sirolimus and Hemangioma

The field of pediatric dermatology treatment has been rich in new developments. Several recent therapeutic advances in pediatric dermatology have been made. This review will focus on critical approach to the new treatments for several entities encountered in pediatric dermatology. The use of biologics and small molecules in children with atopic dermatitis and psoriasis, exciting advances in the use of propranolol and other beta-blockers for the treatment of infantile hemangiomas, the use of sirolimus for vascular anomalies will be discussed.

Topics: Adrenergic beta-Antagonists; Biological Products; Child; Dermatitis, Atopic; Hemangioma; Humans; Phosphodiesterase 4 Inhibitors; Psoriasis; Sirolimus; Skin Diseases

Maffucci syndrome is a rare genetic disease due to somatic mutation of IDH1 gene. Currently there is no medical treatment available for spindle cell hemangioma associated with this disorder. Here we report successful management of these hemangiomas using sirolimus in combination with surgery.

Topics: Adult; Enchondromatosis; Female; Hemangioma; Humans; Sirolimus

The mTOR inhibitor rapamycin is used systemically for the treatment of vascular lesions. We report the first use of topical rapamycin for the successful treatment of two cases of tufted angioma. The evidence for the use of topical rapamycin in other dermatologic conditions is summarized to aid in clinical decision making on preparations and anticipated side effects.

Topics: Administration, Topical; Child; Female; Hemangioma; Humans; Immunosuppressive Agents; Infant; Sirolimus; Skin Neoplasms

With a prevalence of 2.6-4.5 %, infantile haemangiomas (IH) represent the most common tumour of infancy. While the majority of IH does not require therapy and regresses spontaneously, about 10 % of IH exhibit complications such as obstruction, ulceration or disfigurement. With the advent of oral propranolol, many conventional treatment options have become obsolete. This paper summarizes current recommendations for management of complicated IH. These recommendations have been written by an expert group after a consensus process including bibliographic review, several drafts of synthesis, meetings with quantitative voting system and redaction of an approved final manuscript.. Oral propranolol is the first-line agent for the treatment of complicated IH.. • Infantile haemangiomas (IH) are the most common tumours of infancy. Within a very short period after its discovery and long before the publication of randomized controlled trials, propranolol has become the number one agent for the treatment of complicated IH. What is New: • We report IH treatment recommendations of an international, interdisciplinary team of experts, based on an up-to-date review of the literature.

Topics: Administration, Topical; Adrenergic beta-Antagonists; Aortic Coarctation; Cryotherapy; Diagnosis, Differential; Esthetics; Eye Abnormalities; Glucocorticoids; Hemangioma; Humans; Immunosuppressive Agents; Infant; Laser Therapy; Neurocutaneous Syndromes; Phototherapy; Propranolol; Risk Factors; Sirolimus; Vascular Neoplasms; Watchful Waiting

Topics: Hemangioma; Humans; Retrospective Studies; Sirolimus; Skin Diseases, Vascular; Skin Neoplasms

Topics: Hemangioma; Humans; Retrospective Studies; Sirolimus; Skin Diseases, Vascular; Skin Neoplasms

We have previously developed several kinds of rapamycin-encapsulated nanoparticles to achieve sustained release of rapamycin to treat hemangioma. However, lack of intrinsic targeting and easy clearance by the immune system are major hurdles that artificial fabricated nanoparticles must overcome. We constructed rapamycin-encapsulated macrophage-derived exosomes mimic nanoparticles-in-microspheres (RNM), to achieve the goal of continuous targeted therapy of hemangiomas. The rapamycin-encapsulated exosome mimic nanoparticles (RN) were firstly prepared by the extrusion-based method from the U937 cells (the human macrophage cell line). After then, RN was encapsulated with PLGA (poly(lactic-co-glycolic acid)) microspheres to obtain RNM. The release profile, targeting activity, and biological activity of RN and RNM were investigated on hemangioma stem cells (HemSCs). RN has a size of 100 nm in diameter, with a rapamycin encapsulation efficacy (EE) of 83%. The prepared microspheres RNM have a particle size of ~30 µm), and the drug EE of RNM is 34%. The sustained release of RNM can remarkably be achieved for 40 days. As expected, RN and RNM showed effective inhibition of cellular proliferation, significant cellular apoptosis, and remarkable repressed expression of angiogenesis factors in HemSCs. Our results showed that RNM is an effective approach for prolonged and effective delivery of rapamycin to hemangiomas.

Topics: Animals; Apoptosis; Biomimetics; Cell Proliferation; Drug Delivery Systems; Drug Liberation; Exosomes; Female; Hemangioma; Humans; Mice; Microspheres; Nanoparticles; Particle Size; Polylactic Acid-Polyglycolic Acid Copolymer; Sirolimus; U937 Cells

The mechanisms underlying the success of propranolol in the treatment of infantile hemangioma (IH) remain elusive and do not fully explain the rapid regression of hemangiomatous lesions following drug administration. As autophagy is critically implicated in vascular homeostasis, we determined whether β-blockers trigger the autophagic flux on infantile hemangioma-derived endothelial cells (Hem-ECs) in vitro.. Fresh tissue specimens, surgically removed for therapeutic purpose to seven children affected by proliferative IH, were subjected to enzymatic digestion. Cells were sorted with anti-human CD31 immunolabeled magnetic microbeads. Following phenotypic characterization, expanded Hem-ECs, at P2 to P6, were exposed to different concentrations (50 μM to 150 μM) of propranolol, atenolol or metoprolol alone and in combination with the autophagy inhibitor Bafilomycin A1. Rapamycin, a potent inducer of autophagy, was also used as control. Autophagy was assessed by Lysotracker Red staining, western blot analysis of LC3BII/LC3BI and p62, and morphologically by transmission electron microscopy.. Hem-ECs treated with either propranolol, atenolol or metoprolol displayed positive LysoTracker Red staining. Increased LC3BII/LC3BI ratio, as well as p62 modulation, were documented in β-blockers treated Hem-ECs. Abundant autophagic vacuoles and multilamellar bodies characterized the cytoplasmic ultrastructural features of autophagy in cultured Hem-ECs exposed in vitro to β-blocking agents. Importantly, similar biochemical and morphologic evidence of autophagy were observed following rapamycin while Bafilomycin A1 significantly prevented the autophagic flux promoted by β-blockers in Hem-ECs.. Our data suggest that autophagy may be ascribed among the mechanisms of action of β-blockers suggesting new mechanistic insights on the potential therapeutic application of this class of drugs in pathologic conditions involving uncontrolled angiogenesis.

Topics: Adrenergic beta-Antagonists; Amines; Atenolol; Autophagy; Cell Proliferation; Child; Endothelial Cells; Hemangioma; Humans; Macrolides; Metoprolol; Propranolol; Sirolimus

Congenital hepatic hemangioma (CHH) is a common benign vascular tumor of the liver, seen in infancy. The clinical manifestations vary from incidental findings to life-threatening complications. The authors present here a case of an infant with massive CHH who developed systemic hypertension because of compression of the right renal artery by the CHH and did not respond to other lines of treatment. After sirolimus therapy, the CHH size decreased and antihypertensive drugs were no longer necessary. In a critical situation, if the embolization and/or steroids do not seem to control the situation, then adding sirolimus may be considered as secondary therapy with good additive effects.

Topics: Embolization, Therapeutic; Hemangioma; Humans; Hypertension; Infant; Liver Neoplasms; Sirolimus

Recently, sirolimus has emerged as a safe and effective treatment modality for unresectable vascular lesions. In the present study, we investigated the effectiveness and safety of sirolimus from our early experience with patients with unresectable vascular anomalies.. Six patients with unresectable vascular anomalies were treated with sirolimus for ≥10 months. Their median age at the initiation of sirolimus treatment was 17 months (range, 8-67 months). The median duration of treatment was 13 months (range, 10-16 months). One patient had a good response, four had an intermediate response, and one had no response to sirolimus therapy. None of the patients had discontinued sirolimus therapy because of adverse effects.. Sirolimus can be used effectively and safely for patients with unresectable vascular anomalies. However, further prospective studies are warranted to evaluate the long-term effects of sirolimus and clarify the indications for early intervention.

Topics: Antibiotics, Antineoplastic; Child, Preschool; Female; Hemangioma; Humans; Infant; Male; Retrospective Studies; Sirolimus; Treatment Outcome; Vascular Malformations

Topics: Hemangioma; Humans; Liver Neoplasms; Sirolimus

Mammalian target of rapamycin (mTOR) inhibitors have been shown to have excellent effects in the management of kaposiform hemangioendothelioma (KHE); however, the mechanism of action is unclear. This study identified the expressions of mTOR pathway-related proteins in different vascular tumors to provide insight into the pathogenesis of KHE.. We retrospectively reviewed the pathologic specimens of 30 patients (KHE, 15; tufted angioma [TA], 5; infantile hemangioma [IH], 5; and lymphatic malformation [LM], 5). The immunohistochemical expression of mTOR-related proteins tuberous sclerosis complex 2 (TSC2), phosphatase and tensin homologue (PTEN), phosphorylated eukaryotic translation initiation factor 4E binding protein 1 (p-4EBP1), phosphorylated mTOR (p-mTOR), and phosphorylated ribosomal protein S6 kinase B1 (p-P70S6K) were analyzed using Image-Pro Plus software. KHE had the following pattern of expression in the spindle vascular endothelial cells: TSC2 (-); PTEN (-); p-4EBP1 (+); p-mTOR (+); and p-P70S6K (+).. All 3 patients treated with sirolimus had good responses. The TA results were similar to KHE with no significant differences (p-4EBP1: p = 0.0687; p-mTOR: p = 0.0832). The expressions of TSC2, PTEN, p-4EBP1, p-mTOR, and p-P70S6K were negative or weakly positive in IH with a statistically significant difference compared to KHE (p-4EBP1: p < 0.001; p-mTOR: p < 0.001; p-P70S6K: p < 0.001). LM had no significant differences when compared to KHE.. The absence of TSC2 and PTEN caused abnormal activation of the mTOR signaling pathway and may be involved in the pathogenesis of KHE. The expression of mTOR-related proteins in TA and LM was similar to KHE, unlike IH. The KHE pattern of expression [PTEN (-), TSC2 (-), p-mTOR (+), p-P70S6K (+), and p-4EBP1 (+)] suggested that sirolimus may be a good therapeutic choice.

Topics: Antineoplastic Agents; Endothelial Cells; Hemangioendothelioma; Hemangioma; Humans; Immunohistochemistry; Kasabach-Merritt Syndrome; Lymphatic Abnormalities; Retrospective Studies; Sarcoma, Kaposi; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Adult; Female; Glucocorticoids; Hemangioma; Humans; Kasabach-Merritt Syndrome; Liver; Liver Neoplasms; Sirolimus

Infantile hemangiomas are the most common benign vascular tumors in childhood. Propranolol is the first-line treatment for infantile hemangiomas, but failures may occur. Sirolimus, an mTOR inhibitor, is a promising drug for the treatment of vascular malformations and vascular tumors. We present the case of a child with multiple infantile hemangiomasthat was successfully treated with sirolimus and propranolol after failure of combined propranolol and prednisolone treatment.

Topics: Adrenergic beta-Antagonists; Child; Hemangioma; Hemangioma, Capillary; Humans; Infant; Prednisolone; Propranolol; Sirolimus; Treatment Outcome

Hepatic hemangioma (HH) is a common asymptomatic, self-limiting benign vascular tumor of the liver in neonates. Although complicated HHs are rare, they have significant risks of morbidity and mortality, especially during the perinatal period. Because of the high risks of complications from surgical interventions, there is an unmet need for effective medical therapy. We report 2 neonates with life-threatening HH who were evaluated for a liver transplant before being treated successfully with combined medical therapy, which included sirolimus, corticosteroids, and propranolol.

Topics: Drug Therapy, Combination; Embolization, Therapeutic; Female; Glucocorticoids; Hemangioma; Hepatic Artery; Humans; Infant, Newborn; Liver Neoplasms; Male; Methylprednisolone; Propranolol; Sirolimus; Vasodilator Agents

Maffucci syndrome is characterized by multiple benign vascular anomalies and enchondromas present on the distal extremities. Effective treatment options are currently not available for Maffucci syndrome-associated vascular lesions. Sirolimus is a mTOR pathway inhibitor, and has been tried successfully in the treatment of various vascular anomalies. We treated a 23-year-old female with Maffucci syndrome-associated spindle cell hemangiomas with oral sirolimus (2mg/day, 0.04mg/kg/day). There was improvement in pain, but no change in colour or size of the vascular nodules. In view of unsatisfactory response and treatment-related adverse effects (oral aphthae, mild transaminitis), sirolimus was stopped after 6 months.

Topics: Administration, Oral; Enchondromatosis; Female; Hemangioma; Humans; Immunosuppressive Agents; Sirolimus; Treatment Failure; Young Adult

Topics: Adolescent; Antibiotics, Antineoplastic; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Hemangioendothelioma; Hemangioma; Humans; Kasabach-Merritt Syndrome; Male; Prognosis; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms

Topics: Administration, Topical; Antibiotics, Antineoplastic; Female; Hemangioma; Humans; Middle Aged; Sirolimus; Skin Neoplasms; Young Adult

The most common tumors in children are infantile hemangiomas which could cause morbidity and severe complications. The development of novel alternative drugs to treat infantile hemangiomas is necessary, since Hemangeol is the only US Food and Drug Administration-approved drug for infantile hemangiomas. However, Hemangeol has several disadvantages, including a high frequency of administration and adverse effects. Rapamycin is a well‑established antiangiogenic drug, and we have previously developed rapamycin lipid polymer nanoparticles (R‑PLNPs) as a local sustained‑release drug delivery system to achieve controlled rapamycin release and to decrease the frequency of administration and side effects of rapamycin. To improve the targeting of R‑PLNPs to infantile hemangiomas in the present study, R‑PLNPs were modified to include an antibody against vascular endothelial growth factor receptor (VEGF). The characteristics, and the anti‑hemangioma activity of the resulting R‑PLNPs coupled with the anti‑VEGFR2 antibody (named R‑PLNPs‑V) were examined in vitro and in vivo. R‑PLNPs‑V possessed a small size (115 nm) and sustained drug release for 6 days. The anti‑VEGFR2 antibody promoted the targeting and cytotoxic effect of R‑PLNPs‑V to human hemangioma endothelial cells and human umbilical vein endothelial cells. Using a subcutaneous infantile hemangioma xenograft in mice, the in vivo therapeutic effect (evaluated with hemangioma weight, volume, and microvessel density) of R‑PLNPs‑V was demonstrated to be superior compared with rapamycin alone and other non‑targeted nanoparticles, without any total body weight loss. In summary, R‑PLNPs‑V could facilitate targeted delivery and sustained release of rapamycin to infantile hemangiomas, and thus may represent a promising candidate treatment for infantile hemangiomas.

Topics: Anti-Bacterial Agents; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Hemangioma; Human Umbilical Vein Endothelial Cells; Humans; Nanoparticles; Polymers; Sirolimus; Vascular Endothelial Growth Factor A

Superficial vascular anomalies constitute a large group of malformative and tumoral conditions developed from all types of vessels. Vascular tumors are the result of cellular hyperplasia, whereas vascular malformations (VMs) are constituted of dysplastic vessels. The classification from International Society for the Study of Vascular Anomalies (ISSVA) is based on this pathogenic difference. The most common vascular tumor is infantile hemangioma, which treatment, when necessary, is propranolol. Congenital hemangiomas and tumors that might be complicated with Kasabach-Merritt phenomenon, i.e. deep thrombocytopenia, are much rarer. Management of Kasabach-Merritt phenomenon is now largely based on sirolimus. Low-flow VMs include capillary, venous and lymphatic malformations; arteriovenous malformations are high-flow malformations. These different types of VMs might be combined. Currently, there is an increasing work in delineating the different entities based on molecular findings. Treatment of VMs depends on the impairment linked to them, and is decided case by case, in pluridisciplinary consultations. Interventional treatments, especially surgery and sclerotherapy, are usually partially efficient, and management of patients with VMs increasingly involves medical drugs. First-line treatment of coagulation disorders associated with venous malformations is based on low molecular weight heparin; sirolimus seems efficient in hemorrhagic complications refractory to usual treatment. Sirolimus is about to become the standard treatment in painful inflammatory manifestations of mixed and/or complicated lymphatic malformations.

Topics: Adolescent; Adrenergic alpha-1 Receptor Antagonists; Arteriovenous Malformations; Child; Child, Preschool; Hemangioma; Humans; Infant; Kasabach-Merritt Syndrome; Neoplasms, Vascular Tissue; Propranolol; Rare Diseases; Sirolimus; Vascular Malformations; Vasodilator Agents

Topics: Adult; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hand; Hemangioma; Humans; Neoplasm Recurrence, Local; Sirolimus; Skin; Skin Neoplasms; TOR Serine-Threonine Kinases; Treatment Outcome

Topics: Administration, Oral; Antibiotics, Antineoplastic; Child, Preschool; Drug Administration Schedule; Female; Hemangioendothelioma; Hemangioma; Humans; Infant; Kasabach-Merritt Syndrome; Male; Neoplasms, Vascular Tissue; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Treatment Outcome

Diffuse hepatic hemangiomas are a challenging disease that can be life threatening. We present the case of an infant with diffuse hepatic hemangiomas who failed first-line therapies but later responded to sirolimus and high-dose propranolol.

Topics: Adrenergic beta-Antagonists; Hemangioma; Humans; Immunosuppressive Agents; Infant, Newborn; Liver; Liver Neoplasms; Magnetic Resonance Imaging; Male; Propranolol; Sirolimus; Treatment Outcome

Infantile hemangioma is a benign vascular neoplasm that spontaneously involutes over time. Management, when needed, consists of medications, laser treatment and surgical excision. We describe a 3-year-old girl who presented shortly after birth with diffuse cutaneous hemangiomas, hepatosplenomegaly with liver lesions, anemia, and acute heart failure. She was diagnosed with hepatic and cutaneous infantile hemangioma based on skin biopsy. She developed progressive pulmonary hypertension with numerous pulmonary nodules suspicious for pulmonary arteriovenous malformations. She was started on sirolimus and had significant improvement in her pulmonary hypertension and liver lesions. This report supports prior studies that sirolimus is effective for vascular anomalies including IH refractory to conventional therapy.

Topics: Allografts; Child, Preschool; Dyskeratosis Congenita; Female; Hemangioma; Hematopoietic Stem Cell Transplantation; Humans; Hypertension, Pulmonary; Liver Neoplasms; Sirolimus; Skin Neoplasms; Treatment Outcome

Although infantile hemangiomas is benign, its rapid growth may induce serious complications. However, only one drug Hemangeol™ has been approved by US Food and Drug Administration (FDA) to treat infantile hemangiomas. Thus it is necessary to develop novel alternative drugs to treat infantile hemangiomas. Rapamycin is a well-know potent antiangiogenic agent, whereas the daily oral administration of rapamycin exerts undesired metabolic effects due to its inhibition of mechanistic target of rapamycin (mTOR) which is critical in cell metabolism. We hereby developed rapamycin-loaded polymer-lipid hybrid nanoparticles (Rapamycin-PLNPs) as a local controlled release system to realize local and sustained release of rapamycin, aiming to reduce the side effects and frequency of administration of rapamycin. Rapamycin-PLNPs are of a small size (129.1nm), desired drug encapsulation efficiency (63.7%), and sustained drug release for 5 days. Rapamycin-PLNPs were shown to be able to effectively bind to hemangioma endothelia cells (HemECs), induce significant proliferation inhibition and reduce expression of angiogenesis factors in HemECs. The therapeutic effect of Rapamycin-PLNPs against infantile hemangioma in vivo was superior to rapamycin, as reflected by reduced hemangioma volume, weight and microvessel density. Taken together, Rapamycin-PLNPs represent a very promising local approach in the treatment of infantile hemangiomas.

Topics: Animals; Autophagy; Biomarkers; Cell Line, Tumor; Cell Proliferation; Drug Delivery Systems; Drug Liberation; Endocytosis; Female; Fibroblast Growth Factor 2; Flow Cytometry; Hemangioma; Human Umbilical Vein Endothelial Cells; Humans; Inhibitory Concentration 50; Lipids; Mice, Inbred BALB C; Mice, Nude; Microvessels; Nanoparticles; Polymers; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Topics: Hemangioma; Humans; Infant; Kasabach-Merritt Syndrome; Magnetic Resonance Imaging; Male; Protein Kinase Inhibitors; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases; Treatment Outcome

Blue rubber bleb nevus syndrome is a rare disease involving venous malformations.. We present a 6-year-old female with the syndrome, and consumptive coagulopathy.. After management with sirolimus, symptoms resolved.. Sirolimus may be a valuable option for reducing bleeding complications and cosmetic sequelae for the patients with this syndrome.

Topics: Antibiotics, Antineoplastic; Child; Female; Gastrointestinal Neoplasms; Hemangioma; Humans; Nevus, Blue; Sirolimus; Skin; Skin Neoplasms

Endothelial glucose transporter 1 (GLUT1) is a definitive and diagnostic marker for infantile hemangioma (IH), a vascular tumor of infancy. To date, GLUT1-positive endothelial cells in IH have not been quantified nor directly isolated and studied. We isolated GLUT1-positive and GLUT1-negative endothelial cells from IH specimens and characterized their proliferation, differentiation, and response to propranolol, a first-line therapy for IH, and to rapamycin, an mTOR pathway inhibitor used to treat an increasingly wide array of proliferative disorders. Although freshly isolated GLUT1-positive cells, selected using anti-GLUT1 magnetic beads, expressed endothelial markers CD31, VE-Cadherin, and vascular endothelial growth factor receptor 2, they converted to a mesenchymal phenotype after 3 weeks in culture. In contrast, GLUT1-negative endothelial cells exhibited a stable endothelial phenotype in vitro. GLUT1-selected cells were clonogenic when plated as single cells and could be induced to redifferentiate into endothelial cells, or into pericytes/smooth muscle cells or into adipocytes, indicating a stem cell-like phenotype. These data demonstrate that, although they appear and function in the tumor as bona fide endothelial cells, the GLUT1-positive endothelial cells display properties of facultative stem cells. Pretreatment with rapamycin for 4 days significantly slowed proliferation of GLUT1-selected cells, whereas propranolol pretreatment had no effect. These results reveal for the first time the facultative nature of GLUT1-positive endothelial cells in IH.

Topics: Cell Differentiation; Cell Proliferation; Child; Child, Preschool; Endothelial Cells; Female; Glucose Transporter Type 1; Hemangioma; Humans; Infant; Male; Neoplastic Stem Cells; Propranolol; Sirolimus; Stem Cells

Topics: Adult; Antibiotics, Antineoplastic; Enchondromatosis; Hemangioma; Humans; Male; Sirolimus; Skin Neoplasms; Treatment Failure

Endothelial microparticles (EMPs) are complex vesicular structures with great significance in vascular pathophysiology. Here, we aimed to determine the impact of therapeutic drugs for infantile hemangioma, a common vascular tumor of infancy, on the biochemical features of EMPs. We exposed human umbilical vein endothelial cells to propranolol (Pro), dexamethasone (Dex), or rapamycin (Rap). Compared with controls, Pro and Rap dramatically augmented EMP release, whereas Dex significantly suppressed EMP generation. Drug-stimulated EMPs could inherit but tended to lose specific endothelial surface antigens from their parental cells. On the one hand, markedly distinct messenger RNA expression patterns were observed within and between drug-stimulated endothelial cells and derived EMPs. On the other hand, Rap-treated endothelial cells and Pro-induced EMPs displayed downregulation of multiple angiogenesis-related molecules at messenger RNA level compared with corresponding controls. Meanwhile, among tested angiogenesis-associated microRNAs, twelve microRNAs were downregulated in drug-induced EMPs, whereas only let-7b and miR-133a were markedly upregulated. Collectively, these data may indicate selective and distinctive package of biomolecules into EMPs depending on specific drugs. Our findings may provide novel insights into the underlying mechanisms of pharmacological therapy for infantile hemangioma.

Topics: Cells, Cultured; Dexamethasone; Endothelium, Vascular; Flow Cytometry; Hemangioma; Human Umbilical Vein Endothelial Cells; Humans; MicroRNAs; Microscopy, Electron, Transmission; Neovascularization, Pathologic; Propranolol; Sirolimus; Vascular Endothelial Growth Factor A

The therapy of vascular tumors and malformations should be interdisciplinary and performed according to available guidelines. Infantile hemangiomas (IH) are the most frequent vascular tumors of childhood and do not require treatment in most cases. If the IH is complicated by its location (e.g. facial or genital) or if the lesion threatens to cause loss of function, small localized IH should be treated by laser- or cryotherapy. If the IH is diffuse or rapidly growing it can be successfully treated using the β blocker propranolol. The mechanism underlying the efficacy of this medication-based therapy is not completely understood and this still represents an experimental therapy. The results of molecular studies on vascular malformations have indicated new strategies for medical therapies. However, lymphatic malformations (LM) are still treated by surgery where possible, or sclerotherapy. Further investigations are necessary to determine whether new drugs such as the mTOR inhibitor rapamycin may be effective for treatment of diffuse LM. First case reports seem to be promising.

Topics: Antibiotics, Antineoplastic; Female; Head and Neck Neoplasms; Hemangioma; Humans; Infant; Infant, Newborn; Lymphatic Abnormalities; Lymphatic Vessel Tumors; Male; Propranolol; Sirolimus; Vasodilator Agents

Hemangiomas are tumors formed by hyper-proliferation of vascular endothelial cells. This is caused by elevated vascular endothelial growth factor (VEGF) signaling through VEGF receptor 2 (VEGFR2). Here we show that elevated VEGF levels produced by hemangioma endothelial cells are reduced by the mTOR inhibitor rapamycin. mTOR activates p70S6K, which controls translation of mRNA to generate proteins such as hypoxia inducible factor-1 (HIF-1). VEGF is a known HIF-1 target gene, and our data show that VEGF levels in hemangioma endothelial cells are reduced by HIF-1α siRNA. Over-expression of HIF-1α increases VEGF levels and endothelial cell proliferation. Furthermore, both rapamycin and HIF-1α siRNA reduce proliferation of hemangioma endothelial cells. These data suggest that mTOR and HIF-1 contribute to hemangioma endothelial cell proliferation by stimulating an autocrine loop of VEGF signaling. Furthermore, mTOR and HIF-1 may be therapeutic targets for the treatment of hemangiomas.

Topics: Antibiotics, Antineoplastic; Autocrine Communication; Cell Line; Cell Proliferation; Endothelial Cells; Gene Expression; Gene Expression Regulation, Neoplastic; Hemangioma; Humans; Hypoxia-Inducible Factor 1; Phosphatidylinositol 3-Kinases; Phosphorylation; Ribosomal Protein S6 Kinases, 70-kDa; RNA Interference; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Infantile hemangioma (IH) is a common childhood vascular tumor. Although benign, some hemangiomas cause deformation and destruction of features or endanger life. The current treatments, corticosteroid or propranolol, are administered for several months and can have adverse effects on the infant. We designed a high-throughput screen to identify the Food and Drug Administration-approved drugs that could be used to treat this tumor. Rapamycin, an mTOR (mammalian target of Rapamycin) inhibitor, was identified, based on its ability to inhibit proliferation of a hemangioma-derived stem cell population, human vasculogenic cells, which we had previously discovered. In vitro and in vivo studies show that Rapamycin reduces the self-renewal capacity of the hemangioma stem cells, diminishes differentiation potential, and inhibits the vasculogenic activity of these cells in vivo. Longitudinal in vivo imaging of blood flow through vessels formed with hemangioma stem cells shows that Rapamycin also leads to regression of hemangioma blood vessels, consistent with its known anti-angiogenic activity. Finally, we demonstrate that Rapamycin-induced loss of stemness can work in concert with corticosteroid, the current standard therapy for problematic hemangioma, to block hemangioma formation in vivo. Our studies reveal that Rapamycin targets the self-renewal and vascular differentiation potential in patient-derived hemangioma stem cells, and suggests a novel therapeutic strategy to prevent formation of this disfiguring and endangering childhood tumor.

Topics: Antineoplastic Agents; Cell Differentiation; Cell Division; Cell Line, Tumor; Coculture Techniques; Dexamethasone; Drug Evaluation, Preclinical; Hemangioma; High-Throughput Screening Assays; Humans; Infant; Neoplastic Stem Cells; Sirolimus

This is a remarkable time to be a student of infantile hemangiomas (IHs). IH is a common tumor, estimated to occur in approximately 4% of infants. Studied for many decades, the acquisition of knowledge and pace of IH research are accelerating. The article by Greenberger et al. in this issue is a welcome addition to the literature. It examines rapamycin as a possible treatment for IH that could potentially be curative because suppression of self-renewal of stem cells might deplete hemangiomas of the stem cells from which they originate. However, before we get too enthusiastic about using rapamycin for IHs, it is important to reflect on lessons learned from previous hemangioma therapies.

Topics: Antineoplastic Agents; Cell Differentiation; Cell Division; Hemangioma; Humans; Neoplastic Stem Cells; Sirolimus

Tuberous sclerosis complex (TSC) is a familial tumor disorder for which there is no effective medical therapy. Disease-causing mutations in the TSC1 or TSC2 gene lead to increased mammalian target of rapamycin (mTOR) kinase activity in the conserved mTOR signaling pathway, which regulates nutrient uptake, cell growth, and protein translation. The normal function of TSC1 and TSC2 gene products is to form a complex that reduces mTOR kinase activity. Thus, mTOR kinase inhibition may be a useful targeted therapeutic approach. Elevated interferon-gamma (IFN-gamma) expression is associated with decreased severity of kidney tumors in TSC patients and mouse models; therefore, IFN-gamma also has therapeutic potential. We studied cohorts of Tsc2+/- mice and a novel mouse model of Tsc2-null tumors in order to evaluate the efficacy of targeted therapy for TSC. We found that treatment with either an mTOR kinase inhibitor (CCI-779, a rapamycin analog) or with IFN-gamma reduced the severity of TSC-related disease without significant toxicity. These results constitute definitive preclinical data that justify proceeding with clinical trials using these agents in selected patients with TSC and related disorders.

Topics: Animals; Cystadenoma; Disease Models, Animal; Drug Therapy, Combination; Hemangioma; Interferon-gamma; Kidney Neoplasms; Liver Neoplasms, Experimental; Mice; Mice, Knockout; Mice, Nude; Phosphorylation; Protein Kinases; Repressor Proteins; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins