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Assessment of Mammalian Target of Rapamycin Pathway Activation in Basal Cell Carcinoma as a New Therapeutic Approach.
- Source :
-
The American Journal of dermatopathology [Am J Dermatopathol] 2024 Sep 01; Vol. 46 (9), pp. 588-592. Date of Electronic Publication: 2024 Apr 23. - Publication Year :
- 2024
-
Abstract
- Abstract: Targeting the mammalian target of rapamycin (mTOR) pathway represents a potentially novel approach to treat basal cell carcinoma (BCC), but activation of this pathway has not been well described in human BCCs. The purpose of this study was to assess whether mTOR pathway activation occurs in BCCs (both sporadic and syndromic) and report a case of a patient with Gorlin syndrome (GS) whose clinically suspicious BCCs responded to mTOR inhibition through topical sirolimus treatment. After Stanford Institutional Review Board Approval, archived BCCs from patients with GS (n = 25), sporadic BCCs (n = 35), and control tissues were subjected to immunohistochemical analysis for the activation of mTOR pathway, and immunohistochemical staining intensity was evaluated by a dermatopathologist. BCCs (compared with normal skin) had elevated levels of eIF4EBP1 ( Padjusted = 0.0336), which is downstream of mTOR. a serine/threonine kinase Phospho-(AKT), which interacts with mTOR, was also significantly elevated (perinuclear: Padjusted < 0.0001; cytoplasmic: Padjusted = 0.0021). When off-label topical 1% sirolimus was used on a pediatric patient with GS, we noted reduction of new BCC development and decreased size of existing neoplasms clinically suspicious for BCCs. This treatment was well tolerated after 2 years of continuous use, with no other treatments needed during this period. Topical sirolimus is a promising therapeutic candidate against both sporadic and GS-associated BCC. Multicenter, prospective studies are needed to understand the efficacy and safety of topical mTOR inhibitors in BCC treatment, and ascertain whether the immunohistochemical markers downstream of mTOR could have predictive value in identifying BCCs most likely to respond to topical mTOR inhibitors, such as sirolimus.<br /> (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)
- Subjects :
- Humans
Male
Female
Middle Aged
Adult
Aged
Basal Cell Nevus Syndrome drug therapy
Basal Cell Nevus Syndrome pathology
Basal Cell Nevus Syndrome metabolism
Immunohistochemistry
Antibiotics, Antineoplastic
Child
Adolescent
Young Adult
Aged, 80 and over
Proto-Oncogene Proteins c-akt metabolism
Off-Label Use
Treatment Outcome
Cell Cycle Proteins
Adaptor Proteins, Signal Transducing
Skin Neoplasms drug therapy
Skin Neoplasms pathology
Skin Neoplasms metabolism
Carcinoma, Basal Cell drug therapy
Carcinoma, Basal Cell pathology
Carcinoma, Basal Cell metabolism
TOR Serine-Threonine Kinases metabolism
TOR Serine-Threonine Kinases antagonists & inhibitors
Sirolimus pharmacology
Sirolimus therapeutic use
Signal Transduction drug effects
MTOR Inhibitors pharmacology
MTOR Inhibitors therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1533-0311
- Volume :
- 46
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The American Journal of dermatopathology
- Publication Type :
- Academic Journal
- Accession number :
- 38648034
- Full Text :
- https://doi.org/10.1097/DAD.0000000000002718