Our Science

Jessie Villanueva, Ph.D.

Jessie Villanueva, Ph.D.

  • Assistant Professor, Molecular and Cellular Oncogenesis Program
  • Member, The Wistar Institute Melanoma Research Center
  • 215-898-3971, Office
Summary

The laboratory of Jessie Villanueva investigates the molecular signaling pathways that become deregulated in melanoma with the goal of identifying suitable targets for therapy. The Villanueva lab is actively studying the molecular mechanisms mediating drug resistance in melanoma aiming at designing effective therapies that will overcome it. The team is particularly interested in 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.

Villanueva joined The Wistar Institute in 2006 as a postdoctoral fellow in the laboratory of Meenhard Herlyn, D.V.M., D.Sc., where she later became a staff scientist. Jessie studied biology at Universidad Peruana Cayetano Heredia in her native Peru, where she received her Bachelor of Science degree. Following graduation, she moved to Pennsylvania to become a research specialist at the University of Pittsburgh School of Medicine. She then enrolled in the graduate program at University of Miami School of Medicine where she began her dissertation studies on the role of adhesion and signaling pathways in regulating the cell cycle—work with great relevance to the part these pathways play in the development of cancer.

In 2003, she earned a Ph.D. in Molecular Cell and Developmental Biology. She then pursued postdoctoral training at the University of Pennsylvania School of Medicine. There, she began to further investigate the role of a mutation in the BRAF gene present in half of all cases of melanoma, an aggressive form of skin cancer whose rates have climbed steadily in recent years. The mutant BRAF turns on a signaling pathway that drives cell division and, tumor formation.

At Wistar, Villanueva’s work has demonstrated that recently developed RAF inhibitors are, at best, transient in their tumor-killing effectiveness, as tumor cells are able to adapt to RAF inhibitors and find a way to bypass the effects of the drug.

As melanoma is a highly heterogeneous disease, multiple mechanisms of resistance are likely to arise in patients. The Villanueva laboratory is using an array of biochemical and genetic approaches to identify additional mechanisms of intrinsic and acquired resistance and test combinations of different inhibitors targeting pathways including MEK and PI3K. Their goal is to identify the best combination therapies that can overcome drug resistance and could move forward into clinical trials.

Selected Publications

1.    Villanueva, J., Infante, J., Krepler, C., Reyes-Uribe, P., Samanta, M., Chen, H-Y, Li, B., Swoboda, R., Wilson, M., Vultur, A., Fukunaga-Kalabis, M., Wubbenhorst, B., Chen T., Liu, Q., Sproesser, K., DeMarini, D., Gilmer, T., Martin, A-M., Marmorstein, R., Schultz, D., Speicher, D., Karakousis, G., Xu, W., Amaravadi, R., Xu, X.,  Schuchter, L., Herlyn, M., Nathanson, K.: Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Reports, 2013, in press.

2.   Roesch A, Vultur A, Bogeski I, Wang H, Zimmermann KM, Speicher D, Körbel C, Laschke MW, Gimotty PA, Philipp SE, Krause E, Pätzold S, Villanueva J, Krepler C, Fukunaga-Kalabis M, Hoth M, Bastian BC, Vogt T, Herlyn M. Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B (high) cells. Cancer Cell. 2013;23(6):811-25. PMID: 23764003

3.    Vultur A, Villanueva J, Krepler C, Rajan G, Chen Q, Xiao M, Li L, Gimotty PA, Wilson M, Nathanson KL, Herlyn M. MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene. 2013; Apr 29. doi: 10.1038/onc.2013.131. [Epub ahead of print] PMID: 23624919

4.    Krepler C, Chunduru SK, Halloran MB, He X, Xiao M, Vultur AM, Villanueva J, Mitsuuchi Y, Neiman EM, Benetatos C, Nathanson KL, Amaravadi R, Pehamberger H, McKinlay M, Herlyn M. The novel SMAC mimetic Birinapant exhibits potent activity against human melanoma cells. Clin Cancer Res. 2013 Feb 12. [Epub ahead of print] PMID: 23403634

5.    Desai BM *, Villanueva J *, Nguyen T-T K, Lioni M, Xiao M, Kong J, Krepler C, Vultur A, Flaherty KT, Nathanson KL, Smalley KSM, and Herlyn M. The anti-melanoma activity of dinaciclib, a cyclin-dependent kinase inhibitor, is dependent on p53 signaling. Plos One. 2013;8(3):e59588. PMID: 23527225. (* Co-first authors).

6.    Balaburski GM, Leu JI, Beeharry N, Hayik S, Andrake MD, Zhang G, Herlyn M, Villanueva J, Dunbrack RL Jr, Yen T, George DL, Murphy ME. A modified HSP70 inhibitor shows broad activity as an anticancer agent. Mol Cancer Res. 2013 Jan 9. Mol Cancer Res. 2013 Mar;11(3):219-29. doi: 10.1158/1541-7786.MCR-12-0547-T. Epub 2013 Jan 9. PMID: 23303345.

7.    Schayowitz A, Bertenshaw G, Jeffries E, Schatz T, Cotton J, Villanueva J, Herlyn M, Krepler C, Vultur A, Xu W, Yu GH, Schuchter L, Clark DP. Functional Profiling of Live Melanoma Samples Using a Novel Automated Platform. PLoS ONE 2012; 7(12): e52760. PMID: 23285177

8.    Chae YC, Caino MC, Lisanti S, Ghosh JC, Dohi T, Danial NC, Villanueva J, Ferrero S, Vaira V, Santambrogio L, Bosari S, Languino L, Herlyn M and Altieri DC. Control of Tumor Bioenergetics and Survival Stress Signaling by Mitochondrial HSP90s. Cancer Cell. 2012; 22(3):331-344. PMID: 22975376

9.    Somasundaram R, Villanueva J, Herlyn M. Intratumoral heterogeneity as a therapy resistance mechanism: role of melanoma subpopulations. Adv Pharmacol. 2012; 65:335-59. PMID: 22959031

10   Herlyn M, Villanueva J. Sorting through the many opportunities for melanoma therapy. Pigment Cell Melanoma Res. 2011 Sep 8. [Epub ahead of print] (PMID: 21899726)

11   Villanueva J, Vultur A, Herlyn M. Resistance to BRAF inhibitors: unraveling mechanisms and future treatment  options. Cancer Res. 71:7137-40, 2011. (PMID: 22131348).

12   Vultur, A, Villanueva J, Herlyn, M. Targeting BRAF in advanced melanoma: a first step towards manageable disease. Clin Cancer Res. 2011;17(7):1658-63. (PMID: 21447722)

13   Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, Wubbenhorst B, Xu X, Gimotty PA, Kee D, Santiago-Walker AE, Letrero R, D'Andrea K, Pushparajan A, Hayden JE, Brown KD, Laquerre S, McArthur GA, Sosman JA, Nathanson KL, Herlyn M. Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K. Cancer Cell. 2010; 18(6):683-95. (PMID: 21156289)

14   Vultur A, Villanueva J, Herlyn M. BRAF inhibitor unveils its potential against advanced melanoma. Cancer Cell. 2010; 18(4):301-2. (PMID: 20951940)

15   Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P, Elder DE, Wang Y, Nathanson KL, Herlyn M. CRAF inhibition induces Bcl-2 dependent apoptosis in melanoma cells with non-V600E BRAF mutations. Oncogene. 2009; 28(1):85-94. (PMID: 18794803)