltransferase inhibitor is tipifamib. In some embodiments of any of the aspects, the at least one famesyltransferase inhibitor comprises tipifamib. In some embodiments of any of the aspects, the at least one famesyltransferase inhibitor consists of tipifamib. In some embodiments of any of the aspects, the at least one famesyltransferase inhibitor consists essentially of tipifamib.
  • the famesyltransferase inhibitor is lonfamib. In some embodiments of any of the aspects, the at least one famesyltransferase inhibitor comprises lonfamib. In some embodiments of any of the aspects, the at least one famesyltransferase inhibitor consists of lonfamib. In some embodiments of any of the aspects, the at least one famesyltransferase inhibitor consists essentially of lonfamib.
  • geranylgeranyltransferase inhibitor refers to refers to an agent that reduces the rate and/or amount of tranfer of a geranylgeranyl group to pre-Ras by geranylgeranyltransferase (GGTase). This reduces the isoprenylation of Ras, which is necessary for signal transduction through Ras.
  • exemplary geranylgeranyltransferase inhibitors include GGTI-2418; and FGTI-2734.
  • the subject is administered at least one famesyltransferase inhibitor. In some embodiments of any of the aspects, the subject is administered at least one geranylgeranyltransferase inhibitor. In some embodiments of any of the aspects, the subject is administered at least one famesyltransferase inhibitor and at least one geranylgeranyltransferase inhibitor. In some embodiments of any of the aspects, the subject is administered at least one famesyltransferase inhibitor and is not administered a geranylgeranyltransferase inhibitor. In some embodiments of any of the aspects, the subject is administered at least one geranylgeranyltransferase inhibitor and is not administered a famesyltransferase inhibitor.
  • the subject is further administered at least one statin, beta-blocker, mTOR inhibitor, and/or steroid.
  • statins refers to a class of drugs also known as HGM-CoA reductase inhibitors that are known to lower cholesterol. Statins are well known in the art. In some embodiments of any of the aspects, the at least one statin is selected from the group consisting of simvastatin; atorvastatin; cerivastatin; fluvastatin; lovastatin; mevastatin; pitavastatin; pravastatin; and rosuvastatin.
  • the at least one statin is selected from the group consisting of simvastatin; atorvastatin; fluvastatin; lovastatin; mevastatin; pitavastatin; pravastatin; and rosuvastatin.
  • the at least one statin comprises simvastatin. In some embodiments of any of the aspects, the at least one statin comprises atorvastatin. In some embodiments of any of the aspects, the at least one statin comprises fluvastatin. In some embodiments of any of the aspects, the at least one statin comprises lovastatin. In some embodiments of any of the aspects, the at least one statin comprises mevastatin. In some embodiments of any of the aspects, the at least one statin comprises pitavastatin. In some embodiments of any of the aspects, the at least one statin comprises pravastatin. In some embodiments of any of the aspects, the at least one statin comprises rosuvastatin.
  • the at least one statin consists of simvastatin. In some embodiments of any of the aspects, the at least one statin consists of atorvastatin. In some embodiments of any of the aspects, the at least one statin consists of fluvastatin. In some embodiments of any of the aspects, the at least one statin consists of lovastatin. In some embodiments of any of the aspects, the at least one statin consists of mevastatin. In some embodiments of any of the aspects, the at least one statin consists of pitavastatin. In some embodiments of any of the aspects, the at least one statin consists of pravastatin. In some embodiments of any of the aspects, the at least one statin consists of rosuvastatin.
  • beta-blocker refers to a chemical which inhibits or blocks the activity of one or more beta-adrengenic receptors. Some beta-blockers antagonize one specific subtype of beta- adrenergic receptors (e.g., a beta-1 selective beta blocker which selectively antagonizes the beta-1 adrenergic receptor), whereas other beta-blockers are non-selective. In some embodiments, a betablocker can inhibit the effect of, e.g., noradrenaline or norepinephrine on one or more beta-adrengenic receptors.
  • beta-blocker refers to all types of antagonists or inhibitors of beta-adrenergic receptors, regardless of whether the beta-blocker antagonizes one, two or more beta-adrenergic receptors and regardless of whether they affect other processes.
  • beta-blockers include, but are not limited to: acebutolol, alprenolol, atenolol, betaxolol, bisoprolol, bopindolol, bucindolol, butaxamine, carteolol, carvedilol, celiprolol, esmolol, labetalol, levobunolol, medroxalol, metipranolol, metoprolol, nadolol, nebivolol, nadolol, oxprenolol, penbutolol, pindolol, propafenone, propranolol, sotalol, timolol, eucommia bark, ICI-118,551, and SR59230A.
  • beta-blocker can include, but is not limited to, the following generic and brand name beta-blockers: R+ propranolol, HEMANGEOL (oral propranolol) SOTACORTM, BETAPACETM (sotalol), N0V0-TIM0LTM, APO-TIMOLTM, BLOCADRENTM (timolol), BREVIBLOCTM (esmolol), CARTROLTM (carteolol), COREGTM (carvedilol), CORGARDTM (nadolol), INDERALTM (propranolol), INDERAL-LATM, APOPROPRANOLOLTM (propranolol), KERLONETM (betaxolol), LEVATOLTM (penbutolol), BETALOCTM, LOPRESSORTM, NOVOMETOPROLTM (metoprolol), NORMODYNETM (labetalol), SECTRALTM
  • the beta-blocker is selected from the group consisting of: R+ atenolol; atenolol; nadolol; propranolol; R+propranolol; and timolol. In some embodiments of any of the aspects, the beta-blocker is selected from the group consisting of: R+ atenolol; atenolol; propranolol; R+propranolol, and timolol. In some embodiments of any of the aspects, the beta-blocker is selected from the group consisting of: R+ atenolol; atenolol; propranolol; and R+propranolol.
  • a beta-blocker can be atenolol (e.g. a compound having the structure of Formula I), nadolol (e.g. a compound having the structure of Formula II), propranolol (e.g. a compound having the structure of Formula III), or timolol (e.g. a compound having the structure of Formula IV).
  • Methods of synthesizing beta-blockers are well known in the art and such compounds are also commercially available, e.g. timolol (Cat. No. T6394, Sigma-Aldrich; St. Louis, MO) and propranolol (Cat. No. P8688, Sigma-Aldrich; St. Louis, MO).
  • the at least one beta-blocker is selected from the group consisting of atenolol; R+ atenolol; nadolol; propranolol; R+propranolol; and timolol.
  • the at least one beta-blocker comprises atenolol. In some embodiments of any of the aspects, the at least one beta-blocker comprises R+ atenolol. In some embodiments of any of the aspects, the at least one beta-blocker comprises nadolol. In some embodiments of any of the aspects, the at least one beta-blocker comprises propranolol. In some embodiments of any of the aspects, the at least one beta-blocker comprises R+propranolol. In some embodiments of any of the aspects, the at least one beta-blocker comprises timolol.
  • the at least one beta-blocker consists of atenolol. In some embodiments of any of the aspects, the at least one beta-blocker consists of R+atenolol. In some embodiments of any of the aspects, the at least one beta-blocker consists of nadolol. In some embodiments of any of the aspects, the at least one beta-blocker consists of propranolol. In some embodiments of any of the aspects, the at least one beta-blocker consists of R+propranolol. In some embodiments of any of the aspects, the at least one beta-blocker consists of timolol.
  • the subject is administered simvastatin and atenolol. In some embodiments of any of the aspects, the subject is administered simvastatin and R+atenolol. In some embodiments of any of the aspects, the subject is administered simvastatin and nadolol. In some embodiments of any of the aspects, the subject is administered simvastatin and propranolol. In some embodiments of any of the aspects, the subject is administered simvastatin and R+propranolol. In some embodiments of any of the aspects, the subject is administered simvastatin and timolol.
  • the subject is administered atorvastatin and atenolol. In some embodiments of any of the aspects, the subject is administered atorvastatin and R+atenolol. In some embodiments of any of the aspects, the subject is administered atorvastatin and nadolol. In some embodiments of any of the aspects, the subject is administered atorvastatin and propranolol. In some embodiments of any of the aspects, the subject is administered atorvastatin and R+propranolol. In some embodiments of any of the aspects, the subject is administered atorvastatin and timolol.
  • the subject is administered tipifamib, simvastatin and atenolol. In some embodiments of any of the aspects, the subject is administered tipifamib, simvastatin and R+atenolol. In some embodiments of any of the aspects, the subject is administered tipifamib, simvastatin and nadolol. In some embodiments of any of the aspects, the subject is administered tipifamib, simvastatin and propranolol. In some embodiments of any of the aspects, the subject is administered tipifamib, simvastatin and R+propranolol. In some embodiments of any of the aspects, the subject is administered tipifamib, simvastatin and timolol.
  • the subject is administered tipifamib, atorvastatin and atenolol. In some embodiments of any of the aspects, the subject is administered tipifamib, atorvastatin and R+atenolol. In some embodiments of any of the aspects, the subject is administered tipifamib, atorvastatin and nadolol. In some embodiments of any of the aspects, the subject is administered tipifamib, atorvastatin and propranolol. In some embodiments of any of the aspects, the subject is administered tipifamib, atorvastatin and R+propranolol. In some embodiments of any of the aspects, the subject is administered tipifamib, atorvastatin and timolol.
  • the subject is administered lonfamib, simvastatin and atenolol. In some embodiments of any of the aspects, the subject is administered lonfamib, simvastatin and R+atenolol. In some embodiments of any of the aspects, the subject is administered lonfamib, simvastatin and nadolol. In some embodiments of any of the aspects, the subject is administered lonfamib, simvastatin and propranolol. In some embodiments of any of the aspects, the subject is administered lonfamib, simvastatin and R+propranolol. In some embodiments of any of the aspects, the subject is administered lonfamib, simvastatin and timolol.
  • the subject is administered lonfamib, atorvastatin and atenolol. In some embodiments of any of the aspects, the subject is administered lonfamib, atorvastatin and R+atenolol. In some embodiments of any of the aspects, the subject is administered lonfamib, atorvastatin and nadolol. In some embodiments of any of the aspects, the subject is administered lonfamib, atorvastatin and propranolol. In some embodiments of any of the aspects, the subject is administered lonfamib, atorvastatin and R+propranolol. In some embodiments of any of the aspects, the subject is administered lonfamib, atorvastatin and timolol.
  • rapamycin reduces stem cell properties of hemangioma stem cells and blocks vessel formation in vivo. It was shown that a 4 day treatment with rapamycin in vitro, prior to implantation in vivo, blocked hemangioma vessel formation (Greenberger et al. J Invest Dermatol 2011 131:2467-76 (PMID: 21938011); which is incorporated by reference herein in its entirety. That is, mTOR inhibitors exert a distinct inhibitory effect on hemangioma stem cells, and it is contemplated herein that this therapeutic effect can be combined, additively or synergistically, with the therapeutic effect of statins demonstrated herein.
  • mTOR inhibitor refers to an agent that can reduce the expression level and/or activity of mTOR protein and/or mRNA. In some embodiments, an mTOR inhibitor can reduce the expression level of mTOR mRNA. In some embodiments, an mTOR inhibitor can reduce the expression level of mTOR polypeptide. In some embodiments, an mTOR inhibitor can reduce the activity of mTOR polypeptide.
  • mTOR refers to a serine/threonine kinase of the PI3K enzyme family that functions as the catalytic subunit of the mTORCl and mT0RC2 complexes (e.g. NCBI Gene ID: 2475).
  • mTOR is also referred to as FRAP, RAFT1, and RAPT.
  • mTOR inhibitors can inhibit mTOR via any known mechanism, including, e.g., binding of a competitive inhibitor, binding of a non-competitive inhibitor, increasing the rate of degradation of mTOR polypeptides, blocking the biosynthesis, transcription, and/or translation of mTOR, blocking the targeting of AKT to mTOR, and increasing the inhibition of mTOR by TSC1/2.
  • mTOR inhibition can be determined by methods well known in the art, e.g.
  • an agent can increase or decrease the expression of a component of the targeted signaling pathway.
  • Components of the mTOR signaling pathway include, but are not limited to RAPTOR, DEPTOR, Rheb, AKT, RICTOR, G[3L, and HIF-1.
  • the mTOR signaling pathways have been described in the art, e.g.
  • Non-limiting examples of mTOR inhibitors for use in the methods and compositions described herein include everolimus (e.g. a compound having the structure of Formula V), temsirolimus (e.g. a compound having the structure of Formula VI), sirolimus (also referred to in the art as rapamycin) (e.g.
  • the at least one mTOR inhibitor is selected from the group consisting of sirolumis; everolimus; temisirolimus; and rapamycin.
  • the at least one mTOR inhibitor comprises sirolumis. In some embodiments of any of the aspects, the at least one mTOR inhibitor comprises everolimus. In some embodiments of any of the aspects, the at least one mTOR inhibitor comprises temisirolimus. In some embodiments of any of the aspects, the at least one mTOR inhibitor comprises rapamycin. [0053] In some embodiments of any of the aspects, the at least one mTOR inhibitor consists of sirolumis. In some embodiments of any of the aspects, the at least one mTOR inhibitor consists of everolimus. In some embodiments of any of the aspects, the at least one mTOR inhibitor consists of temisirolimus. In some embodiments of any of the aspects, the at least one mTOR inhibitor consists of rapamycin.
  • the subject is administered simvastatin and sirolimus. In some embodiments of any of the aspects, the subject is administered simvastatin and everolimus. In some embodiments of any of the aspects, the subject is administered simvastatin and temsirolimus. In some embodiments of any of the aspects, the subject is administered simvastatin and rapamycin.
  • the subject is administered atorvastatin and sirolimus. In some embodiments of any of the aspects, the subject is administered atorvastatin and everolimus. In some embodiments of any of the aspects, the subject is administered atorvastatin and temsirolimus. In some embodiments of any of the aspects, the subject is administered atorvastatin and rapamycin.
  • the subject is administered tipifamib, atorvastatin and sirolimus. In some embodiments of any of the aspects, the subject is administered tipifamib, atorvastatin and everolimus. In some embodiments of any of the aspects, the subject is administered tipifamib, atorvastatin and temsirolimus. In some embodiments of any of the aspects, the subject is administered tipifamib, atorvastatin and rapamycin.
  • the subject is administered lonfamib, atorvastatin and sirolimus. In some embodiments of any of the aspects, the subject is administered lonfamib, atorvastatin and everolimus. In some embodiments of any of the aspects, the subject is administered lonfamib, atorvastatin and temsirolimus. In some embodiments of any of the aspects, the subject is administered lonfamib, atorvastatin and rapamycin.
  • the steroid can be a corticosteroid.
  • the term “steroid” refers to a chemical substance comprising three cyclohexane rings and a cyclopentane ring. The rings are arranged to form tetracyclic cyclopentaphenanthrene, i.e. gonane.
  • the term “corticosteroid” refers to a class of steroid hormones that are produced in the adrenal cortex or produced synthetically. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.
  • Corticosteroids are generally grouped into four classes, based on chemical structure.
  • Group A corticosteroids (short to medium acting glucocorticoids) include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, and prednisone.
  • Group B corticosteroids include triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, and halcinonide.
  • Group C corticosteroids include betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, and fluocortolone.
  • Group D corticosteroids include hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17- butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, and fluprednidene acetate.
  • corticosteroids include, aldostemone, beclomethasone, beclomethasone dipropionate, betametahasone, betametahasone-21 -phosphate disodium, betametahasone valerate, budesonide, clobetasol, clobetasol propionate, clobetasone butyrate, clocortolone pivalate, cortisol, cortisteron, cortisone, deflazacort, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, diflorasone diacetate, dihydroxycortison, flucinonide, fludrocortisones acetate, flumethasone, flunisolide, flucionolone acetonide, fluticasone furate, fluticasone propionate, halcinonide, halpmetasone, hydrocortisone, hydroconrtis
  • corticosteroid can include, but is not limited to, the following generic and brand name corticosteroids: cortisone (CORTONETM ACETATETM, ADRESONTM, ALTESONATM, CORTELANTM, CORTISTABTM, CORTISYLTM, CORTOGENTM, CORTONETM, SCHEROSONTM); dexamethasone-oral (DECADRON-ORALTM, DEXAMETHTM, DEXONETM, HEXADROL-ORALTM, DEXAMETHASONETM INTENSOLTM, DEXONE 0.5TM, DEXONE 0.75TM, DEXONE 1.5TM, DEXONE 4TM); hydrocortisone-oral (CORTEFTM, HYDROCORTONETM); hydrocortisone cypionate (CORTEF ORAL SUSPENSIONTM); methylprednisolone-oral (MEDROL-ORALTM); prednisolone- oral (PRELONETM, DEL
  • a corticosteroid can be a corticosteroid which is active when applied topically, including, but not limited to clobetasol propionate, betamethasone valerate, betamethasone dripropionate, and mometasone furoate.
  • a corticosteroid can be dexamethasone (e.g. a compound having the structure of Formula VIII); prednisone (e.g. a compound having the structure of Formula IX); prednisolone (e.g. a compound having the structure of Formula X); triamcinolone (e.g. a compound having the structure of Formula XI); clobetasol propionate (e.g.
  • betamethasone valerate e.g. a compound having the structure of Formula XIII
  • betamethasone dipropionate e.g. a compound having the structure of Formula XIV
  • mometasone furoate e.g. a compound having the structure of Formula XV.
  • dexamethasone Cat. No. D4902, Sigma- Aldrich; St. Louis, MO
  • predinsone Cat. No. P6254, Sigma-Aldrich; St. Louis, MO.
  • the at least one corticosteroid is selected from the group consisting of dexamethasone; prednisone; prednisolone; triamcinolone; clobetasol propionate; betamethasone valerate; betamethasone dipropionate; and mometasone furoate.
  • the at least one corticosteroid comprises dexamethasone. In some embodiments of any of the aspects, the at least one corticosteroid comprises prednisone. In some embodiments of any of the aspects, the at least one corticosteroid comprises prednisolone. In some embodiments of any of the aspects, the at least one corticosteroid comprises triamcinolone. In some embodiments of any of the aspects, the at least one corticosteroid comprises clobetasol propionate. In some embodiments of any of the aspects, the at least one corticosteroid comprises betamethasone valerate. In some embodiments of any of the aspects, the at least one corticosteroid comprises betamethasone dipropionate. In some embodiments of any of the aspects, the at least one corticosteroid comprises mometasone furoate.
  • the at least one corticosteroid consists of dexamethasone. In some embodiments of any of the aspects, the at least one corticosteroid consists of prednisone. In some embodiments of any of the aspects, the at least one corticosteroid consists of prednisolone. In some embodiments of any of the aspects, the at least one corticosteroid consists of triamcinolone. In some embodiments of any of the aspects, the at least one corticosteroid consists of clobetasol propionate. In some embodiments of any of the aspects, the at least one corticosteroid consists of betamethasone valerate. In some embodiments of any of the aspects, the at least one corticosteroid consists of betamethasone dipropionate. In some embodiments of any of the aspects, the at least one corticosteroid consists of mometasone furoate.
  • the subject is administered simvastatin and dexamethasone. In some embodiments of any of the aspects, the subject is administered simvastatin and prednisone. In some embodiments of any of the aspects, the subject is administered simvastatin and prednisolone. In some embodiments of any of the aspects, the subject is administered simvastatin and triamcinolone. In some embodiments of any of the aspects, the subject is administered simvastatin and clobetasol propionate. In some embodiments of any of the aspects, the subject is administered simvastatin and betamethasone valerate.
  • the subject is administered simvastatin and betamethasone dipropionate. In some embodiments of any of the aspects, the subject is administered simvastatin and mometasone furoate. [0063] In some embodiments of any of the aspects, the subject is administered atorvastatin and dexamethasone. In some embodiments of any of the aspects, the subject is administered atorvastatin and prednisone. In some embodiments of any of the aspects, the subject is administered atorvastatin and prednisolone. In some embodiments of any of the aspects, the subject is administered atorvastatin and triamcinolone.
  • the subject is administered atorvastatin and clobetasol propionate. In some embodiments of any of the aspects, the subject is administered atorvastatin and betamethasone valerate. In some embodiments of any of the aspects, the subject is administered atorvastatin and betamethasone dipropionate. In some embodiments of any of the aspects, the subject is administered atorvastatin and mometasone furoate.
  • the subject is administered tipifamib, atorvastatin and dexamethasone. In some embodiments of any of the aspects, the subject is administered tipifamib, atorvastatin and prednisone. In some embodiments of any of the aspects, the subject is administered tipifamib, atorvastatin and prednisolone. In some embodiments of any of the aspects, the subject is administered tipifamib, atorvastatin and triamcinolone. In some embodiments of any of the aspects, the subject is administered tipifamib, atorvastatin and clobetasol propionate.
  • the subject is administered tipifamib, atorvastatin and betamethasone valerate. In some embodiments of any of the aspects, the subject is administered tipifamib, atorvastatin and betamethasone dipropionate. In some embodiments of any of the aspects, the subject is administered tipifamib, atorvastatin and mometasone furoate.
  • the subject is administered lonfarib, atorvastatin and dexamethasone. In some embodiments of any of the aspects, the subject is administered lonfarib, atorvastatin and prednisone. In some embodiments of any of the aspects, the subject is administered lonfarib, atorvastatin and prednisolone. In some embodiments of any of the aspects, the subject is administered lonfarib, atorvastatin and triamcinolone. In some embodiments of any of the aspects, the subject is administered lonfarib, atorvastatin and clobetasol propionate.
  • the subject is administered lonfarib, atorvastatin and betamethasone valerate. In some embodiments of any of the aspects, the subject is administered lonfarib, atorvastatin and betamethasone dipropionate. In some embodiments of any of the aspects, the subject is administered lonfarib, atorvastatin and mometasone furoate.
  • the subject is administered tipifamib, simvastatin and dexamethasone. In some embodiments of any of the aspects, the subject is administered tipifamib, simvastatin and prednisone. In some embodiments of any of the aspects, the subject is administered tipifamib, simvastatin and prednisolone. In some embodiments of any of the aspects, the subject is administered tipifamib, simvastatin and triamcinolone. In some embodiments of any of the aspects, the subject is administered tipifamib, simvastatin and clobetasol propionate.
  • the subject is administered tipifamib, simvastatin and betamethasone valerate. In some embodiments of any of the aspects, the subject is administered tipifamib, simvastatin and betamethasone dipropionate. In some embodiments of any of the aspects, the subject is administered tipifamib, simvastatin and mometasone furoate.
  • the subject is administered lonfarib, simvastatin and dexamethasone. In some embodiments of any of the aspects, the subject is administered lonfarib, simvastatin and prednisone. In some embodiments of any of the aspects, the subject is administered lonfarib, simvastatin and prednisolone. In some embodiments of any of the aspects, the subject is administered lonfarib, simvastatin and triamcinolone. In some embodiments of any of the aspects, the subject is administered lonfarib, simvastatin and clobetasol propionate.
  • the subject is administered lonfarib, simvastatin and betamethasone valerate. In some embodiments of any of the aspects, the subject is administered lonfarib, simvastatin and betamethasone dipropionate. In some embodiments of any of the aspects, the subject is administered lonfarib, simvastatin and mometasone furoate.
  • the subject is further administered nifedipine (e.g. a compound having the structure of Formula XVI); antimycin A; chelidonine monohydrate; lycorine hydrochloride; ionomycin; LY -294, 002; cerulenin; or monensin sodium.
  • nifedipine e.g. a compound having the structure of Formula XVI
  • antimycin A e.g. a compound having the structure of Formula XVI
  • antimycin A chelidonine monohydrate
  • lycorine hydrochloride e.g. a compound having the structure of Formula XVI
  • ionomycin e.g. LY -294, 002
  • cerulenin e.g. a compound having the structure of Formula XVI
  • monensin sodium e.g. a compound having the structure of Formula XVI
  • monensin sodium e.g. a compound having the structure of Formula XVI
  • antimycin A
  • the subject is further administered antimycin A. In some embodiments of any of the aspects, the subject is further administered chelidonine monohydrate. In some embodiments of any of the aspects, the subject is further administered lycorine hydrochloride. In some embodiments of any of the aspects, the subject is further administered ionomycin. In some embodiments of any of the aspects, the subject is further administered LY- 294,002. In some embodiments of any of the aspects, the subject is further administered cerulenin. In some embodiments of any of the aspects, the subject is further administered monensin sodium.
  • the subject is administered tipifamib and simvastatin. In some embodiments of any of the aspects, the subject is administered tipifamib and atorvastatin. In some embodiments of any of the aspects, the subject is administered tipifamib and atenolol. In some embodiments of any of the aspects, the subject is administered tipifamib and R+atenolol. In some embodiments of any of the aspects, the subject is administered tipifamib and nadolol. In some embodiments of any of the aspects, the subject is administered tipifamib and propranolol. In some embodiments of any of the aspects, the subject is administered tipifamib and R+propranolol.
  • the subject is administered tipifamib and timolol. In some embodiments of any of the aspects, the subject is administered tipifamib and sirolimus. In some embodiments of any of the aspects, the subject is administered tipifamib and everolimus. In some embodiments of any of the aspects, the subject is administered tipifamib and temsirolimus. In some embodiments of any of the aspects, the subject is administered tipifamib and rapamycin. In some embodiments of any of the aspects, the subject is administered tipifamib and dexamethasone. In some embodiments of any of the aspects, the subject is administered tipifamib and prednisone.
  • the subject is administered tipifamib and triamcinolone. In some embodiments of any of the aspects, the subject is administered tipifamib and clobetasol propionate. In some embodiments of any of the aspects, the subject is administered tipifamib and betamethasone valerate. In some embodiments of any of the aspects, the subject is administered tipifamib and betamethasone dipropionate. In some embodiments of any of the aspects, the subject is administered tipifamib and mometasone furoate.
  • the subject is administered lonfamib and simvastatin. In some embodiments of any of the aspects, the subject is administered lonfamib and atorvastatin. In some embodiments of any of the aspects, the subject is administered lonfamib and atenolol. In some embodiments of any of the aspects, the subject is administered lonfamib and R+atenolol. In some embodiments of any of the aspects, the subject is administered lonfamib and nadolol. In some embodiments of any of the aspects, the subject is administered lonfamib and propranolol. In some embodiments of any of the aspects, the subject is administered lonfamib and R+propranolol. In some embodiments of any of the aspects, the subject is administered lonfamib and timolol.
  • the subject is administered lonfamib and clobetasol propionate. In some embodiments of any of the aspects, the subject is administered lonfamib and betamethasone valerate. In some embodiments of any of the aspects, the subject is administered lonfamib and betamethasone dipropionate. In some embodiments of any of the aspects, the subject is administered lonfamib and mometasone furoate.
  • the methods described herein relate to administering to a subject having, or diagnosed as having, a vascular anomaly at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor.
  • Subjects having a vascular anomaly can be identified by a physician using current methods of diagnosing vascular anomalies, as described herein.
  • Symptoms of vascular anomalies which characterize these conditions and aid in diagnosis are well known in the art and include but are not limited to, discolorations of the epidermis or the presence of a vascular tissue tumor. Tests that aid in a diagnosis of vascular anomalies, e.g.
  • hemangioma include, but are not limited to, ultrasound, MRI, and histochemical examination of biopsies.
  • a family history of hemangiomas can also aid in determining if a subject is likely to have a hemangioma or in making a diagnosis of hemangioma.
  • compositions and methods described herein can be administered to a subject having, or diagnosed as having, a vascular anomaly.
  • the methods described herein comprise administering an effective amount of a composition described herein, e.g at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor, to a subject in order to alleviate a symptom of a vascular anomaly.
  • "alleviating a symptom” is ameliorating any condition or symptom associated with the vascular anomaly, e.g. tumor size, extent of the irregular vasculature, or growth of irregular vasculature.
  • compositions described herein to subjects are known to those of skill in the art. Such methods can include, but are not limited to oral, parenteral, intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, cutaneous, topical, injection, intralesionally, or intratumoral administration. Administration can be local or systemic.
  • a statin, an mTOR inhibitor, steroid, and/or beta-blocker can be administered topically. In some embodiments, a statin, an mTOR inhibitor, steroid, and/or beta-blocker can be administered orally.
  • the term “effective amount” as used herein refers to the amount of composition needed to alleviate at least one or more symptoms of the disease or disorder, and relates to a sufficient amount of pharmacological composition to provide the desired effect.
  • the term "therapeutically effective amount” therefore refers to an amount of a composition that is sufficient to effect a particular anti-vasculogenesis effect when administered to a typical subject.
  • An effective amount as used herein in various contexts would also include an amount sufficient to delay the development of a symptom of the disease, alter the course of a symptom disease (for example but not limited to, slowing the progression of a symptom of the disease), or reverse a symptom of the disease. Thus, it is not generally practicable to specify an exact “effective amount” .
  • Effective amounts, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dosage can vary depending upon the dosage form employed and the route of administration utilized.
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED50.
  • Compositions and methods that exhibit large therapeutic indices are preferred.
  • a therapeutically effective dose can be estimated initially from cell culture assays as described herein.
  • the technology described herein relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor, and optionally, a statin, a steroid, mTOR inhibitor and/or beta-blocker as described herein, and optionally a pharmaceutically acceptable carrier.
  • the composition can comprise multiple famesyltransferase inhibitors, multiple geranylgeranyl transferase inhibitors, multiple statins, multiple steroids, multiple mTOR inhibitors, multiple beta-blockers, or any combination thereof.
  • a combination or kit comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor and at least one statin, at least one beta-blocker, mTOR inhibitor, and/or steroid.
  • the a) at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor and b) at least one statin, beta-blocker, mTOR inhibitor, and/or steroid are provided in the same formulation.
  • the a) at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor and b) at least one statin, beta-blocker, mTOR inhibitor, and/or steroid are provided in separate formulations.
  • combination refers to a group of two or more substances for use together, e.g., for use in treating vascular anomalies.
  • the two or more substances can be present in the same formulation in any molecular or physical arrangement, e.g, in an admixture, in a solution, in a mixture, in a suspension, in a colloid, in an emulsion.
  • the formulation can be a homogeneous or heterogenous mixture.
  • the two or more substances active compound(s) can be comprised by the same or different superstructures, e.g., nanoparticles, liposomes, vectors, cells, scaffolds, or the like, and said superstmcture is in solution, mixture, admixture, suspension with a solvent, carrier, or some of the two or more substances.
  • the two or more substances can be present in two or more separate formulations, e.g., in a kit or package comprising multiple formulations in separate containers, to be mixed or brought into contact with each other when an assay is to be performed.
  • a kit is an assemblage of materials or components, including at least one reagent described herein. The exact nature of the components configured in the kit depends on its intended purpose.
  • a kit includes instructions for use. “Instructions for use” typically include a tangible expression describing the technique to be employed in using the components of the kit, e.g., to treat a vascular anomaly. Still in accordance with the present invention, “instructions for use” may include a tangible expression describing the preparation of at least one element described herein, such as dilution, mixing, or dosing instructions, and the like, typically for an intended purpose.
  • the kit also contains other useful components, such as, measuring tools, diluents, buffers, syringes, pharmaceutically acceptable carriers, or other useful paraphernalia as will be readily recognized by those of skill in the art.
  • a package refers to a suitable solid matrix or material such as glass, plastic, paper, foil, polyester (such as polyethylene terephthalate, or Mylar) and the like, capable of holding the individual kit components.
  • a package can be a glass vial used to contain suitable quantities of a composition containing a volume of at least one reagent described herein.
  • the packaging material generally has an external label which indicates the contents and/or purpose of the kit and/or its components.
  • the kit or combination comprises at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor; and at least one statin. In some embodiments of any of the aspects, the kit or combination comprises at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor; and at least one beta-blocker. In some embodiments of any of the aspects, the kit or combination comprises at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor; and at least one mTOR inhibitor.
  • the kit or combination comprises at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor; and at least one steroid.
  • the combination or kit comprises tipifamib and simvastatin. In some embodiments of any of the aspects, the combination or kit comprises tipifamib and atorvastatin. In some embodiments of any of the aspects, the combination or kit comprises tipifamib and atenolol. In some embodiments of any of the aspects, the combination or kit comprises tipifamib and nadolol. In some embodiments of any of the aspects, the combination or kit comprises tipifamib and propranolol. In some embodiments of any of the aspects, the combination or kit comprises tipifamib and R+propranolol. In some embodiments of any of the aspects, the combination or kit comprises tipifamib and timolol.
  • the combination or kit comprises lonfamib and simvastatin. In some embodiments of any of the aspects, the combination or kit comprises lonfamib and atorvastatin. In some embodiments of any of the aspects, the combination or kit comprises lonfamib and atenolol. In some embodiments of any of the aspects, the combination or kit comprises lonfamib and nadolol. In some embodiments of any of the aspects, the combination or kit comprises lonfamib and propranolol. In some embodiments of any of the aspects, the combination or kit comprises lonfamib and R+propranolol. In some embodiments of any of the aspects, the combination or kit comprises lonfamib and timolol.
  • the combination or kit comprises tipifamib and sirolimus. In some embodiments of any of the aspects, the combination or kit comprises tipifamib and everolimus. In some embodiments of any of the aspects, the combination or kit comprises tipifamib and temsirolimus. In some embodiments of any of the aspects, the combination or kit comprises tipifamib and rapamycin.
  • the combination or kit comprises lonfamib and sirolimus. In some embodiments of any of the aspects, the combination or kit comprises lonfamib and everolimus. In some embodiments of any of the aspects, the combination or kit comprises lonfamib and temsirolimus. In some embodiments of any of the aspects, the combination or kit comprises lonfamib and rapamycin.
  • the combination or kit comprises tipifamib and dexamethasone. In some embodiments of any of the aspects, the combination or kit comprises tipifamib and prednisone. In some embodiments of any of the aspects, the combination or kit comprises tipifamib and prednisolone. In some embodiments of any of the aspects, the combination or kit comprises tipifamib and triamcinolone. In some embodiments of any of the aspects, the combination or kit comprises tipifamib and clobetasol propionate. In some embodiments of any of the aspects, the combination or kit comprises tipifamib and betamethasone valerate.
  • the combination or kit comprises tipifamib and betamethasone dipropionate. In some embodiments of any of the aspects, the combination or kit comprises tipifamib and mometasone furoate. [0090] In some embodiments of any of the aspects, the combination or kit comprises lonfamib and dexamethasone. In some embodiments of any of the aspects, the combination or kit comprises lonfamib and prednisone. In some embodiments of any of the aspects, the combination or kit comprises lonfamib and prednisolone. In some embodiments of any of the aspects, the combination or kit comprises lonfamib and triamcinolone.
  • the combination or kit comprises lonfamib and clobetasol propionate. In some embodiments of any of the aspects, the combination or kit comprises lonfamib and betamethasone valerate. In some embodiments of any of the aspects, the combination or kit comprises lonfamib and betamethasone dipropionate. In some embodiments of any of the aspects, the combination or kit comprises lonfamib and mometasone furoate.
  • Pharmaceutically acceptable carriers and diluents include saline, aqueous buffer solutions, solvents and/or dispersion media.
  • the use of such carriers and diluents is well known in the art.
  • Some non-limiting examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, microcrystalline cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean
  • wetting agents, coloring agents, release agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservative and antioxidants can also be present in the formulation.
  • the terms such as “excipient”, “carrier”, “pharmaceutically acceptable carrier” or the like are used interchangeably herein.
  • the carrier inhibits the degradation of the active agent as described herein.
  • topical dosage forms can include, but are not limited to, creams, lotions, ointments, gels, shampoos, sprays, aerosols, solutions, emulsions, patches, and other forms known to one of skill in the art. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams, and Wilkins, Philadelphia PA. (2005); and Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, 9th Ed., Lippincott, Williams, and Wilkins, Philadelphia, PA. (2011).
  • viscous to semi-solid or solid forms comprising a carrier or one or more excipients compatible with topical application and having a dynamic viscosity preferably greater than water are typically employed.
  • suitable formulations include, without limitation, solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, and the like, which are, if desired, sterilized or mixed with auxiliary agents (e.g., preservatives, stabilizers, wetting agents, buffers, or salts) for influencing various properties, such as, for example, osmotic pressure.
  • auxiliary agents e.g., preservatives, stabilizers, wetting agents, buffers, or salts
  • suitable topical dosage forms include sprayable aerosol preparations wherein the active ingredient, e.g.
  • At least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor preferably in combination with a solid or liquid inert carrier, is packaged in a mixture with a pressurized volatile (e.g., a gaseous propellant, such as freon), or in a squeeze bottle.
  • a pressurized volatile e.g., a gaseous propellant, such as freon
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams, and Wilkins, Philadelphia PA. (2005).
  • Transdermal and mucosal dosage forms of the compositions described herein are not limited to, patches, sprays, aerosols, creams, lotions, suppositories, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams, and Wilkins, Philadelphia PA. (2005); and Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems, 9th Ed., Lippincott, Williams, and Wilkins, Philadelphia, PA. (2011).
  • Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes, as oral gels, or as buccal patches.
  • Additional transdermal dosage forms include "reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredient.
  • Suitable excipients e.g., carriers and diluents
  • other materials that can be used to provide transdermal and mucosal dosage forms encompassed by this disclosure are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue or organ to which a given pharmaceutical composition or dosage form will be applied.
  • typical excipients include, but are not limited to water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1,3 -diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof, to form dosage forms that are nontoxic and pharmaceutically acceptable.
  • penetration enhancers can be used to assist in delivering the active ingredients to or across the tissue.
  • Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, an tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as TWEEN 80 (polysorbate 80) and SPAN 60 (sorbitan monostearate).
  • the pharmaceutical composition described herein can be a parenteral dose form. Since administration of parenteral dosage forms typically bypasses the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. In addition, controlled-release parenteral dosage forms can be prepared for administration of a patient, including, but not limited to, administration DUROS®-type dosage forms, and dose-dumping.
  • Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. Examples include, without limitation: sterile water; water for injection USP; saline solution; glucose solution; aqueous vehicles such as but not limited to, sodium chloride injection, Ringer's injection, dextrose Injection, dextrose and sodium chloride injection, and lactated Ringer's injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and propylene glycol; and non-aqueous vehicles such as, but not limited to, com oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • Compounds that alter or modify the solubility of a pharmaceutically acceptable salt of an agent as disclosed herein can also be incorporated into the parenteral dosage forms of the disclosure, including conventional and controlled- release parenteral dosage forms.
  • compositions described herein can also be formulated to be suitable for oral administration, for example as discrete dosage forms, such as, but not limited to, tablets (including without limitation scored or coated tablets), pills, caplets, capsules, chewable tablets, powder packets, cachets, troches, wafers, aerosol sprays, or liquids, such as but not limited to, syrups, elixirs, solutions or suspensions in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion.
  • Such compositions contain a predetermined amount of the pharmaceutically acceptable salt of the disclosed compounds, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams, and Wilkins, Philadelphia PA. (2005).
  • Conventional dosage forms generally provide rapid or immediate drug release from the formulation. Depending on the pharmacology and pharmacokinetics of the drug, use of conventional dosage forms can lead to wide fluctuations in the concentrations of the drug in a patient's blood and other tissues. These fluctuations can impact a number of parameters, such as dose frequency, onset of action, duration of efficacy, maintenance of therapeutic blood levels, toxicity, side effects, and the like.
  • controlled-release formulations can be used to control a drug's onset of action, duration of action, plasma levels within the therapeutic window, and peak blood levels.
  • controlled- or extended-release dosage forms or formulations can be used to ensure that the maximum effectiveness of a drug is achieved while minimizing potential adverse effects and safety concerns, which can occur both from under-dosing a drug (i.e., going below the minimum therapeutic levels) as well as exceeding the toxicity level for the drug.
  • composition described herein can be administered in a sustained release formulation.
  • Controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled release counterparts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Controlled-release formulations include: 1) extended activity of the drug; 2) reduced dosage frequency; 3) increased patient compliance; 4) usage of less total drug; 5) reduction in local or systemic side effects; 6) minimization of drug accumulation; 7) reduction in blood level fluctuations; 8) improvement in efficacy of treatment; 9) reduction of potentiation or loss of drug activity; and 10) improvement in speed of control of diseases or conditions.
  • Kim Chemg-ju, Controlled Release Dosage Form Design, 2 (Technomic Publishing, Lancaster, Pa.: 2000).
  • Controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, ionic strength, osmotic pressure, temperature, enzymes, water, and other physiological conditions or compounds.
  • a variety of known controlled- or extended-release dosage forms, formulations, and devices can be adapted for use with the salts and compositions of the disclosure. Examples include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5674,533; 5,059,595; 5,591 ,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,733,566; and 6,365,185 Bl ; each of which is incorporated herein by reference.
  • dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems (such as OROS® (Alza Corporation, Mountain View, Calif. USA)), or a combination thereof to provide the desired release profde in varying proportions.
  • active ingredients for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems (such as OROS® (Alza Corporation, Mountain View, Calif. USA)), or a combination thereof to provide the desired release profde in varying proportions.
  • OROS® Alza Corporation, Mountain View, Calif. USA
  • the methods described herein can further comprise administering a second agent and/or further treatment to the subject, e.g. as part of a combinatorial therapy.
  • a second agent and/or further treatment can include one or more of laser surgery, pulsed dye laser, statins, corticosteroid therapy, oral corticosteroid therapy, beta-blockers, topical beta-blockers, vincristine, interferon, surgical removal, and pharmaceutically acceptable salts, acids or derivatives of any of the preceding compounds.
  • an effective dose of a composition as described herein can be administered to a patient once.
  • an effective dose of a composition described herein can be administered to a patient repeatedly.
  • subjects can be administered a therapeutic amount of at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor, such as, e.g. 0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, or more.
  • a composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor can be administered over a period of time, such as over a 5 minute, 10 minute, 15 minute, 20 minute, or 25 minute period or longer.
  • the administration can be repeated, for example, on a regular basis, such as hourly, every 3 hours, 6 hours, 12 hours or longer or such as biweekly (i.e., every two weeks) for one month, two months, three months, four months or longer.
  • the composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor is administered to the subject at a dose of between 0.00001 mg/kg/d and 5000 mg/kg/d. In certain embodiments, the composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor is administered to the subject at a dose of between 0.0001 mg/kg/d and 500 mg/kg/d.
  • the composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor is administered to the subject at a dose of between 0.001 mg/kg/d and 50 mg/kg/d. In certain embodiments, the composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor is administered to the subject at a dose of between 0.001 mg/kg/d and 10 mg/kg/d.
  • the composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor is administered to the subject at a dose of 10 mg/kg/d or higher. In certain embodiments, the composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor is administered to the subject at a dose of between about 0.00001 mg/kg/d and about 5000 mg/kg/d.
  • the composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor is administered to the subject at a dose of between about 0.0001 mg/kg/d and about 500 mg/kg/d. In certain embodiments, the composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor is administered to the subject at a dose of between about 0.001 mg/kg/d and about 50 mg/kg/d.
  • the composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor is administered to the subject at a dose of between about 0.001 mg/kg/d and about 10 mg/kg/d. In certain embodiments, the composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor is administered to the subject at a dose of about 10 mg/kg/d or higher.
  • the at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor can be administered on a less frequent basis.
  • treatment can be repeated once per month, for six months or a year or longer.
  • Treatment according to the methods described herein can reduce levels of a marker or symptom of a condition, e.g. proliferative vascular disorder by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80 % or at least 90% or more.
  • Markers and symptoms of proliferative vascular disorders can include, but are not limited to tumors of the endothelial cells of blood vessels; an increased number of blood vessels and/or capillaries; discoloration of the skin; GLUT-1 expression; hemosiderin pigmentation; ulceration; and bleeding.
  • a composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor and a composition comprising a further agent as described herein can be administered substantially simultaneously with each other or within 5 minutes, or 10 minutes, or 20 minutes, or 60 minutes, or 2 hours, or 3 hours, or 4 hours, or 8 hours, or 12 hours, or 24 hours of administration of the other.
  • routes of administration can be the same or different.
  • composition comprising at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor can be administered by any appropriate route known in the art including, but not limited to orally or systemically, and a beta-blocker can be administered by a different route, e.g. topically, or a route commonly used in the art for administration of the beta-blocker.
  • the dosage of a composition as described herein can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment. With respect to duration and frequency of treatment, it is typical for skilled clinicians to monitor subjects in order to determine when the treatment is providing therapeutic benefit, and to determine whether to increase or decrease dosage, increase or decrease administration frequency, discontinue treatment, resume treatment, or make other alterations to the treatment regimen.
  • the dosing schedule can vary from once a week to daily depending on a number of clinical factors, such as the subject's sensitivity to a statin and any further agents administered.
  • the desired dose or amount of activation can be administered at one time or divided into subdoses, e.g., 2-4 subdoses and administered over a period of time, e.g., at appropriate intervals through the day or other appropriate schedule.
  • administration can be chronic, e.g., one or more doses and/or treatments daily over a period of weeks or months.
  • dosing and/or treatment schedules are administration daily, twice daily, three times daily or four or more times daily over a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months, or more.
  • the dosage ranges for the administration of at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor, and optionally, a further agent described herein, according to the methods described herein depend upon, for example, the form of the compound(s), its potency, and the extent to which symptoms, markers, or indicators of a condition described herein are desired to be reduced, for example the percentage reduction desired for vasculogenesis and/or tumor size.
  • the dosage should not be so large as to cause adverse side effects, such as thrombocytopenia.
  • the dosage will vary with the age, condition, and sex of the patient and can be determined by one of skill in the art.
  • the dosage can also be adjusted by the individual physician in the event of any complication.
  • the efficacy of at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor e.g., the treatment of a condition described herein, or to induce a response as described herein (e.g., reduction of tumor size, extent, or rate of growth) can be determined by the skilled clinician.
  • a treatment is considered “effective treatment,” as the term is used herein, if any one or all of the signs or symptoms of a condition described herein are altered in a beneficial manner, other clinically accepted symptoms are improved, or even ameliorated, or a desired response is induced e.g., by at least 10% following treatment according to the methods described herein.
  • Efficacy can be assessed, for example, by measuring a marker, indicator, symptom, and/or the incidence of a condition treated according to the methods described herein or any other measurable parameter appropriate, e.g., extent of vasculogenesis and/or tumor size. Efficacy can also be measured by a failure of an individual to worsen as assessed by hospitalization, or need for medical interventions (i.e., progression of the disease is halted). Methods of measuring these indicators are known to those of skill in the art and/or are described herein.
  • Treatment includes any treatment of a disease in an individual or an animal (some non-limiting examples include a human or an animal) and includes: (1) inhibiting the disease, e.g., preventing a worsening of symptoms (e.g., pain or inflammation); or (2) relieving the disease, e.g., causing regression of symptoms.
  • An effective amount for the treatment of a disease means that amount which, when administered to a subject in need thereof, is sufficient to result in effective treatment as that term is defined herein, for that disease.
  • Efficacy of an agent can be determined by assessing physical indicators of a condition or desired response, (e.g., decrease in tumor size).
  • In vitro and animal model assays are provided herein which allow the assessment of a given dose of at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor.
  • the effects of a dose of at least one famesyltransferase inhibitor and/or at least one geranylgeranyl transferase inhibitor proliferation is inhibited by the compound in an in vitro or in vivo assay described herein or known in the art as a model for a vascular anomaly.
  • the present invention relates to the herein described compositions, methods, and respective component(s) thereof, as essential to the technology, yet open to the inclusion of unspecified elements, essential or not ("comprising).
  • other elements to be included in the description of the composition, method or respective component thereof are limited to those that do not materially affect the basic and novel characteristic(s) of the technology (e.g., the composition, method, or respective component thereof “consists essentially of’ the elements described herein). This applies equally to steps within a described method as well as compositions and components therein.
  • compositions, methods, and respective components thereof, described herein are intended to be exclusive of any element not deemed an essential element to the component, composition or method (e.g., the composition, method, or respective component thereof “consists of’ the elements described herein). This applies equally to steps within a described method as well as compositions and components therein.
  • “reduction” or “inhibition” does not encompass a complete inhibition or reduction as compared to a reference level.
  • “Complete inhibition” is a 100% inhibition as compared to a reference level.
  • a decrease can be preferably down to a level accepted as within the range of normal for an individual without a given disorder.
  • the terms “increased”, “increase”, “enhance”, or “activate” are all used herein to mean an increase by a statically significant amount.
  • the terms “increased”, “increase”, “enhance”, or “activate” can mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3 -fold, or at least about a 4-fold, or at least about a 5 -fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level.
  • a “increase” is a statistically significant increase
  • a "subject” means a human or animal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomologus monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters.
  • Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon.
  • the subject is a mammal, e.g., a primate, e.g., a human.
  • the terms, “individual,” “patient” and “subject” are used interchangeably herein.
  • the subject is a mammal.
  • the mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but is not limited to these examples. Mammals other than humans can be advantageously used as subjects that represent animal models of a vascular anomaly.
  • a subject can be male or female.
  • the subject is a human.
  • the human is less than 18 years of age, e.g., between birth and their 18 th birthday.
  • the human is between 1 and 2 years of age, e.g., a human at least 12 months old but has not yet reached their third birthday.
  • the human is less than 1 year of age. In some embodiments of any of the aspects, the human is less than 2 years of age.
  • a subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment (e.g. vascular anomaly) or one or more complications related to such a condition, and optionally, have already undergone treatment for the condition or the one or more complications related to the condition.
  • a subject can also be one who has not been previously diagnosed as having the condition or one or more complications related to the condition.
  • a subject can be one who exhibits one or more risk factors for the condition or one or more complications related to the condition or a subject who does not exhibit risk factors.
  • a “subject in need” of treatment for a particular condition can be a subject having that condition, diagnosed as having that condition, or at risk of developing that condition.
  • expression refers to the cellular processes involved in producing RNA and proteins and as appropriate, secreting proteins, including where applicable, but not limited to, for example, transcription, transcript processing, translation and protein folding, modification and processing.
  • Expression can refer to the transcription and stable accumulation of sense (mRNA) or antisense RNA derived from a nucleic acid fragment or fragments of the invention and/or to the translation of mRNA into a polypeptide.
  • “Expression products” include RNA transcribed from a gene, and polypeptides obtained by translation of mRNA transcribed from a gene.
  • the term “gene” means the nucleic acid sequence which is transcribed (DNA) to RNA in vitro or in vivo when operably linked to appropriate regulatory sequences.
  • the gene may or may not include regions preceding and following the coding region, e.g. 5’ untranslated (5’UTR) or “leader” sequences and 3’ UTR or “trailer” sequences, as well as intervening sequences (introns) between individual coding segments (exons).
  • treatment includes not just the improvement of symptoms or markers, but also a cessation of, or at least slowing of, progress or worsening of symptoms compared to what would be expected in the absence of treatment.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, remission (whether partial or total), and/or decreased mortality, whether detectable or undetectable.
  • treatment also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment).
  • treatment is effective if the rate of growth of a vascular anomaly is decreased. In some embodiments, treatment is effective if the size of a vascular anomaly is decreased. In some embodiments, treatment is effective if the visible appearance of a vascular anomaly is decreased.
  • prophylactic refers to the timing and intent of a treatment relative to a disease or symptom, that is, the treatment is administered prior to clinical detection or diagnosis of that particular disease or symptom in order to protect the patient from the disease or symptom.
  • Prophylactic treatment can encompass a reduction in the severity or speed of onset of the disease or symptom, or contribute to faster recovery from the disease or symptom. Accordingly, the methods described herein can be prophylactic relative to further growth of a vascular anomaly. In some embodiments of any of the aspects, prophylactic treatment is not prevention of all symptoms or signs of a disease.
  • the term “pharmaceutical composition” refers to the active agent in combination with a pharmaceutically acceptable carrier e.g. a carrier commonly used in the pharmaceutical industry.
  • a pharmaceutically acceptable carrier e.g. a carrier commonly used in the pharmaceutical industry.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a pharmaceutically acceptable carrier can be a carrier other than water.
  • a pharmaceutically acceptable carrier can be a cream, emulsion, gel, liposome, nanoparticle, and/or ointment.
  • a pharmaceutically acceptable carrier can be an artificial or engineered carrier, e.g., a carrier that the active ingredient would not be found to occur in in nature.
  • nanoparticle refers to particles that are on the order of about 1 to 1,000 nanometers in diameter or width.
  • nanoparticle includes nanospheres; nanorods; nanoshells; and nanoprisms; these nanoparticles may be part of a nanonetwork.
  • nanoparticles also encompasses liposomes and lipid particles having the size of a nanoparticle. Exemplary nanoparticles include lipid nanoparticles or ferritin nanoparticles.
  • Lipid nanoparticles can comprise multiple componenents, including, e.g., ionizable lipids (such as MC3, DLin-MC3-DMA, ALC-0315, or SM-102), pegylated lipids (such as PEG2000-C-DMG, PEG2000-DMG, ALC-0159), phospholipids (such as DSPC), and cholesterol.
  • ionizable lipids such as MC3, DLin-MC3-DMA, ALC-0315, or SM-102
  • pegylated lipids such as PEG2000-C-DMG, PEG2000-DMG, ALC-0159
  • phospholipids such as DSPC
  • Exemplary liposomes can comprise, e.g., DSPC, DPPC, DSPG, Cholesterol, hydrogenated soy phosphatidylcholine, soy phosphatidyl choline, methoxypolyethylene glycol (mPEG-DSPE) phosphatidyl choline (PC), phosphatidyl glycerol (PG), distearoylphosphatidylcholine, and combinations thereof.
  • mPEG-DSPE methoxypolyethylene glycol
  • PC phosphatidyl choline
  • PG phosphatidyl glycerol
  • distearoylphosphatidylcholine and combinations thereof.
  • administering refers to the placement of a compound as disclosed herein into a subject by a method or route which results in at least partial delivery of the agent at a desired site.
  • Pharmaceutical compositions comprising the compounds disclosed herein can be administered by any appropriate route which results in an effective treatment in the subject.
  • administration comprises physical human activity, e.g., an injection, act of ingestion, an act of application, and/or manipulation of a delivery device or machine. Such activity can be performed, e.g., by a medical professional and/or the subject being treated.
  • contacting refers to any suitable means for delivering, or exposing, an agent to at least one cell.
  • exemplary delivery methods include, but are not limited to, direct delivery to cell culture medium, perfusion, injection, or other delivery method well known to one skilled in the art.
  • contacting comprises physical human activity, e.g., an injection; an act of dispensing, mixing, and/or decanting; and/or manipulation of a delivery device or machine.
  • statically significant or “significantly” refers to statistical significance and generally means a two standard deviation (2SD) or greater difference.
  • the mevalonate pathway bifurcates at famesyl-PP into cholesterol biosynthesis and protein prenylation carried out by famesyltransferase (FTase) and geranylgeranyl transferase (GTase).
  • FTase famesyltransferase
  • GTase geranylgeranyl transferase
  • Several proteins that are crucial for vasculogenesis and angiogenesis are activated by prenylation, including the Ras family of small GTPases.
  • FDPS famesyl diphosphatase synthase
  • FTase inhibitor tipifamib in an in vivo xenograft model for infantile hemangioma, wherein HemSC are implanted sub-cutaneously into immune-deficient mice for 7 days while the mice are treated intraperitoneally with tipifamib every day (Fig. 1A).
  • Tipifamib dose response showed significant inhibition of vessel formation beginning at 0.4 mg/kg/d.
  • targeting of protein prenylation is a novel mechanism to block vascular overgrowth in infantile hemangioma, alone or in combination with known treatments.
  • tipifamib and potentially other FTase and GTase inhibitors are contemplated herein as additive and/or alternative therapeutic option in pediatric patients with infantile hemangioma.
  • patients with other vascular anomaly entities in which activation of proteins by prenylation, such as Ras family of small GTPases, is involved can benefit from this novel targeted treatment approach.
  • FIG. 1A depicts a schematic of an embodiment of the method.
  • HemSC hemangioma- derived stem cells
  • FIG. 1A depicts a schematic of an embodiment of the method.
  • HemSC hemangioma- derived stem cells
  • mice were treated with 0.4, 2, 10, and 50 mg/kg/d tipifamib with a maximum concentration of 6.2% DMSO twice a day for 7 days as depicted in the schematic from Seebauer et al., JCI, 2022.
  • Treatment with tipifamib showed a significant reduction in vessel density with any dosage applied, as demonstrated by darkness of the plugs depicted in vehicle and tipifamib (50 mg/kg/d) treated mice, H&E and anti-human CD31 staining.
  • the dose response to tipifamib was quantified as vessel density, expressed in expressed in vessels/mm 2 , versus tipifamib dose in mg/kg/d, as shown in FIG. 1C. P values were calculated using ordinary one-way ANOVA.
  • FIG. ID depicts a chematic of the mevalonate pathway and its inhibitors, statins and tipifamib (gray).
  • Tipifamib farnesyltransferase inhibitor
  • GTI-2418 geranylgeranyltransferase inhibitor
  • FIG. IE depicts a schematic of an embodiment of the IH xenograft model.
  • HemSC isolated from IH patient were pre-treated with 100 nM tipifamib or GGTI-2418 or vehicle (0.001% DMSO), suspended in Matrigel with 50 nM tipifamib or GGTI-2418 (0.0005% DMSO), and injected subcutaneously into nude mice, with 2 implants/mouse. Mice were treated with 0.001 - 10 mg/kg/d tipifamib or GGTI-2418 twice a day via intraperitoneal injections. Matrigel implants harvested after 7 days of tipifamib treatment are shown in the top right panel of FIG. IF.
  • FIG. 1G depicts the quantification of human CD31 positive vessels/mm 2 in a dose response experiment, where the dose of tipifamib administered ranges from 0.001 - 10 mg/kg/d.
  • IH depicts the quantification of human CD31 positive vessels/mm 2 in a dose response experiment, where the dose of GTI-2418 administered ranges from 0.001 - 10 mg/kg/d.
  • the results show a significant reduction in vessel density in the implants of tipifamib- and GGTI-2418-treated mice compared to control mice. Both dmgs achieved a significant inhibition of vessel formation at of 0.001 mg/kg/day.
  • P values were calculated using one-way ANOVA and the Tukey’s multiple comparison test. Data are shown as mean ⁇ SD.
  • FIG. II and FIG. 1 J show the percent change of mouse body weight versus days for tipifamib treated mice (FIG. II) and GTI-2418 treated mice (FIG. 1 J). The body weight of the mice in both treatment groups was unaffected compared to vehicle controls at all drug dosages.

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Abstract

La technologie décrite dans la présente invention concerne des méthodes et des compositions relatives au traitement d'anomalies vasculaires, par exemple des hémangiomes, qui se fondent sur la découverte selon laquelle des inhibiteurs de la farnésyltransférase et/ou de la géranylgéranyltransférase ciblent les voies qui commandent la différenciation de cellules souches dérivées d'hémangiome.
PCT/US2024/054845 2023-11-10 2024-11-07 Méthodes et compositions pour le traitement d'anomalies vasculaires Pending WO2025101692A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050154451A1 (en) * 2003-12-18 2005-07-14 Medtronic Vascular, Inc. Medical devices to treat or inhibit restenosis
WO2006052718A2 (fr) * 2004-11-05 2006-05-18 Janssen Pharmaceutica N.V. Utilisation therapeutique d'inhibiteurs de farnesyltransferase et procedes de controle de leur efficacite
US20130202553A1 (en) * 2008-03-12 2013-08-08 Children's Hospital Medical Center Mobilization of hematopoietic stem cells

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050154451A1 (en) * 2003-12-18 2005-07-14 Medtronic Vascular, Inc. Medical devices to treat or inhibit restenosis
WO2006052718A2 (fr) * 2004-11-05 2006-05-18 Janssen Pharmaceutica N.V. Utilisation therapeutique d'inhibiteurs de farnesyltransferase et procedes de controle de leur efficacite
US20130202553A1 (en) * 2008-03-12 2013-08-08 Children's Hospital Medical Center Mobilization of hematopoietic stem cells

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