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Caveat mTOR revisited: Neurofibromatosis


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By Warren R. Heymann, MD, FAAD
Feb. 14, 2024
Vol. 6, No. 7

Dr. Warren Heymann photo
An abridged version of this commentary was published in "A Clinician's Perspective" in the April 2023 issue of the JAAD.

It is understandable how dermatologists may forget about many details of rare genodermatoses after taking their board examinations. Neurofibromatosis Type 1 (NF1, aka von Recklinghausen disease, OMIM 162200) must be an exception — every dermatologist will encounter patients in their practice, as the birth incidence is approximately 1 in 2,600 to 3000. (1)

Café au lait macules, skin-fold freckling [Crowe sign], Lisch nodules [iris hamartoma], optic pathway gliomas, and bone deformities characterize NF1. NF1 patients are prone to developing innumerable peripheral nerve sheath tumors. Cutaneous neurofibromas (NFs), while benign, have significant psychosocial implications due to itchiness, physical disfigurement, and sometimes pain. Similarly, plexiform neurofibromas (PNFs) often cause pain, deformity, and can potentially develop into highly aggressive malignant peripheral nerve sheath tumors. NF1 patients are often burdened by a low quality of life, correlating with pain, anxiety, and depression. (2,3)

Mateos et al succinctly define the pathogenesis of NF1 and a pathway to nonsurgical treatment: “Neurofibromatosis type 1 is caused by heterozygous loss of function mutations of NF1, a tumor-suppressor gene located on chromosome 17q11.2. Elevated levels of endogenous Ras due to inactivation of the NF1 gene product neurofibromin, a growth regulator that inhibits Ras-promoting activity, ultimately producing constitutive upregulation of the serine-threonine kinase mammalian target of rapamycin (mTOR). The mTOR pathway is involved in regulating cell growth, apoptosis, protein translation, angiogenesis, and proliferation. Knowledge of the molecular pathways involved in the growth of NF1-related tumors and the advent of molecularly targeted anti-cancer drugs has resulted in the development of potential medical treatments to cease PN progression in patients diagnosed with NF1.” (4)

Previously in DWI&I we have explored the role of rapalogs (drugs that inhibit the mTOR pathway, including sirolimus [rapamycin], temsirolimus, everolimus, and deforolimus) for vascular malformations (5), lymphatic malformations (6), and nevus sebaceus (7). This commentary focuses on their use in NF1.

Photo of for DWII on Caveat mTOR revisited: Neurofibromatosis
Image from JAAD 2021; 84(6): 1667-1676.
Malhotra et al detailed the case of a 14-year-old boy with NF1 who presented with a painful neurofibroma on his right palm. The lesion was treated with topical sirolimus, resulting in decreased size and pain and improvement in the motor function of his hand. Within a month of therapy, the NF was no longer painful; by 17 months the lesion was “barely visible or palpable on his outstretched hand”. The medication was discontinued at 18 months, with no clinical evidence of recurrence a year later. (8)

Wataya-Kaneda et al performed a randomized, placebo-controlled study of 18 patients with NF1 (9 men and 9 women, aged 27 to 68 years, with all but 1 completing the trial) utilizing topical sirolimus 0.2% and 0.4% gel. The primary endpoint was tumor volume reduction at 24 weeks measured by CT scanning with volumetric software. (I smiled when I read that the secondary endpoint was the average tumor size reduction of 3 target tumors using an old-fashioned ruler!) Sirolimus levels were measured. The CT results indicated that a dose-dependent tumor volume reduction occurred. A dose-dependent reduction in tumor volume was observed. Tumor volume was reduced in the 0.4% sirolimus group, and tumors grew more slowly in the 0.2% sirolimus group than in the placebo group, which increased rapidly during the same period. No significant adverse events were observed; the major adverse drug reaction was pruritus. The highest blood sirolimus concentration, 0.73 ng/mL, was transient and was 1/10 to 1/20 lower than when administered orally. The authors concluded that sirolimus gel appears to be tolerated for long-term administration to shrink small tumors; they suggested that early initiation and long-term continuation may prevent further growth of NFs. (9)

On April 10, 2020, the FDA approved selumetinib (Koselugo, AstraZeneca) for pediatric patients, 2 years of age and older, with NF1 who have symptomatic, inoperable PNFs. Selumetinib, a mitogen-activated protein kinase inhibitor (MEKi), is the first therapy approved for pediatric patients with NF1. MEKi block downstream targets of RAS. (10,11) Drugs under investigation for NF1 mainly act on the MAPK/ERK and PI3K/AKT/mTOR pathways, tumor microenvironment, or aberrantly over-expressed cell surface receptors. In a systematic review, selumetinib was the most effective medication for treating a neurofibromatosis type 1-associated tumor with approximately 68%-71% partial response for inoperable or progressive PNFs in children 2 years of age and older. (12) Selumetinib specifically blocks ATP-dependent MAP kinases 1 and 2. Blegen et al reported clinical improvement of elephantiasis neuromatosa (the most extreme form of PNFs) in an 11-year-old girl treated with selumetinib. (13).

The reader is encouraged to review the adverse reactions to selumetinib. According to ePocrates, serious reactions (cardiomyopathy, retinal vein occlusion, retinal pigment epithelial detachment, severe diarrhea, rhabdomyolysis, hypoxia, acute kidney injury, severe rash) and common side effects (with vomiting and rash leading a long list) may be observed. Selumetinib-induced rashes tend to vary depending on the patient’s age; morbilliform eruptions are mostly observed in young children and acneiform rashes are typically described in post-pubertal subjects. (14)

Surgery remains the first-line therapy for NFs and PNFs. (2) Regardless, advances in targeted therapies have radically altered the therapeutic landscape for patients with NF1 — we can anticipate further progress in treating and even preventing NFs.

Point to Remember: Targeting the MAPK/ERK and PI3K/AKT/mTOR pathway has led to the use of topical sirolimus for neurofibromas and oral selumetinib for children with plexiform neurofibromas.

Our expert’s viewpoint

Andrew C. Krakowski, MD, FAAD
Network Chair of Dermatology
Program Director for the Residency in Dermatology
St. Luke’s University Health Network
Bethlehem, Pennsylvania

A grande time for patients with too many café au laits…

I have been fortunate to have witnessed at least three miracles in my career as a pediatric dermatologist. The first was the serendipitous discovery that propranolol shrinks hemangiomas. The second has been the use of dupilumab to shut down atopic dermatitis — and a seemingly endless list of other inflammatory conditions! — in patients as young as 6 months of age. The third has been the growing armamentarium of psoriasis medications that offer the promise of true PASI 100 response rates with low side-effect profiles. Indeed, it is a scalding hot time to be a dermatologist, and I find myself coming to expect more miracles with each cup of my morning joe. Recently, a few tasty, eye-opening ones have percolated into the realm of a condition that we, as board-certified dermatologists, recognize as being most classically associated with having too many café au laits: Neurofibromatosis-1 (NF).

In NF, neurofibromas tend to manifest by adolescence and may continue throughout adulthood, varying in size and number by affected individual. These lesions are debilitating to patients, and they are near-impossible to manage effectively and prospectively. It would be amazing if topical sirolimus worked as well for neurofibromas as it does for tuberous sclerosis-related angiofibromas. After all, adolescence is already a time frothed with anxiety and high emotion, so anything that can help these patients feel less isolated from their peers would be greatly appreciated.

At the risk of sounding like a total drip, however, I must espresso to you that this has not been my experience. By no means am I chai-ing to roast Dr. Heymann’s take on topical sirolimus as an emerging treatment for neurofibromas. Maybe my grind and his grind are not the same, but I have never seen topical sirolimus work that well for neurofibromas with any real substance to them. As Clay Davis from HBO’s The Wire would say, “Siiiiiiiiiiiiiiiiip.” (15) Even if it did, the sheer number of neurofibromas one would have to potentially treat on any individual patient might make this topical medication absorb systemically at a rate that could pose safety concerns. That would leave a bitter taste in my mouth.

Perk up because where I see topical sirolimus being potentially useful would be as a very early-on, limited intervention for an emerging neurofibroma in an anatomically or cosmetically sensitive area — similar to how we use topical timolol for infantile hemangiomas. That would mocha me feel much safer. The potential for intralesional or laser-assisted delivery sirolimus to an entire field area might also generate some caffeine-buzz down the line.

More worthy of all the brewhaha is oral selumetinib for what it appears to do for plexiform neurofibromas (PN). Seen in about 30-50% of NF-1 patients, PNs tend to occur in infancy and childhood, and they may even be congenital. These lesions, which are highly variable in terms of their size, shape, and growth rate may be difficult to detect clinically, especially because young children may not be able to easily characterize changes in their symptoms. Magnetic resonance imaging is helpful for detecting extracutaneous lesions. If PNs progress, which about 20% of them do, then they may do so quite rapidly, and progression can lead to localized pain along with, based on anatomical involvement, motor, vision, bowel, bladder, and airway comorbidities. Surgery has been the conventional mainstay of therapy, however, it is never a sure thing. PNs may be in too close of anatomic proximity to vital organs or so vascularized — and at great risk of bleeding — that they may not be able to be completely removed. Sip, sip, hooray: Oral selumetinib offers an alternative to surgery and true promise for pediatric patients suffering from symptomatic PNs! Most notable are its relatively low side-effect profile and durable response (greater than 1 year) for clinically significant reductions in reported pain.

The enticing blend of topical sirolimus and oral selumetinib to treat neurofibromas and plexiform neurofibromas, respectively, offers the promise of a brewtiful tomorrow. These latte-est miracles afford tremendous clinical opportunities where, before, none existed. Perhaps most importantly, their real impact may be the novel research and drug development they inspire and the cup of hope they bring to NF patients for an improved quality of life.

For a condition like NF that is relatively so common and yet has been seemingly so ignored by the pharmaceutical industry, these emerging therapies are truly grounds for celebration!

  1. Roman Souza G, Abdalla A, Mahadevan D. Clinical trials targeting neurofibromatoses-associated tumors: a systematic review. Neurooncol Adv. 2022 Jan 16;4(1):vdac005. doi: 10.1093/noajnl/vdac005. PMID: 35291225; PMCID: PMC8919406.

  2. McLarney RM, Schnur RE. Neurofibromatosis, Type 1. In Lebwohl MG, Heymann WR, Coulson IH, Murrell DF (eds) Treatment of Skin Disease. Elsevier, 2022, pp 578-580.

  3. Hamoy-Jimenez G, Kim R, Suppiah S, Zadeh G, Bril V, Barnett C. Quality of life in patients with neurofibromatosis type 1 and 2 in Canada. Neurooncol Adv. 2020 Jan 10;2(Suppl 1):i141-i149. doi: 10.1093/noajnl/vdaa003. PMID: 32642740; PMCID: PMC7317053.

  4. Mateos ME, López-Laso E, Vicente J, Ortega R, Vázquez F, Pérez-Navero JL. Response to everolimus of a progressive plexiform neurofibroma in Neurofibromatosis type 1. Pediatr Int. 2020 Jul;62(7):857-859. doi: 10.1111/ped.14183. Epub 2020 Jul 6. PMID: 32027426

  5. https://www.aad.org/dw/dw-insights-and-inquiries/medical-dermatology/rapalogs-for-vascular-lesions-caveat-mtor

  6. https://www.aad.org/dw/dw-insights-and-inquiries/medical-dermatology/sirolimus-for-microcystic-lymphatic-malformations-caviar-for-frog-spawn

  7. https://www.aad.org/dw/dw-insights-and-inquiries/archive/2022/ever-changing-world-of-nevus-sebaceus

  8. Malhotra N, Levy JMS, Fiorillo L. Topical sirolimus as an effective treatment for a deep neurofibroma in a patient with neurofibromatosis type I. Pediatr Dermatol. 2019 May;36(3):360-361. doi: 10.1111/pde.13782. Epub 2019 Mar 3. PMID: 30828862.

  9. Wataya-Kaneda M, Watanabe Y, Nakamura A, Yamamoto K, Okada K, Maeda S, Nimura K, Saga K, Katayama I. Pilot study for the treatment of cutaneous neurofibromas in neurofibromatosis type 1 patients using topical sirolimus gel. J Am Acad Dermatol. 2022 Nov 2:S0190-9622(22)02808-0. doi: 10.1016/j.jaad.2022.08.066. Epub ahead of print. PMID: 36334988.

  10. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selumetinib-neurofibromatosis-type-1-symptomatic-inoperable-plexiform-neurofibromas

  11. de Blank PMK, Gross AM, Akshintala S, Blakeley JO, Bollag G, Cannon A, Dombi E, Fangusaro J, Gelb BD, Hargrave D, Kim A, Klesse LJ, Loh M, Martin S, Moertel C, Packer R, Payne JM, Rauen KA, Rios JJ, Robison N, Schorry EK, Shannon K, Stevenson DA, Stieglitz E, Ullrich NJ, Walsh KS, Weiss BD, Wolters PL, Yohay K, Yohe ME, Widemann BC, Fisher MJ. MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus. Neuro Oncol. 2022 Nov 2;24(11):1845-1856. doi: 10.1093/neuonc/noac165. PMID: 35788692; PMCID: PMC9629420.

  12. Roman Souza G, Abdalla A, Mahadevan D. Clinical trials targeting neurofibromatoses-associated tumors: a systematic review. Neurooncol Adv. 2022 Jan 16;4(1):vdac005. doi: 10.1093/noajnl/vdac005. PMID: 35291225; PMCID: PMC8919406.

  13. Blegen K, Ortiz-Romero SE, Juarez O, Voeller J. Clinical impact of selumetinib on pediatric elephantiasis neuromatosa. Pediatr Dermatol. 2022 Sep;39(5):764-766. doi: 10.1111/pde.15044. Epub 2022 Jun 23. PMID: 35739628.

  14. Volontè M, Isoletta E, Gordon S, Foiadelli T, Bassanese F, Rossi A, Marseglia GL, Savasta S, Brazzelli V. Acneiform rash as a side effect of selumetinib in a child with neurofibromatosis type 1 treated for inoperable plexiform neurofibromas: Good results with doxycycline. Dermatol Ther. 2022 Aug;35(8):e15607. doi: 10.1111/dth.15607. Epub 2022 Jun 9. PMID: 35638252; PMCID: PMC9541585.

  15. Fitz-Gerald, Sean. "Master the Art of Saying ‘Sheeeeeeeeeit’ at Isiah Whitlock Jr.’s Acting Academy," Vulture, Wednesday, December 31, 2014.



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