There is a critical need to develop new strategies to prevent and treat melanoma brain metastases. Melanoma has a higher risk of CNS involvement than any other tumor type, and brain metastasis is the leading cause of death from this disease. There are no molecular markers that identify melanoma patients with an increased risk for brain metastasis, and no systemic therapies effectively prevent or treat these tumors. In a pilot study, we identified increased activation of the PI3K-AKT signaling pathway in melanoma brain metastases as compared to other distant metastases. In addition, patients with increased activation of the PI3K-AKT pathway in regional metastases had a higher risk of CNS involvement. The PI3K-AKT pathway has previously been implicated in melanoma in a number of malignant processes, but not in brain metastasis. Based on our data, we hypothesize that activation of the PI3K-AKT pathway is critical to the development and dismal outcomes of melanoma brain metastases. This hypothesis will be tested using unique clinical resources to define relevant preclinical models, and may lead to clinical strategies that may be tested in patients. First, we will analyze 100 frozen melanoma brain metastases from patients at The M. D. Anderson Cancer Center (MDACC) for genetic aberrations and activation of the PI3K-AKT pathway. The tumors will be analyzed by MIP arrays to identify copy number changes in genes that are in or that regulate this pathway, and mutational analysis of known and candidate regulators will be performed by mass-spectroscopy (MS) genotyping and Sanger sequencing. The expression and activation of proteins in the PI3K-AKT pathway will be measured directly using reverse phase protein arrays (RPPA). The genetic analyses will be compared to the RPPA results to determine the events that activate the pathway in patients, and the effectors/targets that are activated by each. In addition, for patients with available tissue (n=23), parallel profiling will be performed on matched non-CNS metastases to determine if those tumors show the same genetic changes and protein activation as the brain metastases. In order to test if activation of the PI3K-AKT pathway contributes to the development of brain metastases, we will analyze 200 regional melanoma metastases for genetic aberrations and activation of the pathway, and compare these results to the risk of CNS involvement. Using the results of these experiments to prioritize targets, we will then test if activating genetic events in the PI3K-AKT pathway increases the CNS-metastatic potential of human melanoma cells in an established mouse xenograft model. Finally, we will determine if inhibitors against targets in the PI3K-AKT pathway inhibit tumor growth and increase survival in mice with established brain metastases of human melanoma cells. These studies will improve our understanding of the prevalence, regulation, and function of PI3K-AKT activation in melanoma brain metastases. These studies may lead to clinical trials to prevent and/or treat these tumors. The studies will also establish unique resources for future investigations in this important field.

Public Health Relevance

The most common cause of death from melanoma, the most aggressive form of skin cancer, is the spread of cancer cells to the brain. This project is designed to determine the role of activation of a particular set of proteins, the PI3K-AKT pathway, in melanoma brain metastases. This project may lead to new therapies to prevent and/or treat melanoma brain metastases, and may suggest if similar approaches will benefit patients with other types of cancer.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA154710-04
Application #
8606830
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Jhappan, Chamelli
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Hospitals
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77030
Kim, Dae Won; Haydu, Lauren E; Joon, Aron Y et al. (2016) Clinicopathological features and clinical outcomes associated with TP53 and BRAF(N)(on-)(V)(600) mutations in cutaneous melanoma patients. Cancer :
Peng, Weiyi; Chen, Jie Qing; Liu, Chengwen et al. (2016) Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy. Cancer Discov 6:202-16
Chen, Guo; McQuade, Jennifer L; Panka, David J et al. (2016) Clinical, Molecular, and Immune Analysis of Dabrafenib-Trametinib Combination Treatment for BRAF Inhibitor-Refractory Metastatic Melanoma: A Phase 2 Clinical Trial. JAMA Oncol 2:1056-64
Goedert, Lucas; Pereira, Cristiano G; Roszik, Jason et al. (2016) RMEL3, a novel BRAFV600E-associated long noncoding RNA, is required for MAPK and PI3K signaling in melanoma. Oncotarget 7:36711-36718
Roszik, Jason; Wu, Chang-Jiun; Siroy, Alan E et al. (2016) Somatic Copy Number Alterations at Oncogenic Loci Show Diverse Correlations with Gene Expression. Sci Rep 6:19649
McQuade, Jennifer; Davies, Michael A (2015) Converting biology into clinical benefit: lessons learned from BRAF inhibitors. Melanoma Manag 2:241-254
Siroy, Alan E; Boland, Genevieve M; Milton, Denái R et al. (2015) Beyond BRAF(V600): clinical mutation panel testing by next-generation sequencing in advanced melanoma. J Invest Dermatol 135:508-15
Kim, Seung Wook; Kim, Sun-Jin; Langley, Robert R et al. (2015) Modulation of the cancer cell transcriptome by culture media formulations and cell density. Int J Oncol 46:2067-75
Bucheit, Amanda D; Chen, Guo; Siroy, Alan et al. (2014) Complete loss of PTEN protein expression correlates with shorter time to brain metastasis and survival in stage IIIB/C melanoma patients with BRAFV600 mutations. Clin Cancer Res 20:5527-36
Kim, Seung Wook; Choi, Hyun Jin; Lee, Ho-Jeong et al. (2014) Role of the endothelin axis in astrocyte- and endothelial cell-mediated chemoprotection of cancer cells. Neuro Oncol 16:1585-98

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