Lab In The News
Melanoma Researchers Gathered at Wistar to Assess How Far We’ve Come and How Far We Still Need to Go
In a time when targeted therapies and immunotherapies have revolutionized the treatment options for melanoma patients, and yet a substantial proportion of them don’t benefit from these new approaches, researchers are looking for factors that affect the host response and how to modulate them.
The Villanueva Laboratory
The Villanueva laboratory is actively studying the molecular mechanisms mediating drug resistance in melanoma, aiming at designing effective therapies that will overcome it. The lab has extensively investigated the role of the RAF/MEK and PI3K/mTOR pathways as therapeutic targets and the mechanisms underlying resistance to inhibitors that block these signaling cascades. More recently, the team is focusing on identifying new targets or vulnerabilities that can be therapeutically exploited in NRAS mutant melanoma, a tumor type in dire need of new treatments.
Hsin-Yi Chen, Ph.D.
Adam Guterres, Ph.D.
The focus of the Villanueva lab is to identify novel targets to overcome drug resistance in melanoma.
Mechanisms of Drug Resistance in Melanoma
The Villanueva lab has developed pre-clinical models that show how melanoma gains resistance to BRAF and MEK inhibitors. Using these models, they demonstrated that melanoma cells treated with RAF inhibitors bypass the effects of the drugs by reactivating the MAPK pathway and/or activating alternative signaling pathways, including RTKs, PI3K/mTOR and STAT3. For example, the lab identified a novel MEK2 mutation that, together with BRAF amplification, confers resistance to RAF and MEK inhibitors. Based on these findings, the team tested combination therapies to overcome drug resistance.
Developing Molecular Approaches to Target NRAS Mutant Melanomas
NRAS is a poorly characterized RAS family member, and the biology of NRAS mutant tumors remain inadequately understood. There are very limited treatment options for patients carrying NRAS mutations, which are present in more than 25 percent of all melanomas. As targeting NRAS directly has thus far not been possible, the aim of the lab is to eradicate this type of tumors by blocking critical RAS effectors or pathways that are essential for tumor survival. The team has identified several non-oncogene dependencies that are critical for survival of melanoma cells including BRD4, TERT(*) and the ribosomal serine/threonine kinase S6K2. The lab is investigating the role of these dependencies in melanoma and evaluating the impact of blocking their activity on tumor initiation, maintenance and survival using 3-D organotypic spheroids, patient-derived xenograft (PDX) models and syngeneic mouse models.
Watch the animation below to learn more about our strategies to combat NRAS mutant melanoma.
Echevarría-Vargas, I.M., Reyes-Uribe, P.I., Guterres, A.N., Yin, X., Kossenkov, A.V., Liu, Q., Zhang, G., Krepler, C., Cheng, C., Wei, Z., et al. "Co-targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor-resistant melanoma." EMBO Mol Med. 2018 May;10(5). pii: e8446. doi: 10.15252/emmm.201708446.
Reyes-Uribe, P., Adrianzen-Ruesta, M.P., Deng, Z., Echevarria-Vargas, I., Mender, I., Saheb, S., Liu, Q., Altieri, D.C., Murphy, M.E., Shay, J.W., et al. "Exploiting TERT dependency as a therapeutic strategy for NRAS-mutant melanoma." Oncogene. 2018 Apr 26. doi: 10.1038/s41388-018-0247-7. [Epub ahead of print]
Villanueva, J., Infante, J.R., Krepler, C., Reyes-Uribe, P., Samanta, M., Chen, H.Y., Li, B., Swoboda, R.K., Wilson, M., Vultur, A., et al. "Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma." Cell Rep. 2013 Sep 26;4(6):1090-9. doi: 10.1016/j.celrep.2013.08.023. Epub 2013 Sep 19.
David W. Speicher, Ph.D.
Professor and Program Co-Leader, Molecular & Cellular Oncogenesis Program, The Wistar Institute Cancer Center
Director, Center for Systems & Computational Biology
Member, The Wistar Institute Melanoma Research Center
Scientific Director, Proteomics & Metabolomics Facility