Sirolimus for Retinal Astrocytic Hamartoma Associated with Tuberous Sclerosis Complex

Zhang, Zhiqiao; Shen, Cheng; Long, Qin; Yang, Zhikun; Dai, Rongping; Wang, Jun; Zhang, Weihong; Pan, Qingqing; Zhu, Zhaohui; Xu, Kai‐Feng

doi:10.1016/j.ophtha.2015.03.023

Cited by 33 publications

(18 citation statements)

References 5 publications

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“…Since aberrant activation of mTORC1 is considered to be mainly responsible for TSC-related tumor formation, rapamycin and its analogues have been suggested to be effective drugs for TSC treatment [ 9 , 53 – 55 ]. However, the therapeutic efficacy of such drugs is limited by several reasons, including immunosuppression-associated opportunistic infections [ 56 ] and reactivation of AKT [ 17 , 18 ].…”

Section: Discussionmentioning

confidence: 99%

Hyperactivated mTORC1 downregulation of FOXO3a/PDGFRα/AKT cascade restrains tuberous sclerosis complex-associated tumor development

Wang

Liu

et al. 2017

Oncotarget

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Hyperactivation of mammalian target of rapamycin complex 1 (mTORC1), caused by loss-of-function mutations in either the TSC1 or TSC2 gene, leads to the development of tuberous sclerosis complex (TSC), a benign tumor syndrome with multiple affected organs. mTORC1-mediated inhibition of AKT constrains the tumor progression of TSC, but the exact mechanisms remain unclear. Herein we showed that loss of TSC1 or TSC2 downregulation of platelet-derived growth factor receptor α (PDGFRα) expression was mediated by mTORC1. Moreover, mTORC1 inhibited PDGFRα expression via suppression of forkhead box O3a (FOXO3a)-mediated PDGFRα gene transcription. In addition, ectopic expression of PDGFRα promoted AKT activation and enhanced proliferation and tumorigenic capacity of Tsc1- or Tsc2-null mouse embryonic fibroblasts (MEFs), and vice versa. Most importantly, rapamycin in combination with AG1295, a PDGFR inhibitor, significantly inhibited growth of TSC1/TSC2 complex-deficient cells in vitro and in vivo. Therefore, downregulated FOXO3a/PDGFRα/AKT pathway exerts a protective effect against hyperactivated mTORC1-induced tumorigenesis caused by loss of TSC1/TSC2 complex, and the combination of rapamycin and AG1295 may be a new effective strategy for TSC-associated tumors treatment.

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Section: Discussionmentioning

confidence: 99%

Hyperactivated mTORC1 downregulation of FOXO3a/PDGFRα/AKT cascade restrains tuberous sclerosis complex-associated tumor development

Wang

Liu

et al. 2017

Oncotarget

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“…While symptomatic changes to the fundus due to a retinal hamartoma occur in comparatively few cases, there have been some reports of other changes, including subretinal hard exudates, macular edema, vitreous hemorrhage, and exudative retinal detachment [3,4,5,6,7,8,9,10]. This invasive tumorous lesion tends to be limited to the retinal nerve fiber layer (NFL), and when examined by spectral domain-optical coherence tomography (SD-OCT), NFLs are reportedly observed as dome-like ridges of high intensity [11, 12]. In addition, it has also been reported that pathologically, myelin formation and gliosis are observed in this tumor [2].…”

Section: Discussionmentioning

confidence: 99%

A Case of Proliferative Retinopathy Complicated with Tuberous Sclerosis Treated by Vitreous Surgery

Nemoto

Morishita

Akashi

et al. 2016

Case Rep Ophthalmol

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We report a case of proliferative retinopathy complicated with retinal hamartoma in a tuberous sclerosis patient. This study involved a 16-year-old female patient who was diagnosed as having tuberous sclerosis at birth. Ophthalmic examination revealed retinal hamartoma surrounding the optic disc in both eyes. Vitreous surgery involving a vitrectomy and resection of the proliferative membranes was performed for proliferative retinopathy in her right eye. Postoperative fundus findings showed improvement and decreased exudative changes. The proliferative and exudative changes appeared to be due to the retinal hamartoma, and vitreous surgery proved effective in this case.

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“…Treatment with sirolimus was shown to reduce retinal hamartomas in a series of seven patients, [3] and a recent publication also showed retinal astrocytoma regression in response to everolimus. [4] The aim of this report is to show an easy non-interventional method of monitoring response to treatment, using repeated eye examinations and optical coherence tomography (OCT) measurements of retinal hamartomas.…”

Section: Introductionmentioning

confidence: 93%

Retinal hamartomas respond to everolimus treatment for tuberous sclerosis: A photo essay

Herscu¹,

Cohen²,

Man-Peles³

et al. 2019

cleverjournal

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Background: Tuberous sclerosis is characterized by hamartomas in multiple organs including retinal hamartomas. Everolimus is a novel treatment for tuberous sclerosisrelated lesions. We present a case where everolimus led to lesion shrinkage, the skin tuberomas, as well as the retinal hamartomas, indicating that its effect can be detected, measured, and monitored with an ocular examination. Case Report: We describe a 24-year-old female diagnosed with tuberous sclerosis since birth, with multiorgan involvement. The patients had multiorgan involvement, with angiolipomas of the kidney resistant to treatment. She also underwent subependymal giant cell astrocytoma brain tumor resection. The patient was treated with everolimus after recurrent embolization failed to shrink the renal angiolipomas. The tumors responded well to treatment. Conclusions: Skin lesions disappeared, and fundus photos and repeat retinal optical coherence tomography measurements documented shrinkage of the retinal hamartomas during the 24 months of treatment. We conclude that a simple eye examination can monitor treatment effectiveness.

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Sirolimus for Retinal Astrocytic Hamartoma Associated with Tuberous Sclerosis Complex

Cited by 33 publications

References 5 publications

Hyperactivated mTORC1 downregulation of FOXO3a/PDGFRα/AKT cascade restrains tuberous sclerosis complex-associated tumor development

Hyperactivated mTORC1 downregulation of FOXO3a/PDGFRα/AKT cascade restrains tuberous sclerosis complex-associated tumor development

A Case of Proliferative Retinopathy Complicated with Tuberous Sclerosis Treated by Vitreous Surgery

Retinal hamartomas respond to everolimus treatment for tuberous sclerosis: A photo essay

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