Melanoma brain metastasis (B-Met) carries a dismal prognosis, with a median survival of less than 6 months. Unfortunately, approximately 75% of patients with metastatic melanoma develop B-Mets during the course of their disease. There is no effective treatment and thus far there is no molecular marker(s) that can predict which primary tumors are most likely to progress to B-Met. Our preliminary data strongly support that melanoma B-Mets are not merely the terminal stage of a generally aggressive phenotype and that a B-Met-specific miRNA signature can be detected at the time the primary melanoma. We hypothesize that some of these miRNAs play a critical role in governing the molecular mechanisms responsible for the propagation and establishment of melanoma B-Met, including chemotaxis, adhesion, migration, and proliferation. First, B- Met associated miRNAs will be tested in vivo for their ability to modulate B-Met potential of melanoma cell lines. For the positie hits in the screen we will investigate the biological process and mechanism(s) by which they might contribute to melanoma B-Met. The results from our study will greatly advance the understanding of how miRNA modulate the metastatic process in general and why melanoma cells have a particular penchant for penetrating the blood brain barrier and proliferating in the neural microenvironment. Moreover, the identification of miRNAs and miRNA targets that actively participate in melanoma B-Met has the potential to reveal new avenues for treatment in patients for whom no viable approaches are currently available. In this study we will also evaluate the predictive capacity of the B-Met miRNA signature at the time of diagnosis in a prospective patient cohort. As novel, effective therapies with ability to penetrate the blood brain barrier are becoming available and being tested in the adjuvant setting (i.e. vemurafenib), having a signature with ability to predict B-met may become particularly useful for patient selection. Success from our application would satisfy NCI's goals in that 'improved prediction of clinical risk could help clinicians in communicating risk/benefit profiles for treatment options. (..) Insight into the biological basis for this stratification would be an important advance, with likel relevance to analogous lesions of several tissues'.

Public Health Relevance

Identification of miRNAs and miRNA targets that actively participate in melanoma B-Met has the potential to reveal new avenues for treatment in patients for whom no viable approaches are currently available. A signature with ability to predict B-met would allow selection of patients who could benefit most from increased surveillance or adjuvant therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA163891-05
Application #
9279068
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
2013-07-17
Project End
2018-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
5
Fiscal Year
2017
Total Cost
$351,713
Indirect Cost
$144,213
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Santamaría, Patricia G; Floristán, Alfredo; Fontanals-Cirera, Bárbara et al. (2018) Lysyl oxidase-like 3 is required for melanoma cell survival by maintaining genomic stability. Cell Death Differ 25:935-950
Díaz-Martínez, Marta; Benito-Jardón, Lucía; Alonso, Lola et al. (2018) miR-204-5p and miR-211-5p Contribute to BRAF Inhibitor Resistance in Melanoma. Cancer Res 78:1017-1030
Fontanals-Cirera, Barbara; Hasson, Dan; Vardabasso, Chiara et al. (2017) Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene. Mol Cell 68:731-744.e9
Koetz-Ploch, Lisa; Hanniford, Douglas; Dolgalev, Igor et al. (2017) MicroRNA-125a promotes resistance to BRAF inhibitors through suppression of the intrinsic apoptotic pathway. Pigment Cell Melanoma Res 30:328-338
Vardabasso, Chiara; Gaspar-Maia, Alexandre; Hasson, Dan et al. (2015) Histone Variant H2A.Z.2 Mediates Proliferation and Drug Sensitivity of Malignant Melanoma. Mol Cell 59:75-88
Danielson, Laura S; Reavie, Linsey; Coussens, Marc et al. (2015) Limited miR-17-92 overexpression drives hematologic malignancies. Leuk Res 39:335-41
Hanniford, Doug; Zhong, Judy; Koetz, Lisa et al. (2015) A miRNA-Based Signature Detected in Primary Melanoma Tissue Predicts Development of Brain Metastasis. Clin Cancer Res 21:4903-12
Weiss, Sarah A; Hanniford, Douglas; Hernando, Eva et al. (2015) Revisiting determinants of prognosis in cutaneous melanoma. Cancer 121:4108-23
Hanniford, Doug; Segura, Miguel F; Zhong, Judy et al. (2015) Identification of metastasis-suppressive microRNAs in primary melanoma. J Natl Cancer Inst 107:
Fleming, Nathaniel H; Zhong, Judy; da Silva, Inês Pires et al. (2015) Serum-based miRNAs in the prediction and detection of recurrence in melanoma patients. Cancer 121:51-9

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