RESUMEN
Patients with epidermolysis bullosa (EB) are susceptible to development of squamous cell carcinomas (SCC) at sites of chronic inflammation and fibrosis. While triterpenoids such as RTA 408 (Omaveloxolone) have been shown to reduce inflammation and inhibit tumour growth in various cancer models, the utility of this class of drugs in the treatment of SCC has not been investigated. Given the dual anti-inflammatory and anti-neoplastic properties of triterpenoids, we hypothesized RTA 408 would be an effective treatment for SCCs that arise in the chronic inflammatory setting in EB. We tested the effects of topical RTA 408 on a mouse model of non-Herlitz, junctional EB. RTA 408 significantly reduced phenotypic severity in the affected ears of Lamc2jeb mice. In cultures, RTA 408 reduced cell viability in EB-associated SCC cell lines and normal human epidermal keratinocytes. When administered in vivo, RTA 408 inhibited SCC tumour growth in mice without cutaneous or systemic toxicity. These results suggest that RTA 408 can be a promising new therapy to reduce inflammation and inhibit SCC growth in patients with EB.
Asunto(s)
Carcinoma de Células Escamosas , Epidermólisis Ampollosa Distrófica , Epidermólisis Ampollosa , Neoplasias Cutáneas , Triterpenos , Animales , Carcinoma de Células Escamosas/metabolismo , Epidermólisis Ampollosa/patología , Humanos , Inflamación , Ratones , Índice de Severidad de la Enfermedad , Neoplasias Cutáneas/metabolismo , Triterpenos/farmacología , Triterpenos/uso terapéuticoRESUMEN
BACKGROUND: Recent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. However, the underlying mechanism by which MYC promotes FAO remains poorly understood. METHODS: We used a combination of metabolomics, transcriptomics, bioinformatics, and microscopy to elucidate a potential mechanism by which MYC regulates FAO in TNBC. RESULTS: We propose that MYC induces a multigenic program that involves changes in intracellular calcium signalling and fatty acid metabolism. We determined key roles for fatty acid transporters (CD36), lipases (LPL), and kinases (PDGFRB, CAMKK2, and AMPK) that each contribute to promoting FAO in human mammary epithelial cells that express oncogenic levels of MYC. Bioinformatic analysis further showed that this multigenic program is highly expressed and predicts poor survival in the claudin-low molecular subtype of TNBC, but not other subtypes of TNBCs, suggesting that efforts to target FAO in the clinic may best serve claudin-low TNBC patients. CONCLUSION: We identified critical pieces of the FAO machinery that have the potential to be targeted for improved treatment of patients with TNBC, especially the claudin-low molecular subtype.
Asunto(s)
Claudinas/metabolismo , Ácidos Grasos/metabolismo , Metabolómica/métodos , Proteínas Proto-Oncogénicas c-myc/genética , Neoplasias de la Mama Triple Negativas/genética , Línea Celular Tumoral , Proliferación Celular , Transición Epitelial-Mesenquimal , Femenino , Humanos , TransfecciónRESUMEN
Chondrosarcomas (CSs) consist of a heterogenous group of primary bone cancers arising from malignant cells which produce cartilaginous matrix. As the second most common primary bone cancer, CS are often resistant to systemic chemotherapy due to poor vascularization, slow proliferation, and expression of multidrug-resistant pumps. Immune checkpoint inhibitors have transformed the field of oncology and are now designated as frontline therapy for many solid tumor cancers. Several studies have demonstrated increased expression of programed cell death 1 (PD-1) and PD-L1 in CS tissue in vitro, which has led to the development of multiple clinical trials for immunotherapy in patients with aggressive CS. In this review, we highlight the ongoing investigation into the role for immunotherapy in CS. We also report the case of a 44-year-old female with a history of stage IV primary CS of the right shoulder who underwent radical resection with recurrence and demonstrated a spectacular sustained response to pembrolizumab at our center. Our review highlights the need for further studies investigating the role of immunotherapy in the treatment of aggressive bone sarcomas that are resistant to standard surgical resection, chemotherapy, and radiation treatment.
Chondrosarcoma is a cancer of the cells that make cartilage and is often removed surgically. However, when the cancer spreads to other organs such as the lungs or are in areas unreachable by surgeons, there are not many effective treatments. While targeted treatments are in development, many of them have unclear effectiveness. A new and rapidly growing area of cancer treatment is known as immunotherapy, which uses the body's own immune system to kill cancer cells. In this review, we discuss trials in using immunotherapy against aggressive forms of chondrosarcoma. We also present the case of a patient where an immunotherapy agent called pembrolizumab was highly effective in preventing disease progression.