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Sirolimus: A Therapeutic Advance for Dermatologic Disease

Tess Peters, MSc, MD; Danya Traboulsi, BSc; Lee Anne Tibbles MD, FRCPC; P. Régine Mydlarski MD, FRCPC
Faculty of Medicine, University of Calgary, Calgary, AB, Canada

ABSTRACT

Sirolimus, also known as rapamycin (SRL, Rapamune®), was approved in 1999 by the US Food and Drug Administration to prevent graft rejection in renal transplantation. As a member of the mammalian target of rapamycin (mTOR) inhibitor class, its potent immunosuppressant, anti-angiogenic and anti-proliferative properties are well recognized. When compared to other immunosuppressants, SRL has a lower risk of renal, neurologic and lymphoproliferative complications. It has become a promising treatment modality for angiofibromas, Kaposi's sarcoma and other inflammatory and malignant disorders of the skin. With the recent discovery that mTOR inhibitors extend the lifespan of mice, sirolimus and other rapamycin analogs (rapalogs) are emerging as therapeutic targets for the treatment and prevention of age-related diseases.

Key Words: immunosuppressant, Rapamune, rapamycin, sirolimus, skin disease

Mechanism of Action

Sirolimus (SRL) is a fermentation product of Streptomyces hygroscopicus and belongs to the mammalian target of rapamycin (mTOR) inhibitor class. Discovered on a Canadian expedition to Easter Island "Rapa Nui," it was first utilized for its potent antifungal properties.1 In cells, SRL binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. Unlike cyclosporine and tacrolimus, the sirolimus-FKBP-12 complex has no effect on calcineurin activity. Rather, this complex inhibits the activation of mTOR, a key regulatory kinase. The inhibition of mTOR by sirolimus suppresses T-lymphocyte activation and proliferation, antibody production and prevents cell cycle progression from the G1 to the S phase (Figure 1).

The bound SRL-FKBP-12 complex down-regulates the translation of hypoxia-inducible factor (HIF) 1 and 2 which, in turn, regulates vascular endothelial growth factor (VEGF). Through these, and other mechanisms, SRL plays an important anti-angiogenic role.2,3 More recently, SRL has shown promise as a treatment option for aging and cancer.4,5 New rapamycin analogues [temsirolimus, everolimus and deforolimus (ridaforolimus)] have been developed to improve the pharmacokinetic and pharmacodynamic profile.

Pharmokinetics and Metabolism

Sirolimus is currently available as an oral solution (1 mg/ml) and as tablets (1 mg, 2 mg, 5 mg). Though costly, SRL has been compounded topically in emollient base (i.e., Aquaphor® Healing Ointment), typically in a dose ranging from 0.05% to 2%. As immunosuppressive therapy, SRL blood levels are recommended to fall between 3 and 5 ng/ml. SRL is rapidly absorbed orally, with peak serum concentrations (tmax) of 1 hour in healthy individuals and 2-3 hours in renal transplant recipients.6 It has poor oral bioavailability of approximately 15% and a long halflife of 57-62 hours.7,8 Of the absorbed drug, 95% is bound to blood elements.8 SRL is metabolized by the hepatic cytochrome P450 (CYP) 3A4 enzyme and p-glycoprotein intestinal countertransport pump.9 The seven metabolites of SRL contribute little to its pharmacological action, two of which show ≤30% of its in vitro immunosuppressive activity.8 Fecal excretion of the parent compound accounts for 90% of drug elimination with the remainder by urinary excretion.

Adverse Effects

As compared to calcineurin inhibitors, SRL shows lower rates of hypertension, nephrotoxicity, neurotoxicity and lymphoproliferative complications.10 In most patients, it is well tolerated. In clinical studies, common adverse reactions of SRL include (>30%): hypertriglyceridemia, hypercholesterolemia, hypertension, arthralgia, anemia, thrombocytopenia, headache, fever, peripheral edema, urinary tract and latent viral infections, as well as gastrointestinal effects such as anorexia, abdominal pain, diarrhea, and constipation. Potentially serious adverse events include upper respiratory infections and non-infective pneumonitis.10

Possible dermatologic complications include: acne, folliculitis, exanthema, mouth ulcers and onychopathy.11 Impaired wound healing and wound dehiscence have been reported in patients receiving SRL following solid organ transplantation.12-14 Lymphocele and lymphedema were also described in a case series of eight transplant patients receiving SRL.15

Upon entering the cell, sirolimus binds the intracellular receptor, FKBP-12, in turn preventing the interaction between mTOR and Raptor within the mTORC1 complex. Downstream effector molecules of mTORC1, including eIF4E and p70S6K1, are inhibited, preventing cell proliferation, cell survival, tumor growth, angiogenesis and protein synthesis. In the presence of sirolimus, upstream regulatory molecules, including the tuberous sclerosis complex (TSC) are no longer able to regulate the activation of mTORC1. (Abbreviations: GF, growth factor; SRL, sirolimus; AKT, also known as protein kinase B; Rheb: Ras homolog enriched in brain; mTORC2, mTOR complex 2; Rictor, rapamycin-insensitive companion of mTOR; 4E-BP1, 4E binding protein 1; mLST8, mammalian lethal with SEC13 protein 8; mSIN1, mammalian stress activated protein kinase interacting protein 1; GbL, G protein beta subunit-like.

Figure 1: Mechanism of action of sirolimus

Clinical Uses

Skin Cancer in Solid Organ Transplantation

The risk of developing skin cancer, most notably squamous cell carcinoma (SCC), is 65-fold greater in organ transplant recipients (OTRs) as compared to the general population. The role of SRL in preventing SCCs in OTRs has recently been reviewed.16,17 In renal transplant recipients, SRL therapy after cyclosporine withdrawal was shown to reduce the risk of SCC and basal cell carcinoma (BCC).18 Further, results from five multi-center studies demonstrated that the incidence of skin and non-skin malignancies was significantly lower in patients receiving SRL monotherapy versus combination SRL and cyclosporine.19 A prospective, randomized, controlled trial reported that SRL monotherapy induced regression of pre-existing keratotic dysplasia and reduced the incidence of non-melanoma skin cancer.19 Another trial confirmed that switching from calcineurin inhibitors to sirolimus had an anti-tumoral effect among kidneytransplant recipients with previous SCCs.20 Finally, a multi-center, randomized-controlled trial found that there was a statistically significant reduction in the rate of melanoma development in patients treated with SRL.21

Kaposi's Sarcoma

Sirolimus decreases the production of VEGF in vivo and inhibits the stimulation of vascular endothelial cells. The anti-angiogenic properties of SRL make it an attractive therapeutic option for Kaposi's sarcoma (KS) and other malignancies. In a case series of 15 renal transplant recipients with KS, Stallone et al. reported complete clinical remission of cutaneous KS 3 months following the initiation of SRL.22 Histological remission was confirmed after 6 months of therapy. In a patient with pemphigus vulgaris and iatrogenic KS, remission of both was maintained at 24 months with low dose prednisone, dapsone and SRL, 2 mg daily.23 Extensive cutaneous KS with pulmonary, gastric and hepatic lesions, resolved with cessation of cyclosporine and initiation of SRL at a target serum level of 4-7 ng/ml.24 In addition to the effects of SRL on VEGF, Nichols et al. demonstrated that SRL can repress the expression of the Kaposi's sarcoma-associated herpes virus lytic master switch protein, thereby impairing virion production.25 Though the use of an immunosuppressant to control a malignancy seems paradoxical, the anti-angiogenic, anti-proliferative and anti-viral effects of SRL make it an important treatment option for KS.

Cutaneous T-Cell Lymphomas

Cutaneous T-cell lymphomas (CTCL) incorporate a group of heterogenous lymphoproliferative disorders characterized by the localization of neoplastic T lymphocytes to the skin. The mTORC1 pathway has been identified as a possible therapeutic target for CTCL, although its cytostatic action may limit its efficacy as monotherapy.26 SRL has little effect on apoptosis despite inhibiting cell growth of primary cell lines in patients with CTCL and Sézary syndrome both in vitro and in vivo.27 A prospective clinical trial is currently underway to determine the efficacy and safety of topical 1% SRL in the treatment of early stage CTCL.

Tuberous Sclerosis

Tuberous sclerosis (TS) is an autosomal dominant condition characterized by the formation of multisystem hamartomatous tumors. Mutations in the TSC1 or TSC2 genes, which encode tuberin and hamartin, result in dysregulation of mTOR signalling.28 As mTOR is downstream of the tuberous sclerosis complex (TSC), the main cellular function of the TSC1/2 proteins is to inhibit the mTOR pathway. Immunosuppressive treatment with SRL in a TS patient who underwent renal transplantation was reported to reduce facial angiofibromas.29 Topical SRL 1% ointment was also shown to reduce and, in some instances, induce complete regression of angiofibromas.30,31 In a left-right comparison, SRL 2% showed a greater reduction in angiofibroma elevation, size and erythema as compared to tacrolimus 0.03%.32 Furthermore, a pilot study found that topical 0.1% sirolimus was rapidly effective for clearing angiofibromas in four children with the TS complex.33 The authors suggest that the lower dose of topical SRL is as effective as the higher dose and less invasive than standard pulse dye laser therapy. Systemic treatment with SRL also reduced the volume of renal angiomyolipomas in TS, thereby preserving renal function.34-36 As topical SRL has the potential to become a first-line treatment for facial angiofibromas, a multicenter, randomized, prospective, double-blind, placebo-controlled trial is currently underway.

Muir-Torre Syndrome

Muir-Torre syndrome (MTS) is an autosomal dominant cancer syndrome considered to be a variant of hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome.37 It is characterized by the presence of visceral malignancy, sebaceous neoplasms and keratoacanthomas.38 Levi et al. reported a case of unrecognized MTS in a kidney transplant recipient who experienced an eruption of multiple sebaceous tumors following immunosuppression with tacrolimus.39 Switching to SRL prevented the development of new sebaceous tumors. Griffard et al. also reported a patient with MTS who developed 18 sebaceous adenomas and 9 sebaceous carcinomas while on cyclosporine for renal transplantation.40 Switching to SRL resulted in the patient developing only 5 sebaceous adenomas in the following 18 months, suggesting that SRL may prevent the development of new lesions and the malignant transformation of pre-existing adenomas.

Pachyonychia Congenita

Pachyonychia congenita (PC) is a rare autosomal dominant disorder characterized by focal palmoplantar hyperkeratosis, hypertrophic nail dystrophy, follicular hyperkeratosis and oral leukokeratosis.41 It is divided into two main variants, PC-1 (Jadassohn-Lewandowsky type) and PC-2 (Jackson-Lawler type), with mutations in the genes encoding keratin K6A or K16 and K6B or K17, respectively.42 Interestingly, it has been demonstrated that SRL inhibits keratinocyte proliferation by selectively blocking expression of keratin K6A.43 Treatment with 2 mg SRL daily resulted in clinical improvement in three patients with PC, as measured by a subjective pain rating and the Dermatology Life Quality Index. As SRL was shown to down-regulate expression of K6A in human keratinocytes, it is not surprising that response to treatment was reported to be greatest in a patient known to have a K6A mutation.43

Psoriasis

In a randomized, controlled trial comparing SRL to a subtherapeutic dose of cyclosporine for the treatment of severe plaque psoriasis, SLR 3 mg/m2 + cyclosporine 1.25 mg/kg demonstrated significantly better results than cyclosporine 1.25 mg/kg alone, as measured by a mean percentage decrease in PASI score.44 The addition of SRL improved clinical scores, however monotherapy with SRL 3 mg/m2 was shown to be ineffective in the treatment of psoriasis. Ormerod et al. conducted a randomized, controlled trial to determine the efficacy of topically applied SRL, 2.2% and 8% in plaque psoriasis.45 Topical SRL was shown to penetrate normal skin and reduce the number of CD4+ T-cells in the epidermis. The improvement in clinical score was significant with topical SRL, however secondary outcome measures, which included plaque thickness and plaque erythema, did not demonstrate significant improvement. The concomitant administration of SRL to a subtherapeutic dose of cyclosporine may limit their respective toxicities, most notably cyclosporine-induced nephrotoxicity.46 Topical SRL has also shown limited benefit in the treatment of psoriasis.45

Graft Versus Host Disease (GVHD)

Preliminary evidence for the use of SRL as first-line therapy in acute GVHD demonstrates response rates of 50%, similar to the rates observed with glucocorticoids.47 In 32 patients who underwent allogeneic hematopoietic cell transplantation, 16 achieved complete response of acute GVHD following primary therapy with SRL without the addition of systemic glucocorticoids or any other immunosuppressive agents.48 The 16 patients who achieved complete resolution of acute GVHD did so within a median of 14 days. An additional 38% achieved complete resolution of acute GVHD when a glucocorticoid dose of less than 1 mg/kg was added to their treatment regime. In an early Phase I trial, 10 of 21 patients discontinued SRL therapy due to toxicity or lack of improvement.49 The use of SRL in steroid refractory acute GVHD showed a complete resolution rate of 44% for a minimum of 1 month following initiation of SRL without additional immunosuppressants.49 In a retrospective singlecenter study of 22 patients with steroid refractory acute GVHD, the rate of sustained remission was 72%.50 This data suggests that SRL may be an effective alternative to high-dose glucocorticoid therapy, which can lead to early and late complications.

Anti-Aging

The discovery that SRL extended the lifespan of genetically heterogenous mice was considered in 2009 by Science as a top 10 scientific breakthrough.51 The mTOR-dependent and mTORindependent mechanisms of life span extension have been thoroughly reviewed elsewhere.5 Newer analogs of rapamycin (or rapalogs), such as temsirolimus, everolimus and deforolimus, are currently under clinical investigation as potential anti-aging therapeutics.

Other Uses

SRL has successfully treated blue rubber bleb nevus syndrome, microcystic lymphatic malformations and kaposiform hemangioendothelioma with Kasabach-Merritt syndrome.52 It has served as a useful adjunct to pulse dye laser therapy in the treatment of port-wine stains.53 Experimental evidence suggests that it may also be of benefit for the treatment of keloids and hypertrophic scars.54 Further, clinical trials are currently underway to study the efficacy of SRL in patients with complex venous malformations, chronic urticaria, erosive oral lichen planus, scleroderma, systemic lupus erythematosus, pemphigus vulgaris, melanoma, basal cell nevus syndrome, neurofibromatosis and Birt-Hogg-Dubé syndrome.

Conclusion

Sirolimus has been successfully used to treat a variety of vascular, inflammatory and neoplastic skin disorders. With established anti-cancer and anti-aging properties, SRL and the new rapalogs are emerging as targeted therapy for the treatment and prevention of age-related diseases. As compared to other immunosuppressants, these therapies have a lower risk of renal, neurologic and lymphoproliferative complications. Given their potential for use in dermatology, randomized clinical trials are warranted to validate their safety and efficacy.

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In this issue:

  1. Sirolimus: A Therapeutic Advance for Dermatologic Disease
  2. Review of Evidence for Dietary Influences on Atopic Dermatitis
  3. Update on Drugs and Drug News - July-August 2014