RESUMO
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.
Assuntos
Carcinoma Basocelular , Inibidores de MTOR , Transdução de Sinais , Sirolimo , Neoplasias Cutâneas , Serina-Treonina Quinases TOR , Humanos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/patologia , Carcinoma Basocelular/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Masculino , Feminino , Transdução de Sinais/efeitos dos fármacos , Pessoa de Meia-Idade , Inibidores de MTOR/farmacologia , Inibidores de MTOR/uso terapêutico , Adulto , Idoso , Síndrome do Nevo Basocelular/tratamento farmacológico , Síndrome do Nevo Basocelular/patologia , Síndrome do Nevo Basocelular/metabolismo , Imuno-Histoquímica , Antibióticos Antineoplásicos , Criança , Adolescente , Adulto Jovem , Idoso de 80 Anos ou mais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Uso Off-Label , Resultado do Tratamento , Proteínas de Ciclo Celular , Proteínas Adaptadoras de Transdução de SinalRESUMO
Although basal cell carcinomas arise from ectopic Hedgehog pathway activation and can be treated with pathway inhibitors, sporadic basal cell carcinomas display high resistance rates, whereas tumors arising in patients with Gorlin syndrome with germline Patched (PTCH1) alterations are uniformly suppressed by inhibitor therapy. In rare cases, patients with Gorlin syndrome on long-term inhibitor therapy will develop individual resistant tumor clones that rapidly progress, but the basis of this resistance remains unstudied. In this study, we report a case of an SMO inhibitor-resistant tumor arising in a patient with Gorlin syndrome on suppressive SMO inhibitor for nearly a decade. Using a combination of multiomics and spatial transcriptomics, we define the tumor populations at the cellular and tissue level to conclude that Gorlin tumors can develop resistance to SMO inhibitors through the previously described basal to squamous cell carcinoma transition. Intriguingly, through spatial whole-exome genomic analysis, we nominate PCYT2, ETNK1, and the phosphatidylethanolamine biosynthetic pathway as genetic suppressors of basal to squamous cell carcinoma transition resistance. These observations provide a general framework for studying tumor evolution and provide important clinical insight into mechanisms of resistance to SMO inhibitors for not only Gorlin syndrome but also sporadic basal cell carcinomas.
Assuntos
Síndrome do Nevo Basocelular , Carcinoma Basocelular , Carcinoma de Células Escamosas , Resistencia a Medicamentos Antineoplásicos , Neoplasias Cutâneas , Receptor Smoothened , Humanos , Síndrome do Nevo Basocelular/genética , Síndrome do Nevo Basocelular/patologia , Síndrome do Nevo Basocelular/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Receptor Smoothened/genética , Receptor Smoothened/antagonistas & inibidores , Receptor Smoothened/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma Basocelular/genética , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Basocelular/patologia , Masculino , Anilidas/uso terapêutico , Feminino , Transdução de Sinais/efeitos dos fármacos , Piridinas/uso terapêuticoAssuntos
Anilidas , Síndrome do Nevo Basocelular , Piridinas , Qualidade de Vida , Humanos , Síndrome do Nevo Basocelular/tratamento farmacológico , Estudos Retrospectivos , Masculino , Feminino , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Anilidas/uso terapêutico , Anilidas/efeitos adversos , Pessoa de Meia-Idade , Adulto , Resultado do Tratamento , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológicoAssuntos
Síndrome do Nevo Basocelular , Consenso , Proteínas Hedgehog , Neoplasias Cutâneas , Humanos , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Síndrome do Nevo Basocelular/tratamento farmacológico , Síndrome do Nevo Basocelular/diagnóstico , Síndrome do Nevo Basocelular/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Anilidas/uso terapêutico , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacosRESUMO
A terapia fotodinâmica é uma alternativa eficaz de tratamento para neoplasias cutâneas não melanoma e tem como princípio a utilização de substâncias fotossensibilizantes que, após serem irradiadas com uma fonte de luz de comprimento de onda adequado, destroem seletivamente as células neoplásicas. A Síndrome do Nevobasocelular é uma genodermatose que cursa com o desenvolvimento de inúmeros carcinomas basocelulares em uma idade precoce, submetendo os pacientes a vários procedimentos cirúrgicos, muitas vezes desfigurantes. Este artigo tem como objetivo demonstrar o excelente resultado do tratamento de carcinomas basocelulares no couro cabeludo de uma paciente com a Síndrome do Nevobasocelular.
Photodynamic therapy is an effective alternative for the treatment of non-melanoma skin cancer, selectively destroying the neoplastic cells through the use of photosensitizer substances that are irradiated with a source of light of adequate wave length. Nevoid Basal Cell Carcinoma Syndrome is a genodermatosis characterized by multiples basal cell carcinomas occurring at an early age, compelling patients to various surgeries, some of them disfiguring. The aim of this article is to show the excellent result of the treatment of multiple basal cell carcinomas on the scalp of a patient suffering from Nevoid Basal Cell Carcinoma Syndrome.