It is becoming increasingly clear that some rare diseases share characteristics in terms of both symptoms and underlying pathogenesis. Birt-Hogg-Dubé (BHD) syndrome is an excellent example of this. BHD shares kidney symptoms with the cancer syndromes Von Hippel Lindau (VHL) and tuberous sclerosis complex (TSC); lung symptoms with Lymphangioleiomyomatosis (LAM); and skin symptoms with TSC and Familial Multiple Discoid Fibromas (FMDF). Overactive mTOR signalling has been implicated in all of these syndromes, and consequently mTOR inhibitors have been trialled as treatments for a number of different symptoms associated with these syndromes.
The mTOR signalling pathway is an important regulator of metabolism and homeostasis, modifying cellular function in response to nutrient availability (Laplante and Sabatini, 2012). Rapamycin (also known as Sirolimus) is made by a species of bacterium native to Easter Island, and inhibits the mTOR pathway by preventing the activation of mTORC1 (Sehgal, 2003). Sirolimus received FDA-approval in 1999 to be used as an immunosuppressant during organ transplant procedures (Sehgal, 2003). Two derivatives of Sirolimus – Everolimus and Temsirolimus – also have FDA approval.
A number of clinical trials have shown Sirolimus to be effective in the treatment of the kidney angiomyolipomas characteristic of TSC and LAM and indeed, mTOR inhibitors are now commonly used to treat non-syndromic kidney cancer (Mihaly et al., 2012). Interestingly, Sirolimus partially reverses the cystic kidney phenotype seen in a mouse model of BHD (Baba et al., 2008).
In 2011, the MILES trial showed that Sirolimus halted the progression of cyst formation in the lungs of LAM patients (McCormack et al., 2011). However, Sirolimus did not reverse the damage done to the lungs by LAM, and once patients stopped taking the drug, their disease progressed. Pre-clinical data shows that in the mouse model of LAM, combined therapy with Sirolimus and simvastatin – which is a licensed cholesterol lowering drug – not only halted the progression of LAM, but seemed to partially reverse the lung damage in these animals (Goncharova et al., 2012).
Wee et al. recently described the case of two siblings with FMDF. Although the causative gene has not been found, topical treatment with Sirolimus for 8 weeks reduced the size and redness of the skin lesions, suggesting that mTOR dysregulation was an underlying cause. A reduction in the severity of TSC-associated skin lesions has also been reported in several studies (Dabora et al., 2011; Hofbauer et al., 2008; Micozkadioglu et al., 2010). A clinical trial to test whether topical Sirolimus is an effective treatment for the fibrofolliculomas found in BHD has been conducted and the results are currently under evaluation.
Aside from skin, lung and kidney lesions, two recent small studies show that Sirolimus and Everolimus are effective therapies for epileptic seizures and glioneuronal brain tumours which effect children with TSC (Canpolat et al., 2013; Capellano et al., 2013. Clearly, the dysregulation of mTOR signalling can cause myriad disease symptoms, and has even been linked to ageing and Alzheimer’s Disease (Johnson et al., 2013; Tang et al., 2013). Thus, although rigorous clinical testing must be done for each new indication, and hopefully Sirolimus and its derivatives may prove an effective therapy – either alone or in combination with other drugs – for a wide range of diseases, including BHD.
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- Canpolat M, Per H, Gumus H, Yikilmaz A, Unal E, Patiroglu T, Cinar L, Kurtsoy A, & Kumandas S (2013). Rapamycin has a beneficial effect on controlling epilepsy in children with tuberous sclerosis complex: results of 7 children from a cohort of 86. Child’s nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery PMID: 23743820
- Cappellano AM, Senerchia AA, Adolfo F, Paiva PM, Pinho R, Covic A, Cavalheiro S, & Saba N (2013). Successful everolimus therapy for SEGA in pediatric patients with tuberous sclerosis complex. Child’s nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery PMID: 23743818
- Dabora SL, Franz DN, Ashwal S, Sagalowsky A, DiMario FJ Jr, Miles D, Cutler D, Krueger D, Uppot RN, Rabenou R, Camposano S, Paolini J, Fennessy F, Lee N, Woodrum C, Manola J, Garber J, & Thiele EA (2011). Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease. PloS one, 6 (9) PMID: 21915260
- Goncharova EA, Goncharov DA, Fehrenbach M, Khavin I, Ducka B, Hino O, Colby TV, Merrilees MJ, Haczku A, Albelda SM, & Krymskaya VP (2012). Prevention of alveolar destruction and airspace enlargement in a mouse model of pulmonary lymphangioleiomyomatosis (LAM). Science translational medicine, 4 (154) PMID: 23035046
- Hofbauer GF, Marcollo-Pini A, Corsenca A, Kistler AD, French LE, Wüthrich RP, & Serra AL (2008). The mTOR inhibitor rapamycin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosis. The British journal of dermatology, 159 (2), 473-5 PMID: 18547304
- Johnson SC, Rabinovitch PS, & Kaeberlein M (2013). mTOR is a key modulator of ageing and age-related disease. Nature, 493 (7432), 338-45 PMID: 23325216
- Laplante M, & Sabatini DM (2012). mTOR signaling in growth control and disease. Cell, 149 (2), 274-93 PMID: 22500797
- McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC, National Institutes of Health Rare Lung Diseases Consortium, & MILES Trial Group (2011). Efficacy and safety of sirolimus in lymphangioleiomyomatosis. The New England journal of medicine, 364 (17), 1595-606 PMID: 21410393
- Micozkadioglu H, Koc Z, Ozelsancak R, & Yildiz I (2010). Rapamycin therapy for renal, brain, and skin lesions in a tuberous sclerosis patient. Renal failure, 32 (10), 1233-6 PMID: 20954988
- Mihaly Z, Sztupinszki Z, Surowiak P, & Gyorffy B (2012). A comprehensive overview of targeted therapy in metastatic renal cell carcinoma. Current cancer drug targets, 12 (7), 857-72 PMID: 22515521
- Sehgal SN (2003). Sirolimus: its discovery, biological properties, and mechanism of action. Transplantation proceedings, 35 (3 Suppl) PMID: 12742462
- Tang Z, Bereczki E, Zhang H, Wang S, Li C, Ji X, Branca RM, Lehtiö J, Guan Z, Filipcik P, Xu S, Winblad B, & Pei JJ (2013). Mammalian Target of Rapamycin (mTor) Mediates Tau Protein Dyshomeostasis: IMPLICATION FOR ALZHEIMER DISEASE. The Journal of biological chemistry, 288 (22), 15556-70 PMID: 23585566
- Wee JS, Chong H, Natkunarajah J, Mortimer PS, & Moosa Y (2013). Familial multiple discoid fibromas: unique histological features and therapeutic response to topical rapamycin. The British journal of dermatology PMID: 23495951
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.