Methods and compositions for the treatment of vascular anomalies

Abstract

The technology described herein is directed to methods and compositions relating to the treatment of vascaular anomalies, e.g. hemangiomas, including the discovery that famesyltransferase and / or geranylgeranyltransferas inhibitors target pathways controlling the differentiation of hemangioma-derived stem cells.

Description

METHODS AND COMPOSITIONS FOR THE TREATMENT OF VASCULAR ANOMALIESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit under 35 U.S.C. § 119 of U.S. Provisional Application No. 63 / 597,724 filed on November 10, 2023, the content of which is incorporated herein by reference in its entirety.GOVERNMENT SUPPORT

[0002] This invention was made with government support under Grant No. HL096384-12 awarded by the National Institutes of Health. The government has certain rights in the invention.TECHNICAL FIELD

[0003] The technology described herein relates to the treatment of vascular anomalies, e.g., infantile hemangioma.BACKGROUND

[0004] 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. For example, 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. Although benign and usually a harmless tumor, some IH deform or destroy facial features and cause functional impairment such as obstructing vision or imparing breathing. Forty to eighty percent result in permanent cutaneous residua, which can be disfiguring. Corticosteroids were the traditional first-line therapy, however, the adverse effects are numerous (Boon et al., Plast Reconstr Surg 1999 104: 1616-1623) and approximately 16% of hemangiomas do not respond (Bennett et al., Arch Dermatol 2001 137: 1208-1213). 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)). However, its use is not without risks, and not all tumors respond (Frieden and Drolet. Pediatr Dermatol 2009 26:642-644). Concerning side effects of propranolol are due to its antagonistic effect on [3-adrenergic receptors and include sleep disorder, bronchospasm, bradycardia, hypotension, and hypoglycemia. More effective therapies could improve outcomes and / or shorten treatment duration, thereby reducing the risk of adverse side effects.SUMMARY

[0005] 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.

[0007] In one aspect of any of the embodiments, described herein is 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. In one aspect of any of the embodiments, described herein is 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.

[0008] In one aspect of any of the embodiments, described herein is a composition comprising at least one famesyltransferase inhibitor and / or at least one geranylgeranyltranserase inhibitor, for use in treating a vascular anomaly.

[0009] In some embodiments of any of the aspects, 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. In some embodiments of any of the aspects, 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.

[0010] In some embodiments of any of the aspects, 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. In some embodiments of any of the aspects, the vascular anomaly is infantile hemangioma.

[0011] In some embodiments of any of the aspects, the subject is further administered at least one statin, beta-blocker, mTOR inhibitor, and / or steroid.

[0012] In some embodiments of any of the aspects, the statin is selected from the group consisting of: simvastatin; atorvastatin; cerivastatin; fluvastatin; lovastatin; mevastatin; pitavastatin; pravastatin; and rosuvastatin. In some embodiments of any of the aspects, the statin is simvastatin. In some embodiments of any of the aspects, the statin is atorvastatin. In some embodiments of any of the aspects, 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-blockeris 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. In some embodiments of any of the aspects, the mTOR inhibitor is rapamycin. In some embodiments of any of the aspects, the steroid is a corticosteroid. In some embodiments of any of the aspects, the corticosteroid is selected from the group consisting of: dexamethasone; prednisone; prednisolone; triamcinolone; clobetasol propionate; betamethasone valerate; betamethasone dipropionate; and mometasone furoate.

[0013] In some embodiments of any of the aspects, 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.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figs. 1A-1D demonstrate that tipifamib inhibits vessel formation in a murine xenograft model for infantile hemangioma. (Fig. 1A) Hemangioma-derived stem cells (HemSC), 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. IB) Tipifamib was administered by i.p. injections. Matrigel implants were harvested on day 8, sectioned and stained for H&E. Blood vessels were identified by luminal stmctures containing 1 or more red blood cells and counted in 5 fields / section, 2 sections / implant from the middle of the implant. Each field was 1331.95 x 650.7 pm = 0.86671 mm2 . 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. (Fig. 1C) Quantification of vessel density, expressed in vessels / mm2 . P values were calculated using ordinary one-way ANOVA. Data show the mean ± SEM and were collected from 2 implants in each mouse, leading to an observation sample size of n=18 for vehicle control and 50 mg / kg / d and n=8 for 0.4, 2, 10 mg / kg / d tipifamib. (Fig. ID) Schematic of the mevalonate pathway and its inhibitors, statins and tipifamib (gray).

[0015] 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).

[0016] 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 injectedsubcutaneously 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.

[0017] 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.

[0018] 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. Data were collected for 2 implants in each mouse, leading to the following observation sample sizes: vehicle n=10; 0.001 mg / kg / d n=; 0.01 mg / kg / d n=6; 0.1 mg / kg / d n=8 ; 1 mg / kg / d n=6; 10 mg / kg / d n=6.

[0019] 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. Data were collected for 2 implants in each mouse, leading to the following observation sample sizes: vehicle n=8; 0.001 mg / kg / d n=8;0.01 mg / kg / d n=8; 0.1 mg / kg / d n=8 ;1 mg / kg / d n=8; 10 mg / kg / d n=8.

[0020] Fig. II depicts the body weight change in percent versus day of treatment at all drug doses of Tipifamib compared to the control (vehicle).

[0021] 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).DETAILED DESCRIPTION

[0022] As demonstrated herein, the inventors have discovered that 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.

[0023] 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 thesubject. In one aspect of any of the embodiments, described herein is at least one famesyltransferase inhibitor and / or at least one geranylgeranyl transferase inhibitor for use in a method of treating a vascular anomaly.

[0024] 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. 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. Moreover, mixed vascular malformations and malformations associated with other anomalies are specified. Non-limiting examples of 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). The diagnosis and biology of hemangiomas are well known in the art, e.g,. as described in Richter et al. Int J Pediatr 2012:645678 (PMID 22611412);Merrow et al. RadioGraphics 2016 36: 1494-516 (PMID 27517361); Queisser et al. Circulation Research 2021 129: 155-173 (PMID 34166070), Mahady et al. Quant Imaging Med Surg 2015 5:886-97 (PMID 26807370); and Behr et al. AJR 2013 200:414-422 (PMID 23345366); each of which is incorporated by reference herein in its entirety.

[0025] In some embodiments of any of the aspects, 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. In some embodiments, 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. arteriovenous fistula, and arteriovenous malformation), and combined-complex vascular malformations. Methods of diagnosing vascular malformations are well known in the art, see, e.g. Buckmiller et al. Oral Diseases 2010 16:405-418; Flors et al. RadioGraphics 2011 31: 1321-1340; Paltiel et al. Radiology 2000 214:747-754; and Werner et al. Eur Arch Otorhiolaryngol 2001 258: 141-9; each of which is incorporated by reference herein in its entireties. 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.

[0026] In some embodiments, vascular anomalies can be a hemangioma or vascular tumor. As used herein “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. Examples of hemangioma include, but are not limited to: infantile hemangioma, congenital hemangioma, kaposiform hemangioendothelioma, infant nevoid 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. Clinics in plastic surgery 2011 38 (1): 1-5; Ememann, U. et al. European journal of radiology 2010 75(1): 2-11; and Gupta, A. et al. Clinics in plastic surgery 2011 38 (1): 31-44; each of which is incorporated by reference herein in its entireties.

[0027] 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.

[0028] 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.

[0029] As used herein “famesyltransferase inhibitor” refers to an agent that reduces the rate and / or amount of tranfer of a famesyl group from famesyl pyrophosphate (FPP) to pre-Ras by famesyltransferase (FTase). This reduces the isoprenylation of Ras, which is necessary for signaltransduction through Ras. 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.

[0030] In some embodiments of any of the aspects, 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.

[0031] In some embodiments of any of the aspects, 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.

[0032] As used herein “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. For further discussion of geranylgeranyltransferase inhibitors, see, e.g., Kazi et al. Clin Cancer Res 25:5984-5996 (2019) and Karasic et al. Target Oncol 14:613-618 (2019); each of which is incorporated by reference herein in its entirety.

[0033] In some embodiments of any of the aspects, 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.

[0034] In some embodiments of any of the aspects, the subject is further administered at least one statin, beta-blocker, mTOR inhibitor, and / or steroid.

[0035] As used herein, “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. In some embodiments of any of the aspects, the at least one statin is selected from the group consistingof simvastatin; atorvastatin; fluvastatin; lovastatin; mevastatin; pitavastatin; pravastatin; and rosuvastatin.

[0036] In some embodiments of any of the aspects, 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.

[0037] In some embodiments of any of the aspects, 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.

[0038] As used herein, “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. In context of the technology described herein, the term “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. Examples of 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. As used herein, the term “beta-blocker” can include, but is not limited to, the following generic and brand name beta-blockers: R+ propranolol, HEMANGEOL (oral propranolol) SOTACOR™, BETAPACE™ (sotalol), N0V0-TIM0L™, APO-TIMOL™, BLOCADREN™ (timolol), BREVIBLOC™ (esmolol), CARTROL™ (carteolol), COREG™ (carvedilol), CORGARD™ (nadolol), INDERAL™ (propranolol), INDERAL-LA™, APOPROPRANOLOL™ (propranolol), KERLONE™ (betaxolol), LEVATOL™ (penbutolol), BETALOC™, LOPRESSOR™, NOVOMETOPROL™ (metoprolol), NORMODYNE™ (labetalol), SECTRAL™ (acebutolol),TENORMIN™, NOVO-ATENOL™ (atenolol), TOPROL-XL™ (metoprolol), TRANDATE™ (labetalol), NOVOPINDOL™, VISKEN™ (pindolol), ZEBETA™ (bisoprolol), TRASICOR™ (oxprenolol), APOATENOLOL™ (atenolol), and MONITAN™ and SECTRAL™ (acebutolol). In some embodiments of any of the aspects, 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. In some embodiments, 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).Formula IV

[0039] In some embodiments of any of the aspects, the at least one beta-blocker is selected from the group consisting of atenolol; R+ atenolol; nadolol; propranolol; R+propranolol; and timolol.

[0040] In some embodiments of any of the aspects, 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.

[0041] In some embodiments of any of the aspects, 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.

[0042] In some embodiments of any of the aspects, 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.

[0043] In some embodiments of any of the aspects, 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.

[0044] In some embodiments of any of the aspects, 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.

[0045] In some embodiments of any of the aspects, 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.

[0046] In some embodiments of any of the aspects, 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.

[0047] In some embodiments of any of the aspects, 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.

[0048] The mTOR inhibitor rapamycin (sirolimus) 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.

[0049] As used herein, the term “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. As used herein, the term “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 canbe determined by methods well known in the art, e.g. by detecting the level of phosphorylation of mTOR targets such as p70-S6 kinase 1 (S6K1), 4E-BP1, and Akt, where inhibition or a decreased in the phosphorylation of these targets indicates effective inhibition of mTOR. In certain embodiments, 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. in Dunlop and Tee Cell Signal 2009 26:827-835; Laplante and Sabatini J Cell Sci 2009 122:3589- 3594; Kudchodkar et al. PNAS 2006 103: 14182-7; which are incorporated by reference herein in their entireties. Transcriptional assays are well known to those of skill in the art (see e.g. United States Patent 7,319,933, 6,913,880 which is incorporated herein by reference in its entirety).

[0050] 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. a compound having the structure of Formula VII), deforolimus, TOP216, OSI-027, TAFA93, nab-rapamycin, tacrolimus, biolimus, CI-779, ABT-578, AP -23675, BEZ-235, QLT-0447, ABI-009, BC-210, salirasib, AP-23841, AP-23573, KU-0059475, 32-deoxorapamycin, 16-pent-2- ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32 (S or R)-dihydro-rapamycin, 16-pent-2-ynyloxy- 32 (S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, 32- deoxorapamycin; 16-pent-2-ynyloxy-32(S)-dihydrorapamycin; socalledrapalogs; AP23464; PI-103, PP242, PP30, Torinl; and derivatives or pharmaceutically acceptable salts thereof as well as and compounds described in, e.g. U.S. Patent Publications 2011 / 0178070; 2011 / 0021515; 2007 / 0112005; 2011 / 0054013; International Patent Publications WO98 / 02441; WOOl / 14387; WO99 / 15530;WO07 / 135411; WO03 / 64383; WO96 / 41807; WO95 / 16691; W094 / 09010; European Patent No. EP1880723; and U.S. Patent Nos. 8,163,775; 6,329,386; 6,200,985; 6,117,863; 6,015,815; 6,015,809; 6,004,973; 5,985,890; 5,955,457; 5,922,730; 5,912,253; 5,780,462; 5,665,772; 5,637,590; 5,567,709; 5,563,145; 5,559,122; 5,559,120; 5,559,119; 5,559,112; 5,550,133; 5,541,192; 5,541,191; 5,532,355; 5,530,121; 5,530,007; 5,525,610; 5,521,194; 5,519,031; 5,516,780; 5,508,399; 5,508,290; 5,508,286; 5,508,285; 5,504,291; 5,504,204; 5,491,231; 5,489,680; 5,489,595; 5,488,054; 5,486,524; 5,486,523; 5,486,522; 5,484,791; 5,484,790; 5,480,989; 5,480,988; 5,463,048; 5,446,048; 5,434,260; 5,411,967; 5,391,730; 5,389,639; 5,385,910; 5,385,909; 5,385,908; 5,378,836; 5,378,696; 5,373,014; 5,362,718; 5,358,944; 5,346,893; 5,344,833; 5,302,584; 5,262,424; 5,262,423; 5,260,300; 5,260,299; 5,233,036; 5,221,740; 5,221,670; 5,202,332; 5,194,447; 5,177,203; 5,169,851; 5,164,399; 5,162,333; 5,151,413; 5,138,051; 5,130,307; 5,120,842; 5,120,727; 5,120,726; 5,120,725; 5,118,678; 5,118,677; 5,100,883; 5,023,264; 5,023,263; and 5,023,262; which are incorporated by reference herein in their entireties.Formula VII

[0051] In some embodiments of any of the aspects, the at least one mTOR inhibitor is selected from the group consisting of sirolumis; everolimus; temisirolimus; and rapamycin.

[0052] In some embodiments of any of the aspects, 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.

[0054] In some embodiments of any of the aspects, 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.

[0055] In some embodiments of any of the aspects, 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.

[0056] In some embodiments of any of the aspects, 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.

[0057] In some embodiments of any of the aspects, 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.

[0058] In some embodiments, the steroid can be a corticosteroid. As used herein, 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. As used herein, 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 sodiumphosphate, 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. Non-limiting examples of 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, hydroconrtisone acetate, hydrocortisone succinate, 16a-hydroxyprednisolone, isoflupredone acetate, medrysone, methylprednisolone, prednacinolone, predricarbate, prednisolone, prednisolone acetate, prednisolone sodium succinate, prednisone, triamcinolone, triamcinolone, and triamcinolone diacetate. As used herein, the term “corticosteroid” can include, but is not limited to, the following generic and brand name corticosteroids: cortisone (CORTONE™ ACETATE™, ADRESON™, ALTESONA™, CORTELAN™, CORTISTAB™, CORTISYL™, CORTOGEN™, CORTONE™, SCHEROSON™); dexamethasone-oral (DECADRON-ORAL™, DEXAMETH™, DEXONE™, HEXADROL-ORAL™, DEXAMETHASONE™ INTENSOL™, DEXONE 0.5™, DEXONE 0.75™, DEXONE 1.5™, DEXONE 4™); hydrocortisone-oral (CORTEF™, HYDROCORTONE™); hydrocortisone cypionate (CORTEF ORAL SUSPENSION™); methylprednisolone-oral (MEDROL-ORAL™); prednisolone- oral (PRELONE™, DELTA-CORTEF™, PEDIAPRED™, ADNISOLONE™, CORTALONE™, DELTACORTRIL™, DELTASOLONE™, DELTASTAB™, DI-ADRESON F™, ENCORTOLONE™, HYDROCORTANCYL™, MEDISOLONE™, METICORTELONE™, OPREDSONE™, PANAAFCORTELONE™, PRECORTISYL™, PRENISOLONA™, SCHERISOLONA™, SCHERISOLONE™); prednisone (DELTASONE™, LIQUID PRED™, METICORTEN™, ORASONE 1™, ORASONE 5™, ORASONE 10™, ORASONE 20™, ORASONE 50™, PREDNICEN-M™, PREDNISONE INTENSOL™, STERAPRED™, STERAPRED DS™, ADASONE™, CARTANCYL™, COLISONE™, CORDROL™, CORTAN™, DACORTIN™, DECORTIN™, DECORTISYL™, DELCORTIN™, DELLACORT™, DELTADOME™, DELTACORTENE™, DELTISONA™, DIADRESON™, ECONOSONE™, ENCORTON™, FERNISONE™, NISONA™, NOVOPREDNISONE™, PANAFCORT™, PANASOL™, PARACORT™, PARMENISON™, PEHACORT™, PREDELTIN™, PREDNICORT™, PREDNICOT™, PREDNIDIB™, PREDNIMENT™, RECTODELT™, ULTRACORTEN™, WINPRED™); triamcinoloneoral (KENACORT™, ARISTOCORT™, ATOLONE™, SHOLOG A™, TRAMACORT-D™, TRI-MED™, TRIAMCOT™, TRISTOPLEX™, TRYLONE D™, U-TRI- LONE™). In some embodiments, a corticosteroid can be a corticosteroid which is active when appliedtopically, including, but not limited to clobetasol propionate, betamethasone valerate, betamethasone dripropionate, and mometasone furoate. In some embodiments, 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. a compound having the structure of Formula XII); betamethasone valerate (e.g. a compound having the structure of Formula XIII); betamethasone dipropionate (e.g. a compound having the structure of Formula XIV); or mometasone furoate (e.g. a compound having the structure of Formula XV). Methods of synthesizing steroids and corticosteroids are well known in the art and such compounds are also commercially available, e.g. dexamethasone (Cat. No. D4902, Sigma- Aldrich; St. Louis, MO) and predinsone (Cat. No. P6254, Sigma-Aldrich; St. Louis, MO).Formula XFormula XIVFormula XV

[0059] In some embodiments of any of the aspects, 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.

[0060] In some embodiments of any of the aspects, 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.

[0061] In some embodiments of any of the aspects, 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.

[0062] In some embodiments of any of the aspects, 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. In some embodiments of any of the aspects, 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. In some embodiments of any of the aspects, 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.

[0064] In some embodiments of any of the aspects, 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. In some embodiments of any of the aspects, 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.

[0065] In some embodiments of any of the aspects, 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. In some embodiments of any of the aspects, 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.

[0066] In some embodiments of any of the aspects, 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. In some embodiments of any of the aspects, the subject is administered tipifamib, simvastatin and betamethasone valerate. In some embodiments of any of the aspects, the subject is administered tipifamib, simvastatin andbetamethasone dipropionate. In some embodiments of any of the aspects, the subject is administered tipifamib, simvastatin and mometasone furoate.

[0067] In some embodiments of any of the aspects, 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. In some embodiments of any of the aspects, 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.

[0068] In some embodiments of any of the aspects, 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.Formula XVI

[0069] In some embodiments of any of the aspects, 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.

[0070] In some embodiments of any of the aspects, 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 andR+propranolol. In some embodiments of any of the aspects, 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. In some embodiments of any of the aspects, 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.

[0071] In some embodiments of any of the aspects, 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.

[0072] In some embodiments of any of the aspects, the subject is administered lonfamib and sirolimus. In some embodiments of any of the aspects, the subject is administered lonfamib and everolimus. In some embodiments of any of the aspects, the subject is administered lonfamib and temsirolimus. In some embodiments of any of the aspects, the subject is administered lonfamib and rapamycin. In some embodiments of any of the aspects, the subject is administered lonfamib and dexamethasone. In some embodiments of any of the aspects, the subject is administered lonfamib and prednisone. In some embodiments of any of the aspects, the subject is administered lonfamib and triamcinolone. In some embodiments of any of the aspects, 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.

[0073] In some embodiments, 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 bya 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.

[0074] The compositions and methods described herein can be administered to a subject having, or diagnosed as having, a vascular anomaly. In some embodiments, 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. As used herein, "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. As compared with an equivalent untreated control, such reduction is by at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, 99% or more as measured by any standard technique. A variety of means for administering the 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.

[0075] In some embodiments, the at least one famesyltransferase inhibitor and / or at least one geranylgeranyl transferase inhibitor is administered orally. In some embodiments, at least one famesyltransferase inhibitor and / or at least one geranylgeranyl transferase inhibitor is administered orally in the form of a syrup or suspension, optionally with an added flavoring.

[0076] In some embodiments, 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.

[0077] 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" . However, for any given case, an appropriate “effective amount" can be determined by one of ordinary skill in the art using only routine experimentation.

[0078] 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. Also, a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the active ingredient which achieves a half-maximal inhibition of a symptom) as determined in cell culture, or in an appropriate animal model. The level of at least one famesyltransferase inhibitor and / or at least one geranylgeranyl transferase inhibitor in plasma can be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay, e.g., an in vitro or in vivo assay for vasculogenesis or tumor size among others. The dosage can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.

[0079] In some embodiments, the technology described herein relates to 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. In some embodiments, 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.

[0080] In one aspect of any of the embodiments, described herein is 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. In some embodiments, 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. In some embodiments, 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.

[0081] As used herein “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. In some embodiments of any of the aspects, 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 asolvent, carrier, or some of the two or more substances. Alternatively, 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.

[0082] 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. In some embodiments of any of the aspects, 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. Optionally, 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.

[0083] The materials or components assembled in the kit can be provided to the practitioner stored in any convenient and suitable ways that preserve their operability and utility. For example, the components can be in dissolved, dehydrated, or lyophilized form; they can be provided at room, refrigerated or frozen temperatures. The components are typically contained in suitable packaging material(s). As employed herein, the phrase “packaging material” refers to one or more physical structures used to house the contents of the kit, such as inventive compositions and the like. The packaging material is constructed by well-known methods, preferably to provide a sterile, contaminant- free environment. The packaging may also preferably provide an environment that protects from light, humidity, and oxygen. As used herein, the term “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. Thus, for example, 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.

[0084] 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 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. 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 steroid.

[0085] In some embodiments of any of the aspects, 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.

[0086] In some embodiments of any of the aspects, 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.

[0087] In some embodiments of any of the aspects, 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.

[0088] In some embodiments of any of the aspects, 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.

[0089] In some embodiments of any of the aspects, 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. In some embodiments of any of the aspects, 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. In some embodiments of any of the aspects, 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.

[0091] 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 oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol (PEG); (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids (23) serum component, such as semm albumin, HDL and LDL; (22) C2-C12 alcohols, such as ethanol; and (23) other non-toxic compatible substances employed in pharmaceutical formulations. 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. In some embodiments, the carrier inhibits the degradation of the active agent as described herein.

[0092] In some embodiments a composition described herein can be administered to a subject topically. In some embodiments, 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). For non-sprayable topical dosage forms, viscous to semi-solid or solid forms comprising a carrier or one ormore 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. Other 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. 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).

[0093] Transdermal and mucosal dosage forms of the compositions described herein but 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.

[0094] Suitable excipients (e.g., carriers and diluents) and 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. With that fact in mind, 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. In some embodiments, 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).

[0095] In some embodiments, the pharmaceutical composition described herein can be a parenteral dose form. Since administration of parenteral dosage forms typically bypasses the patient's naturaldefenses 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.

[0096] 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.

[0097] Pharmaceutical 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).

[0098] 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. Advantageously, 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. In particular, 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. In some embodiments, composition described herein can be administered in a sustained release formulation.

[0099] Controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled release counterparts. Ideally, 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. Advantages of 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).

[0100] Most 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.

[0101] 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. These 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.

[0102] 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. Non-limiting examples of 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.

[0103] In certain embodiments, an effective dose of a composition as described herein can be administered to a patient once. In certain embodiments, an effective dose of a composition described herein can be administered to a patient repeatedly. For systemic administration, subjects can be administered a therapeutic amount of at least one famesyltransferase inhibitor and / or at least onegeranylgeranyl 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.

[0104] 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 0.00001 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. 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 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. 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 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. 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 0.0001 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. 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 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.

[0105] In some embodiments, after an initial treatment regimen, the at least one famesyltransferase inhibitor and / or at least one geranylgeranyl transferase inhibitor can be administered on a less frequent basis. As a non-limiting example, after treatment biweekly for three months, 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 least60%, at least 70%, at least 80 % or at least 90% or more. 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.

[0106] When administered at different times, 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. When at least one famesyltransferase inhibitor and / or at least one geranylgeranyl transferase inhibitor and at least one further agent as described herein are administered in different pharmaceutical compositions, routes of administration can be the same or different. For example, a 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.

[0107] 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. In some embodiments, administration can be chronic, e.g., one or more doses and / or treatments daily over a period of weeks or months. Examples of 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.

[0108] 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. Generally, the dosage will vary with the age, condition, and sex of the patient and can be determined byone of skill in the art. The dosage can also be adjusted by the individual physician in the event of any complication.

[0109] 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. However, 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). It is well within the ability of one skilled in the art to monitor efficacy of administration and / or treatment by measuring any one of such parameters, or any combination of parameters. When using an experimental animal model, efficacy of treatment is evidenced when a statistically significant change in a marker is observed, e.g. extent of vascularization and / or tumor size.

[0110] 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. By way of non-limiting example, 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.

[0111] In one respect, 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). In some embodiments of any of the aspects, 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 andcomponents therein. In other embodiments of any of the aspects, the 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.

[0112] For convenience, the meaning of some terms and phrases used in the specification, examples, and appended claims, are provided below. Unless stated otherwise, or implicit from context, the following terms and phrases include the meanings provided below. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is an apparent discrepancy between the usage of a term in the art and its definition provided herein, the definition provided within the specification shall prevail.

[0113] For convenience, certain terms employed herein, in the specification, examples and appended claims are collected here.

[0114] The terms “decrease”, “reduced”, “reduction”, or “inhibit” are all used herein to mean a decrease by a statistically significant amount. In some embodiments, “reduce,” “reduction" or “decrease" or “inhibit” typically means a decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment or agent) and can include, for example, a decrease by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99% , or more. As used herein, “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.

[0115] The terms “increased”, “increase”, “enhance”, or “activate” are all used herein to mean an increase by a statically significant amount. In some embodiments, 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 areference level. In the context of a marker or symptom, a “increase” is a statistically significant increase in such level.

[0116] As used herein, 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. In some embodiments, the subject is a mammal, e.g., a primate, e.g., a human. The terms, “individual,” “patient” and “subject” are used interchangeably herein.

[0117] Preferably, 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.

[0118] In some embodiments of any of the aspects, the subject is a human. In some embodiments, the human is less than 18 years of age, e.g., between birth and their 18thbirthday. In some embodiments, 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. In some embodiments of any of the aspects, 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.

[0119] 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. Alternatively, 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. For example, 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.

[0120] 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.

[0121] The term "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.

[0122] "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 regulatorysequences. 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).

[0123] As used herein, the terms "treat,” "treatment," "treating,” or “amelioration” refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a condition associated with a disease or disorder, e.g. a vascular anomaly. The term “treating" includes reducing or alleviating at least one adverse effect or symptom of a condition, disease or disorder associated with a vascular anomaly. Treatment is generally “effective" if one or more symptoms or clinical markers are reduced. Alternatively, treatment is “effective" if the progression of a disease is reduced or halted. That is, “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. The term "treatment" of a disease also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment).

[0124] In some embodiments, 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.

[0125] In some embodiments of any of the aspects, described herein is a prophylactic method of treatment. As used herein “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.

[0126] As used herein, 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. The phrase "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. In some embodiments of any of the aspects, a pharmaceutically acceptable carrier can be a carrier other than water. In some embodiments of any of the aspects, a pharmaceutically acceptablecarrier can be a cream, emulsion, gel, liposome, nanoparticle, and / or ointment. In some embodiments of any of the aspects, 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.

[0127] As used herein, the term “nanoparticle” refers to particles that are on the order of about 1 to 1,000 nanometers in diameter or width. The term “nanoparticle” includes nanospheres; nanorods; nanoshells; and nanoprisms; these nanoparticles may be part of a nanonetwork. The term “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.

[0128] 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.

[0129] As used herein, the term "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. In some embodiments, 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.

[0130] As used herein, “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. In some embodiments, 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.

[0131] The term “statistically significant" or “significantly" refers to statistical significance and generally means a two standard deviation (2SD) or greater difference.

[0132] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term “about.” The term “about” when used in connection with percentages can mean ±1%.

[0133] As used herein, the term “comprising” means that other elements can also be present in addition to the defined elements presented. The use of “comprising” indicates inclusion rather than limitation.

[0134] The term "consisting of refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.

[0135] As used herein the term "consisting essentially of refers to those elements required for a given embodiment. The term permits the presence of additional elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment of the invention.

[0136] The singular terms "a," "an," and "the" include plural referents unless context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The abbreviation, "e.g." is derived from the Latin exempli gratia, and is used herein to indicate a nonlimiting example. Thus, the abbreviation "e.g." is synonymous with the term "for example."

[0137] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0138] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art to which this disclosure belongs. It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. Definitions of common terms in immunology and molecular biology can be found in The Merck Manual of Diagnosis and Therapy, 20th Edition, published by Merck Sharp & Dohme Corp., 2018 (ISBN 0911910190, 978-0911910421); Robert S. Porter et al. (eds.), The Encyclopedia of Molecular Cell Biology and Molecular Medicine, published by Blackwell Science Ltd., 1999-2012 (ISBN 9783527600908); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8); Immunology by Werner Luttmann, published by Elsevier, 2006; Janeway's Immunobiology, Kenneth Murphy, Allan Mowat, Casey Weaver (eds.), W. W. Norton & Company, 2016 (ISBN 0815345054, 978-0815345053); Lewin's Genes XI, published by Jones & Bartlett Publishers, 2014 (ISBN- 1449659055); Michael Richard Green and Joseph Sambrook, Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (2012) (ISBN 1936113414); Davis et al., Basic Methods in Molecular Biology, Elsevier Science Publishing, Inc.,New York, USA (2012) (ISBN 044460149X); Laboratory Methods in Enzymology: DNA, Jon Lorsch (ed.) Elsevier, 2013 (ISBN 0124199542); Current Protocols in Molecular Biology (CPMB), Frederick M. Ausubel (ed.), John Wiley and Sons, 2014 (ISBN 047150338X, 9780471503385), Current Protocols in Protein Science (CPPS), John E. Coligan (ed.), John Wiley and Sons, Inc., 2005; and Current Protocols in Immunology (CPI) (John E. Coligan, ADA M Kruisbeek, David H Margulies, Ethan M Shevach, Warren Strobe, (eds.) John Wiley and Sons, Inc., 2003 (ISBN 0471142735, 9780471142737), the contents of which are all incorporated by reference herein in their entireties.

[0139] Other terms are defined herein within the description of the various aspects of the invention.

[0140] All patents and other publications; including literature references, issued patents, published patent applications, and co-pending patent applications; cited throughout this application are expressly incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the technology described herein. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

[0141] The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. For example, while method steps or functions are presented in a given order, alternative embodiments may perform functions in a different order, or functions may be performed substantially concurrently. The teachings of the disclosure provided herein can be applied to other procedures or methods as appropriate. The various embodiments described herein can be combined to provide further embodiments. Aspects of the disclosure can be modified, if necessary, to employ the compositions, functions and concepts of the above references and application to provide yet further embodiments of the disclosure. These and other changes can be made to the disclosure in light of the detailed description. All such modifications are intended to be included within the scope of the appended claims.

[0142] Specific elements of any of the foregoing embodiments can be combined or substituted for elements in other embodiments. Furthermore, while advantages associated with certain embodiments of the disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the disclosure.

[0143] The technology described herein is further illustrated by the following examples which in no way should be construed as being further limiting.EXAMPLESExample 1

[0144] The mevalonate pathway bifurcates at famesyl-PP into cholesterol biosynthesis and protein prenylation carried out by famesyltransferase (FTase) and geranylgeranyl transferase (GTase). Several proteins that are crucial for vasculogenesis and angiogenesis are activated by prenylation, including the Ras family of small GTPases. The inventors hypothesized the R+ propranolol inhibition of vessel formation in infantile hemangioma was a result, in part, of reduced prenylation due to down-regulated mevalonate pathway enzymes including famesyl diphosphatase synthase (FDPS). The inventors tested the effect of the FDA-approved 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. These results indicate that tipifamib and other FTase or GTase inhibitors can be used to block vascular overgrowth that characterizes infantile hemangioma (Figs. 1B-1D).

[0145] Accordingly, targeting of protein prenylation is a novel mechanism to block vascular overgrowth in infantile hemangioma, alone or in combination with known treatments. Hence, tipifamib and potentially other FTase and GTase inhibitors are contemplated herein as additive and / or alternative therapeutic option in pediatric patients with infantile hemangioma. Moreover, 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.Example 2

[0146] Tipifamib inhibits vessel formation in a murine xenograft model for infantile hemangioma. FIG. 1A depicts a schematic of an embodiment of the method. In this embodiment, hemangioma- derived stem cells (HemSC), 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 from Seebauer et al., JCI, 2022. Following tipifamib administration by i.p. injections, matrigel implants were harvested on day 8, sectioned and stained for H&E (FIG. IB: top left = vehicle, top right = 50 mg / kg / d tipifamib treated). Blood vessels were identified by luminal structures containing 1 or more red blood cells and counted in 5 fields / section, 2 sections / implant from the middle of the implant. Each field was 1331.95 x 650.7 pm = 0.86671 mm2(FIG. IB: middle left = vehicle, middle right = 50 mg / kg / d tipifamib treated). 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. (FIG. IB: bottom left = vehicle, bottom right = 50 mg / kg / d tipifamib treated). The doseresponse to tipifamib was quantified as vessel density, expressed in expressed in vessels / mm2, versus tipifamib dose in mg / kg / d, as shown in FIG. 1C. P values were calculated using ordinary one-way ANOVA. Data show the mean ± SEM and were collected from 2 implants in each mouse, leading to an observation sample size of n=18 for vehicle control and 50 mg / kg / d and n=8 for 0.4, 2, 10 mg / kg / d tipifamib. FIG. ID depicts a chematic of the mevalonate pathway and its inhibitors, statins and tipifamib (gray).Example 3

[0147] The prenylation inhibitors Tipifamib (farnesyltransferase inhibitor) and GTI-2418 (geranylgeranyltransferase inhibitor) inhibit blood vessel formation in a xenograft model of infantile hemangioma (IH).FIG. IE depicts a schematic of an embodiment of the IH xenograft model. In this embodiment, 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. H&E staining indicates reduction of blood vessels in Tipifamib treated compared to control mice (middle panels of FIG. IF). Immunofluorescent anti-human CD31 staining (dark gray) confirmed reduced human vessel formation in tipifamib-treated mice compared to controls (bottom panels of FIG. IF). 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 depicts the quantification of human CD31 positive vessels / mm2in a dose response experiment, where the dose of tipifamib administered ranges from 0.001 - 10 mg / kg / d. FIG. IH depicts the quantification of human CD31 positive vessels / mm2in 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. Data were collected for 2 implants in each mouse, leading to the following observation sample sizes: vehicle n=10 (tipifamib) and n=8 (GTI-2418); 0.001 mg / kg / d n=6 (tipifamib) and n=8 (GTI-2418); 0.01 mg / kg / d n=6 (tipifamib) and n=8 (GTI-2418); 0.1 mg / kg / d n=8 (tipifamib) and n=8 (GTI-2418); 1 mg / kg / d n=6 (tipifamib) and n=8 (GTI-2418); 10 mg / kg / d n=6 (tipifamib) and n=8 (GTI-2418).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.

Claims

What is claimed herein is:

1. 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.

2. The method of any one of the preceding claims, wherein 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.

3. The method of any one of the preceding claims, wherein the famesyltransferase inhibitor is tipifamib.

4. The method of any one of the preceding claims, wherein the famesyltransferase inhibitor is lonfamib.

5. The method of any one of the preceding claims, wherein the geranylgeranyltransferase inhibitor is selected from the group consisting of:GGTI-2418; and FGTI-2734.

6. The method of any one of the preceding claims, wherein 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.

7. The method of any one of the preceding claims, wherein the vascular anomaly is infantile hemangioma.

8. The method of any one of the preceding claims, wherein the subject is further administered at least one statin, beta-blocker, mTOR inhibitor, and / or steroid.

9. The method of claim 7, wherein the statin is selected from the group consisting of: simvastatin; atorvastatin; cerivastatin; fluvastatin; lovastatin; mevastatin; pitavastatin; pravastatin; and rosuvastatin.

10. The method of claim 7, wherein the statin is simvastatin.

11. The method of claim 7, wherein the statin is atorvastatin.

12. The method of claim 7, wherein the beta-blocker is selected from the group consisting of:R+ atenolol; atenolol; nadolol; propranolol; R+propranolol; and timolol.

13. The method of claim 7, wherein the beta-blocker is selected from the group consisting of:R+ atenolol; atenolol; propranolol; and R+propranolol.

14. The method of claim 7, wherein the beta-blocker is R+ propranolol.

15. The method of claim 7, wherein the mTOR inhibitor is selected from the group consisting of: sirolimus; everolimus; temisrolimus; and rapamycin.

16. The method of claim 7, wherein the mTOR inhibitor is rapamycin.

17. The method of claim 7, wherein the steroid is a corticosteroid.

18. The method of claim 17, wherein the corticosteroid is selected from the group consisting of: dexamethasone; prednisone; prednisolone; triamcinolone; clobetasol propionate; betamethasone valerate; betamethasone dipropionate; and mometasone furoate.

19. The method of any of the preceeding claims, wherein 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.

20. The method of any of the preceeding claims, wherein 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.

21. The method of any of the preceeding claims, wherein 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.

22. The method of any of the preceeding claims, wherein 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.

23. The method of any of the preceeding claims, wherein 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.

24. The method of any one of the preceding claims, wherein the subject is a mammal.

25. The method of any one of the preceding claims, wherein the subject is a human.

26. 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.

27. A combination or kit comprising:at least one farnesyltransferase 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.

28. A composition comprising at least one farnesyltransferase inhibitor and / or at least one geranylgeranyltransferase inhibitor, for use in treating a vascular anomaly.

29. The combination, kit, or composition of one of the preceding claims, wherein the farnesyltransferase 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.

30. The combination, kit, or composition of one of the preceding claims, wherein the farnesyltransferase inhibitor is tipifamib.

31. The combination, kit, or composition of one of the preceding claims, wherein the farnesyltransferase inhibitor is lonfamib.

32. The combination, kit, or composition of one of the preceding claims, wherein the geranylgeranyltransferase inhibitor is selected from the group consisting of:GGTI-2418; and FGTI-2734.

33. The combination, kit, or composition of one of the preceding claims, wherein the statin is selected from the group consisting of: simvastatin; atorvastatin; cerivastatin; fluvastatin; lovastatin; mevastatin; pitavastatin; pravastatin; and rosuvastatin.

34. The combination, kit, or composition of one of the preceding claims, wherein the statin is simvastatin.

35. The combination, kit, or composition of one of the preceding claims, wherein the statin is atorvastatin.

36. The combination, kit, or composition of one of the preceding claims, wherein the betablocker is selected from the group consisting of:R+ atenolol; atenolol; nadolol; propranolol; R+propranolol; and timolol.

37. The combination, kit, or composition of one of the preceding claims, wherein the betablocker is selected from the group consisting of:R+ atenolol; atenolol; propranolol; and R+propranolol.

38. The combination, kit, or composition of one of the preceding claims, wherein beta-blocker is R+ propranolol.

39. The combination, kit, or composition of one of the preceding claims, wherein the mTOR inhibitor is selected from the group consisting of: sirolimus; everolimus; temisrolimus; and rapamycin.

40. The combination, kit, or composition of one of the preceding claims, wherein the mTOR inhibitor is rapamycin.

41. The combination, kit, or composition of one of the preceding claims, wherein the steroid is a corticosteroid.

42. The combination, kit, or composition of one of the preceding claims, wherein the corticosteroid is selected from the group consisting of: dexamethasone; prednisone; prednisolone; triamcinolone; clobetasol propionate; betamethasone valerate; betamethasone dipropionate; and mometasone furoate.

43. The combination, kit, or composition of one of the preceding claims, wherein the combination, kit, or composition of one of the preceding claims is formulated for oral administration.

44. The combination, kit, or composition of one of the preceding claims, wherein the combination, kit, or composition of one of the preceding claims is a syrup or suspension.

45. The combination, kit, or composition of one of the preceding claims, wherein 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.

46. The combination, kit, or composition of one of the preceding claims, wherein the vascular anomaly is infantile hemangioma.

47. The combination, kit, or composition of one of the preceding claims, wherein the combination, kit, or 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.

48. The combination, kit, or composition of one of the preceding claims, wherein the combination, kit, or 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.

49. The combination, kit, or composition of one of the preceding claims, wherein the combination, kit, or composition comprising 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.

50. The combination, kit, or composition of one of the preceding claims, wherein the combination, kit, or composition comprising 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.

51. The combination, kit, or composition of one of the preceding claims, wherein the combination, kit, or composition comprising 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.

52. The combination, kit, or composition of one of the preceding claims, wherein the combination, kit, or composition is administered to a subject, wherein the subject is a mammal.

53. The combination, kit, or composition of one of the preceding claims, wherein the combination, kit, or composition is administered to a subject, wherein the subject is a human.

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