RESUMO
PURPOSE: Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic epidermolysis bullosa (RDEB). Although emerging data are identifying why patients suffer this fatal complication, therapies for treatment of RDEB SCC are in urgent need.Experimental Design: We previously identified polo-like kinase 1 (PLK1) as a therapeutic target in skin SCC, including RDEB SCC. Here, we undertake a screen of 6 compounds originally designated as PLK1 inhibitors, and detail the efficacy of the lead compound, the multipathway allosteric inhibitor ON-01910, for targeting RDEB SCC in vitro and in vivo. RESULTS: ON-01910 (or rigosertib) exhibited significant specificity for RDEB SCC: in culture rigosertib induced apoptosis in 10 of 10 RDEB SCC keratinocyte populations while only slowing the growth of normal primary skin cells at doses 2 orders of magnitude higher. Furthermore, rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in RDEB SCC shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib. CONCLUSIONS: These data support a "first in RDEB" phase II clinical trial of rigosertib to assess tumor targeting in patients with late stage, metastatic, and/or unresectable SCC.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/etiologia , Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa Distrófica/genética , Glicina/análogos & derivados , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/etiologia , Sulfonas/uso terapêutico , Antineoplásicos/farmacologia , Apoptose , Carcinoma de Células Escamosas/diagnóstico , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Técnicas de Silenciamento de Genes , Genes Recessivos , Glicina/farmacologia , Glicina/uso terapêutico , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Terapia de Alvo Molecular , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro , RNA Interferente Pequeno , Neoplasias Cutâneas/diagnóstico , Sulfonas/farmacologia , Quinase 1 Polo-LikeRESUMO
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin and mucous membrane fragility disorder complicated by early-onset, highly malignant cutaneous squamous cell carcinomas (SCCs). The molecular etiology of RDEB SCC, which arises at sites of sustained tissue damage, is unknown. We performed detailed molecular analysis using whole-exome, whole-genome, and RNA sequencing of 27 RDEB SCC tumors, including multiple tumors from the same patient and multiple regions from five individual tumors. We report that driver mutations were shared with spontaneous, ultraviolet (UV) light-induced cutaneous SCC (UV SCC) and head and neck SCC (HNSCC) and did not explain the early presentation or aggressive nature of RDEB SCC. Instead, endogenous mutation processes associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) deaminases dominated RDEB SCC. APOBEC mutation signatures were enhanced throughout RDEB SCC tumor evolution, relative to spontaneous UV SCC and HNSCC mutation profiles. Sixty-seven percent of RDEB SCC driver mutations was found to emerge as a result of APOBEC and other endogenous mutational processes previously associated with age, potentially explaining a >1000-fold increased incidence and the early onset of these SCCs. Human papillomavirus-negative basal and mesenchymal subtypes of HNSCC harbored enhanced APOBEC mutational signatures and transcriptomes similar to those of RDEB SCC, suggesting that APOBEC deaminases drive other subtypes of SCC. Collectively, these data establish specific mutagenic mechanisms associated with chronic tissue damage. Our findings reveal a cause for cancers arising at sites of persistent inflammation and identify potential therapeutic avenues to treat RDEB SCC.
Assuntos
Desaminases APOBEC/genética , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/genética , Citosina Desaminase/genética , Epidermólise Bolhosa Distrófica/enzimologia , Epidermólise Bolhosa Distrófica/genética , Mutação/genética , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Variações do Número de Cópias de DNA/genética , Reparo do DNA/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Mutagênese/genética , Taxa de Mutação , Transcriptoma/genéticaRESUMO
Radiation-induced sarcoma (RIS) is an unusual but well documented tumor. The frequency of RIS of the head and neck region has been reported as 0.143%. In the literature the median interval between irradiation and development of sarcoma is 11 years. Cases of RIS with a short latent period, that is, less than 4 years are rare. We report a case of a 34-year-old female who developed an osteosarcoma of the scalp, over a previous craniotomy scar, 3 years after excision of a frontal anaplastic oligodendroglioma which had been followed by a course of 6 weeks radiotherapy (58 Gy) and 6 cycles of temozolomide. The histological features were those of a high-grade osteosarcoma with epidermotropism of tumor cells. Lymph nodes were partially replaced by high-grade metastatic osteosarcoma, with extra-nodal lymphatic tumor thrombi. To our knowledge the only other case report of post-radiation osteosarcoma with a short latency period was a case of osteosarcoma in the craniofacial bone 3 years after radiotherapy for maxillary squamous cell carcinoma. The histological finding of prominent replacement of the epidermis by osteosarcoma has not been reported before.