The increasing incidence of melanoma and mortality associated with advanced stages of the disease are cause for concern. Recent reports on the efficacy of therapeutic agents targeting the most common alteration in melanoma, mutant BRAF, have been very encouraging and have shifted the treatment paradigm for this disease. Despite these impressive clinical successes, a significant percentage of patients are intrinsically resistant to BRAF inhibitors and those who initially respond ultimately relapse as a result of acquired resistance. In addition, nearly half of all melanomas contain wild-type BRAF and are therefore not sensitive to mutant BRAF inhibitors. While targeted therapies have the potential to revolutionize cancer care by providing personalized treatment strategies that are less toxic and more effective, maximizing their effectiveness requires increased knowledge of the molecular alterations that drive tumor formation, progression, maintenance, and resistance. In vivo models fulfill this need. We have developed a novel mouse model of melanoma that not only aids in the identification and validation of alterations that drive tumor growth but also provides a means to assess tumor progression and efficacy of therapeutic strategies. Importantly, melanomas can be induced in our model using the same genetic alterations observed in the human disease and specific gene combinations result in both lung and brain metastases, which are responsible for nearly half of all melanoma patient deaths. We have observed that despite their high sequence and functional similarity, AKT2 and AKT3 significantly differ in their ability to promote brain metastases in the context of mutant BRAF in vivo. Interestingly, brain metastases are also not observed in mice with mutant BRAF-driven tumors that lack Pten, which is believed to contribute to melanoma development and progression through deregulated AKT activity. We are uniquely poised to investigate the mechanistic differences between these tumors in vivo using our novel mouse model. We hypothesize that the differential ability of the three AKT isoforms and Pten loss to induce brain metastases is due to differential downstream signaling and that genetic suppression of AKT3 in this context will significantly delay the development and growth of distant metastases. To test this hypothesis, we will define the functional domain(s) that dictate AKT isoform specific melanoma brain metastases in vivo, use functional proteomics to identify AKT3-dependent effectors involved in promoting brain metastases, and utilize an in vivo genetic approach to evaluate the effect of targeting AKT3 on melanoma growth and metastasis. We will further validate our findings in melanoma tissue from patients. The long-term goals of this project are to identify targets that promote brain metastases as well as biomarkers that identify the subset of melanoma patients that are most likely to develop brain metastases and would therefore benefit from more aggressive therapy.

Public Health Relevance

The increasing incidence of melanoma, in particular among young to middle-aged adults, is a significant public health problem. Targeted therapy is showing unprecedented promise in advanced stages of the disease but its effectiveness is hindered by the development of resistance and inability to eliminate brain metastases, which is the leading cause of death from melanoma. The goal of this project is to further our understanding of melanoma progression, particularly the development of brain metastases, such that more effective therapies can be developed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA121118-06A1
Application #
8694701
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
2006-05-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
$250,535
Indirect Cost
$82,391
Name
University of Utah
Department
Surgery
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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VanBrocklin, Matthew W; Robinson, James P; Lastwika, Kristin J et al. (2010) Targeted delivery of NRASQ61R and Cre-recombinase to post-natal melanocytes induces melanoma in Ink4a/Arflox/lox mice. Pigment Cell Melanoma Res 23:531-41
VanBrocklin, Matthew W; Verhaegen, Monique; Soengas, Maria S et al. (2009) Mitogen-activated protein kinase inhibition induces translocation of Bmf to promote apoptosis in melanoma. Cancer Res 69:1985-94
Vanbrocklin, Matthew W; Robinson, James P; Whitwam, Todd et al. (2009) Met amplification and tumor progression in Cdkn2a-deficient melanocytes. Pigment Cell Melanoma Res 22:454-60