Sirolimus for the treatment of complicated vascular anomalies in children

Hammill, Adrienne M.; Wentzel, MarySue; Gupta, Anita; Nelson, Stephen C.; Lucky, Anne W.; Elluru, Ravi; Dasgupta, Roshni; Azizkhan, Richard G.; Adams, Denise M.

doi:10.1002/pbc.23124

Cited by 539 publications

(544 citation statements)

References 36 publications

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“…mTOR is regulated by phosphoinositide-3-kinase (PI3K) [67]. The mTOR inhibitor sirolimus has been shown to inhibit lymphangiogenesis, and it has been successfully used as a treatment option for vascular anomalies in children [28,[68][69][70]. Advantages of sirolimus include oral administration without the need for a central line and more rapid…”

Section: Role Of Mtor Inhibitorsmentioning

confidence: 99%

Clinical Review: Management of Adult Kasabach-Merritt Syndrome Associated with Hemangiomas

Master¹,

Kallam²,

Eo³

et al. 2017

J Blood Disord Transfus

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Kasabach-Merritt syndrome (KMS) consists of a clinical trial of capillary hemangioma, thrombocytopenia and disseminated intravascular coagulation. KMS occurs most commonly in the pediatric population, and its occurrence in adults is rare. Specific guidelines or randomized clinical trials guiding clinical management of KMS in adult patients are lacking. This manuscript provides a comprehensive review of KMS and discusses recent advances in the medical management of KMS. We also propose a systematic therapeutic approach which would serve as a guide in the management of adult patients with KMS caused by hemangiomas.

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Section: Role Of Mtor Inhibitorsmentioning

confidence: 99%

Clinical Review: Management of Adult Kasabach-Merritt Syndrome Associated with Hemangiomas

Master¹,

Kallam²,

Eo³

et al. 2017

J Blood Disord Transfus

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“…19,20 Interferon therapy is complicated by treatment-related toxicities including fever, irritability, malaise, liver function abnormalities, and neutropenia, although the potential for irreversible neurotoxicity (including several reports of spastic diplegia 21,22 ) substantially limits its consideration as second-line therapy. It remains to be demonstrated which of these therapies is most appropriate; however, this report suggests vincristine to be a viable option that carries a tolerable side-effect profile.…”

Section: Discussionmentioning

confidence: 99%

Vincristine for Successful Treatment of Steroid-Dependent Infantile Hemangiomas

et al. 2015

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Infantile hemangiomas (IHs) are common, although systemic therapy has been generally limited to circumstances of potential compromise of vital functions (airway, vision, feeding, or cardiac), risk of disfigurement, or bleeding. IHs have previously been shown to express high levels of type III deiodinase, which catabolizes active thyroid hormone, resulting in a state of severe hypothyroidism, termed “consumptive hypothyroidism.” We describe an infant with diffuse hepatic hemangiomas who developed consumptive hypothyroidism who was initially treated successfully with systemic glucocorticoids and β-blockers. Several efforts to wean her medications were unsuccessful. She subsequently developed severe growth restriction and treatment alternatives were sought. Although previously limited to treatment of life-threatening hemangiomas, a trial of vincristine was initiated. She was ultimately weaned from all systemic therapies, with recovery of a normal growth trajectory. This case highlights broader indications for vincristine as a safe and effective systemic therapy for treatment of IHs. It also stresses the importance of close anthropometric monitoring of infants and toddlers receiving glucocorticoid therapy and intervention when growth compromise becomes evident.

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“…Systemic rapamycin effectively inhibits complicated vascular anomalies. 28 Although the clinical efficacy of rapamycin in patients with infantile hemangioma has not been reported, rapamycin has been shown to reduce the self-renewal capacity and vasculogenic activity of hemangioma stem cells. 27 The drug also reduces the proliferation of hemangioma EC, as well as VEGF and hypoxia-inducible factor-1a levels in these cells.…”

Section: Rapamycin Delivered Systemically or Topically Reduces The mentioning

confidence: 99%

“…26,27 Rapamycin and rapalogs have shown promising results in clinical trials for other types of vascular lesions, including Kaposi's sarcoma, kidney angiomyolipoma and complicated vascular anomalies. 17,28,29 As rapamycin is an immunosuppressive drug, it can cause significant negative side effects in healthy individuals when taken systemically. In recent studies, topical rapamycin has been shown to be effective in the treatment of facial angiofibroma and hypomelanotic macule.…”

mentioning

confidence: 99%

Vascular tumors have increased p70 S6-kinase activation and are inhibited by topical rapamycin

Gerald²,

Perruzzi³

et al. 2013

Laboratory Investigation

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Vascular tumors are endothelial cell neoplasms whose cellular and molecular mechanisms, leading to tumor formation, are poorly understood, and current therapies have limited efficacy with significant side effects. We have investigated mechanistic (mammalian) target of rapamycin (mTOR) signaling in benign and malignant vascular tumors, and the effects of mTOR kinase inhibitor as a potential therapy for these lesions. Human vascular tumors (infantile hemangioma and angiosarcoma) were analyzed by immunohistochemical stains and western blot for the phosphorylation of p70 S6-kinase (S6K) and S6 ribosomal protein (S6), which are activated downstream of mTOR complex-1 (mTORC1). To assess the function of S6K, tumor cells with genetic knockdown of S6K were analyzed for cell proliferation and migration. The effects of topical rapamycin, an mTOR inhibitor, on mTORC1 and mTOR complex-2 (mTORC2) activities, as well as on tumor growth and migration, were determined. Vascular tumors showed increased activation of S6K and S6. Genetic knockdown of S6K resulted in reduced tumor cell proliferation and migration. Rapamycin fully inhibited mTORC1 and partially inhibited mTORC2 activities, including the phosphorylation of Akt (serine 473) and PKCa, in vascular tumor cells. Rapamycin significantly reduced vascular tumor growth in vitro and in vivo. As a potential localized therapy for cutaneous vascular tumors, topically applied rapamycin effectively reduced tumor growth with limited systemic drug absorption. These findings reveal the importance of mTOR signaling pathways in benign and malignant vascular tumors. The mTOR pathway is an important therapeutic target in vascular tumors, and topical mTOR inhibitors may provide an alternative and well-tolerated therapy for the treatment of cutaneous vascular lesions.

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Sirolimus for the treatment of complicated vascular anomalies in children

Cited by 539 publications

References 36 publications

Clinical Review: Management of Adult Kasabach-Merritt Syndrome Associated with Hemangiomas

Clinical Review: Management of Adult Kasabach-Merritt Syndrome Associated with Hemangiomas

Vincristine for Successful Treatment of Steroid-Dependent Infantile Hemangiomas

Vascular tumors have increased p70 S6-kinase activation and are inhibited by topical rapamycin

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