Rapamycin is a lipophilic macrocyclic lactone which was first isolated from a soil bacterium Streptomyces hygroscopicus in Rapa Nui (Easter Island) in 1965,hence the name rapamycin. Though rapamycin was shown to have antifungal properties, later on it was discovered to possess anti-T cell activity and was being used as immunosuppressant in prevention of graft rejection. Rapamycin belongs to a novel class of anti-cancer drugs called as mTOR (mammalian target of rapamycin) inhibitors.
mTOR (mechanistic target of rapamycin) is a large atypical conserved serine-threonine kinase enzyme complex involved in cellular growth, stress, aging and vasculogenesis with a molecular weight of 290 kDa. mTOR pathway is critical for normal cell function as it plays a pivotal role in integrating signals from nutrients, energy status and growth factors to regulate many homeostatic processes, including autophagy, ribosome biogenesis and metabolism modulated by phosphatidylinositol 3- kinases (PI3K)–Akt-dependent mechanisms. Although mammalian cells possess only single mTOR gene located on short arm of chromosome 1p36.2, mTOR pathway is composed of two distinct functional complex proteins- (i) mTORC1 consisting of mTOR, LST8/GβL (G protein beta subunit-like) and regulatory-associated protein of mTOR (raptor) and (ii) mTORC 2 consists of mTOR, GβL, and rapamycin insensitive component of mTOR (rictor). It is to be noted that only mTORC 1 is inhibited by rapamycin and not mTORC2.
Functionally, mTORC1 is mainly responsible for the nutrient-sensitive functions of TOR, whereas TORC2 plays a chief role in cytoskeletal reorganization and cell survival. Under normal circumstances, mTOR signaling causes cell proliferation and is under tight regulation of proteins like tuberin and hamartin. Hamartin and tuberin are the protein products of the tuberous sclerosis genes (TSC1 and TSC2) located on chromosome 9 and 16 respectively. Physiologically, the hamartin-tuberin complex activates the protein Ras homolog enriched in brain (Rheb) and exerts inhibitory control over mTOR. Mutation in these two genes (TSC1 and TSC2) leads to defective functioning of these protein products and results in constitutive activation of mTOR pathway, leading to leading to phosphorylation of downstream targets including p70S6K (p70 S6 kinase) and 4E-BP1 (eukaryotic initiation factor 4E-binding protein 1) culminating in protein synthesis and abnormal cellular proliferation as evident in hamartomas of tuberous sclerosis. Rapamycin can simulate the action of tuberin and hamartin protein and thus can prevent the procarcinogenic action of mTOR signaling.
Mechanism of Action of Rapamycin Figure 1
Rapamycin belongs to the class of macrocyclic immunosuppressive drugs that are active only when bound to immunophilins. Cyclosporine and tacrolimus (FK506) are other members who also act via binding to immunophilins. Intracellularly, rapamycin binds to FKBP12 (FK binding protein 12 kDa), an immunophilin and forms a complex FKBP12-rapamycin. mTOR possess a binding domain portion called FKBP12-rapamycin binding domain (FRB). After binding to FRB domain of mTOR protein, FKBP12-rapamycin complex potently inhibits the activity of mTORC1 complex via autophosphorylation and dissociation of mTORC1 complex and thus blocking the binding of mTOR to its substrates. Inhibition of mTOR pathway blocks cytokine-driven T-cell proliferation by inhibiting the progression from the G1 to the S phase of the cell cycle,thus explaining its role in immunosuppression.
Currently, the only FDA approved indication for rapamycin is to prevent organ rejection after transplant surgery. Off-label indications include topical treatment of facial angiofibromas systemic treatment for renal angiomyolipoma lymphangioleiomyomatosis. brain tumors associated with tuberous sclerosis and for chemotherapy of various malignancies (renal and hepatocellular cancer and mantle cell lymphomas). Other conditions where rapamycin has been used are Kaposi sarcoma, psoriasis and lichen planus.
Rapamycin is very poorly water soluble, severely limiting its bioavailability. Congeners of rapamycin have been developed with better pharmacokinetic properties i.e temsirolimus (CCI-779), everolimus (RAD001) and ridaforolimus (AP23573) and are collectively known as rapalogs. Currently rapamycin (sirolimus) is available in the market in two formulations: Rapamune® oral solution (60mg per 60ml in an amber colored bottle) and Rapamune® tablet available in 1mg (white triangular-shaped tablet) and 2 mg (yellow-to-beige triangular-shaped tablet) strength. Oral solution needs to be kept at cold temperature of 2-8° centigrade.
Topical Rapamycin for Angiofibromas Associated with Tuberous Sclerosis
Angiofibromas shows prominent vascular component owing to increased expression of angiogenic factors like vascular endothelial growth factor (VEGF) and mTOR overactivation that promotes angiogenesis as discussed earlier. Inhibition of mTOR pathway decreases the output of VEGF by inhibiting hypoxia-inducible factor (HIF) expression and by directly repressing VEGF-stimulated endothelial cell proliferation. Facial angiofibromas are a chief cause of concern among the patients having TSC owing to unsightly appearance of facial papules. Rapamycin is a large molecule, difficult to formulate in the ointment form. Various investigators have used different concentrations of topical rapamycin for the management of facial angiofibromas [Table 1].
Irritation and burning sensation is the most common side effect seen after topical rapamycin. Patients should be prescribed topical hydrocortisone 0.1% cream or desonide 0.05% lotion along with liberal emollients to counteract any irritation and ensure compliance. It is practical to use commercially available oral solution of rapamycin (1 mg/ml) as a topical formulation since compounding pharmacies are not always readily accessible and the stability and efficacy of compounded preparation cannot be ensured. The major limiting factor in prescribing topical rapamycin is the high cost of the medication. Haemel et al. compounded topical rapamycin from crushed rapamycin tablet into a 30 ml of 1% ointment and it priced about $3000. Topical rapamycin can be safely prescribed in children in whom angiofibromas are still in the growing phase. Patients receiving rapamycin therapy should avoid taking grapefruit juice as it inhibits the metabolism of rapamycin akin to cyclosporine.
Systemic Side Effects
Topically applied rapamycin has minimal systemic absorption, precluding any adverse systemic effects. If facilities are available, trough drug levels should be monitored by chromatographic and immunoassay methodologies. However, whether this applies to topical rapamycin therapy needs to evaluated. More robust studies are required to evaluate the extent of systemic absorption of topically applied rapamycin and to determine the safety of topically administered rapamycin.
Topical rapamycin appears to be a promising and effective way of treating facial angiofibromas which are cosmetically disfiguring in patients with TSC. Topical rapamycin needs to be studied in a larger cohort of subjects to determine the duration and frequency of application. The major disadvantage is the cost of therapy which is prohibitively expensive at the present date in our resource poor setting.
1. Pópulo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer Int J Mol Sci. 2012;13:1886–918
2. Arns W, Budde K, Eitner F, Gwinner W, Hugo C, Pressmar K, et al [Conversion from a calcineurin inhibitor to a sirolimus-based therapy after renal transplantation - An update of existing recommendations] Dtsch Med Wochenschr. 2011;136:2554–9
3. Dobashi Y, Watanabe Y, Miwa C, Suzuki S, Koyama S. Mammalian target of rapamycin: A central node of complex signaling cascades Int J Clin Exp Pathol. 2011;4:76–95
4. Reiling JH, Sabatini DM. Stress and mTORture signaling Oncogene. 2006;25:6373–83
5. Russell RC, Fang C, Guan KL. An emerging role for TOR signaling in mammalian tissue and stem cell physiology Development. 2011;138:3343–56
6. Kim WS. Mammalian target of rapamycin inhibitors for treatment in tuberous sclerosis
Korean J Pediatr. 2011;54:241–5
7. Franz DN, Leonard J, Tudor C, Chuck G, Care M, Sethuraman G, et al Rapamycin causes regression of astrocytomas in tuberous sclerosis
complex Ann Neurol. 2006;59:490–8
8. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, et al Sirolimus for angiomyolipoma in tuberous sclerosis
complex or lymphangioleiomyomatosis N Engl J Med. 2008;358:140–51
9. Sehgal SN. Rapamune (Sirolimus, rapamycin): An overview and mechanism of action Ther Drug Monit. 1995;17:660–5
10. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism Cell. 2006;124:471–84
11. Gabardi S, Baroletti SA. Everolimus: A proliferation signal inhibitor with clinical applications in organ transplantation, oncology, and cardiology Pharmacotherapy. 2010;30:1044–56
12. Cravedi P, Ruggenenti P, Remuzzi G. Sirolimus for calcineurin inhibitors in organ transplantation: Contra Kidney Int. 2010;78:1068–74
13. Wataya-Kaneda M, Tanaka M, Nakamura A, Matsumoto S, Katayama I. A topical combination of rapamycin and tacrolimus for the treatment of angiofibroma due to tuberous sclerosis
complex (TSC): A pilot study of nine Japanese patients with TSC of different disease severity Br J Dermatol. 2011;165:912–6
14. DeKlotz CM, Ogram AE, Singh S, Dronavalli S, MacGregor JL. Dramatic improvement of facial angiofibromas in tuberous sclerosis
with topical rapamycin: Optimizing a treatment protocol Arch Dermatol. 2011;147:1116–7
15. Cabrera López C, Martí T, Catalá V, Torres F, Mateu S, Ballarín Castán J, et al Effects of rapamycin on angiomyolipomas in patients with tuberous sclerosis
16. Casanova A, María Girón R, Acosta O, Barrón M, Valenzuela C, Ancochea J. Lymphangioleiomyomatosis treatment with sirolimus Arch Bronconeumol. 2011;47:470–2
17. McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, et alNational Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis N Engl J Med. 2011;364:1595–606
18. Major P. Potential of mTOR inhibitors for the treatment of subependymal giant cell astrocytomas in tuberous sclerosis
complex Aging (Albany NY). 2011;3:189–91
19. Koenig MK, Butler IJ, Northrup H. Regression of subependymal giant cell astrocytoma with rapamycin in tuberous sclerosis
complex J Child Neurol. 2008;23:1238–9
20. Voss MH, Molina AM, Motzer RJ. mTOR inhibitors in advanced renal cell carcinoma Hematol Oncol Clin North Am. 2011;25:835–52
21. Riaz H, Riaz T, Hussain SA. mTOR inhibitors: A novel class of anti-cancer agents Infect Agent Cancer. 2012;7:1
22. Saggar S, Zeichner JA, Brown TT, Phelps RG, Cohen SR. Kaposi's sarcoma resolves after sirolimus therapy in a patient with pemphigus vulgaris Arch Dermatol. 2008;144:654–7
23. Ormerod AD, Shah SA, Copeland P, Omar G, Winfield A. Treatment of psoriasis with topical sirolimus: Preclinical development and a randomized, double-blind trial Br J Dermatol. 2005;152:758–64
24. Soria A, Agbo-Godeau S, Taïeb A, Francès C. Treatment of refractory oral erosive lichen planus with topical rapamycin: 7 cases Dermatology. 2009;218:22–5
26. Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, et al Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus Cancer Res. 2006;66:5549–54
27. Haemel AK, O’Brian AL, Teng JM. A novel approach to facial angiofibromas in tuberous sclerosis
Arch Dermatol. 2010;146:715–18
28. Mutizwa MM, Berk DR, Anadkat MJ. Treatment of facial angiofibromas with topical application of oral rapamycin solution (1 mgmL(-1)) in two patients with tuberous sclerosis
Br J Dermatol. 2011;165:922–3
29. Truchuelo T, Díaz-Ley B, Ríos L, Alcántara J, Jaén P. Facial angiofibromas treated with topical rapamycin: An excellent choice with fast response Dermatol Online J. 2012;18:15
30. Foster RS, Bint LJ, Halbert AR. Topical 0.1% rapamycin for angiofibromas in paediatric patients with tuberous sclerosis
: A pilot study of four patients Australas J Dermatol. 2012;53:52–6
31. Salido R, Garnacho-Saucedo G, Cuevas-Asencio I, Ruano J, Galán-Gutierrez M, Vélez A, et al Sustained clinical effectiveness and favorable safety profile of topical sirolimus for tuberous sclerosis
- associated facial J Eur Acad Dermatol Venereol. 2011 doi: 10.1111/j.1468-3083.2011.04212.x
32. Kaufman McNamara E, Curtis AR, Fleischer AB Jr. Successful treatment of angiofibromata of tuberous sclerosis
complex with rapamycin J Dermatolog Treat. 2012;23:46–8
Source of Support: Nil
Conflict of Interest: None declared