New therapies are required for melanoma. Here, we report that multiple cardiac glycosides, including digitoxin and digoxin, are significantly more toxic to human melanoma cells than normal human cells. This reflects on-target inhibition of the ATP1A1 Na(+)/K(+) pump, which is highly expressed by melanoma. MEK inhibitor and/or BRAF inhibitor additively or synergistically combined with digitoxin to induce cell death, inhibiting growth of patient-derived melanomas in NSG mice and synergistically ex ...[more]
Project description:We compare the genetic profiles of the primary tumors of uveal melanoma or metastasis to their corresponding xenografts that have been passaged over time. The study included patient tumors and corresponding xenografts at very early (P1), early (P4), and late (P9) in vivo passages Overall design: The transcriptome of 16 uveal melanoma patient-derived xenografts models were analyzed using Affymetrix Human Exon 1.0 ST Array
Project description:Cells from patient melanoma samples were grown de novo in either a stem cell media (SCM) or in standard serum containing media, as well as xenografts derived from each culture type. The expression profile of these samples were compaired to the expression profile of the original patient tumour sample.
Project description:The therapeutic landscape of melanoma is rapidly changing. While targeted inhibitors yield significant responses, their clinical benefit is often limited by the early onset of drug resistance. This motivates the pursuit to establish more durable clinical responses, by developing combinatorial therapies. But while potential new combinatorial targets steadily increase in numbers, they cannot possibly all be tested in patients. Similarly, while genetically engineered mouse melanoma models have great merit, they do not capture the enormous genetic diversity and heterogeneity typical in human melanoma. Furthermore, whereas in vitro studies have many advantages, they lack the presence of micro-environmental factors, which can have a profound impact on tumor progression and therapy response. This prompted us to develop an in vivo model for human melanoma that allows for studying the dynamics of tumor progression and drug response, with concurrent evaluation and optimization of new treatment regimens. Here, we present a collection of patient-derived xenografts (PDX), derived from BRAFV600E, NRASQ61 or BRAFWT/NRASWT melanoma metastases. The BRAFV600E PDX melanomas were acquired both prior to treatment with the BRAF inhibitor vemurafenib and after resistance had occurred, including six matched pairs. We find that PDX resemble their human donors’ melanomas regarding biomarkers, chromosomal aberrations, RNA expression profiles, mutational spectrum and targeted drug resistance patterns. Mutations, previously identified to cause resistance to BRAF inhibitors, are captured in PDX derived from resistant melanomThis melanoma PDX platform represents a comprehensive public resource to study both fundamental and translational aspects of melanoma progression and treatment in a physiologically relevant setting. Overall design: Melanoma samples pre and post Vemurafenib treatment from patient and matching patient derived xenografts (PDX)
Project description:Cells from patient melanoma samples were grown de novo in either a stem cell media (SCM) or in standard serum containing media, as well as xenografts derived from each culture type. The expression profile of these samples were compared to the expression