Molecular Profiling of Patient-Matched Brain and Extracranial Melanoma Metastases Implicates the PI3K Pathway as a Therapeutic Target

Guo, Cheng; Chakravarti, Nitin; Aardalen, Kimberly; Lazar, Alexander J.; Tetzlaff, Michael T.; Wubbenhorst, Bradley; Kim, Sang Bae; Kopetz, Scott; Ledoux, Alicia A.; Gopal, Y.N. Vashisht; Pereira, Cristiano G.; Deng, Wanleng; Lee, Ju Seog; Nathanson, Katherine L.; Aldape, Kenneth; Prieto, Víctor G.; Stuart, Darrin D.; Davies, Michael A.

doi:10.1158/1078-0432.ccr-13-3003

Cited by 171 publications

(166 citation statements)

References 42 publications

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“…Multidimensional molecular profiling of matched cerebral and extracerebral melanoma metastases found no differences in hotspot mutations, copynumber variations, mRNA and protein expression, but detected increased expression of several activation-specific protein markers of the PI3K-AKT pathway in brain metastases (16). Furthermore, in a retrospective analysis, complete loss of the phosphatase PTEN, which inhibits PI3K, correlated with more rapid brain metastasis formation and decreased overall survival in stage IIIB/C melanoma patients with BRAFV600 mutations (20).…”

Section: The Pi3k Inhibitor Buparlisib Inhibits Growth Of Braf-and Nrmentioning

confidence: 89%

PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain MetastasesIn VitroandIn Vivo

Niessner

Schmitz

Tabatabai

et al. 2016

Clinical Cancer Research

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Purpose: Great advances have recently been made in treating patients with metastatic melanoma. However, existing therapies are less effective on cerebral than extracerebral metastases. This highlights the potential role of the brain environment on tumor progression and drug resistance and underlines the need for "brain-specific" therapies. We previously showed that the PI3K-AKT survival pathway is hyperactivated in brain but not extracerebral melanoma metastases and that astrocyte-conditioned medium activates AKT in melanoma cells in vitro. We therefore tested the PI3K inhibitor buparlisib as an antitumor agent for melanoma brain metastases. Conclusions: These results emphasize the value of targeting the PI3K pathway as a strategy to develop drugs for melanoma brain metastases.

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Section: The Pi3k Inhibitor Buparlisib Inhibits Growth Of Braf-and Nrmentioning

confidence: 89%

PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain MetastasesIn VitroandIn Vivo

Niessner

Schmitz

Tabatabai

et al. 2016

Clinical Cancer Research

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“…Of note, inhibition of the PI3K-AKT pathway with the PI3K inhibitor GDC-0941 leads to growth inhibition of brain metastasis-derived melanoma cells in vitro. Upregulation of the PI3K-AKT pathway was also reported in a recent study of matched cerebral and extracerebral metastasis samples using analysis of hotspot mutations, copy-number variations, mRNA expression patterns, quantitative analysis of protein expression, and activation by reverse-phase protein array analysis (2).…”

Section: ó2015 Aacrsupporting

confidence: 59%

“…1). A preferential upregulation of the PI3K-AKT pathway was recently recognized in cerebral compared with extracerebral metastases (2), and loss of PTEN was correlated with earlier development of brain metastases (3), perhaps as a result of an intrinsic activation of tropism for the cerebral microenvironment. The PI3K-AKT pathway in melanoma is commonly activated via mutations in NRAS or loss of PTEN (4).…”

Section: ó2015 Aacrmentioning

confidence: 99%

PLEKHA5: A Key to Unlock the Blood–Brain Barrier?

Eisele

Gill

Shankar

et al. 2015

Clinical Cancer Research

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Brain metastases represent a devastating complication of melanoma. Our understanding of the mechanisms driving metastasis to the brain is limited. PLEKHA5 functions as a regulator of brain metastasis in melanoma, and further investigation is warranted to explore the use of PLEKHA5 as a potential therapeutic target. Clin Cancer Res; 21(9); 1978-80. Ó2015 AACR.See related article by Jilaveanu et al., p. 2138 In this issue of Clinical Cancer Research, Jilaveanu and colleagues (1) nominate PLEKHA5 as a candidate regulator of brain metastasis in melanoma. Up to 75% of patients with stage IV melanoma develop central nervous system (CNS) metastases during the course of their disease. Historically, overall survival after diagnosis of brain metastases ranges between 4 and 5 months. Recently, remarkable progress has been made in the development of effective therapies in advanced melanoma, specifically with immunotherapy and targeting of the RAS-RAF-MAPK pathway. Although these treatments have demonstrated success in systemic disease, patients often develop brain metastases while on these treatments. Unfortunately, little is known about the mechanisms implicated in CNS evasion of these therapies and cerebrotropism.Jilaveanu and colleagues (1) identify PLEKHA5 as a gene involved in the mechanism of CNS homing of metastatic disease. Through gene expression profiling of a parental melanoma cell line (A375P) and a cerebrotropic derivative (A375Br), the investigators found differential expression of PLEKHA5. Based on an impressive cohort of patients with a variable length of time between diagnosis of melanoma and development of brain metastasis, the authors also demonstrate that PLEKHA5 protein expression correlates with brain metastasis-free survival. Silencing of PLEKHA5 expression by siRNA resulted in decreased cell viability and also decreased in vitro potential for crossing the blood-brain barrier.Although the mechanism by which PLEKHA5 mediates this clinical phenotype has yet to be elucidated, Jilaveanu and colleagues (1) postulate that PLEKHA5 may interact with the PI3K-AKT pathway ( Fig. 1). A preferential upregulation of the PI3K-AKT pathway was recently recognized in cerebral compared with extracerebral metastases (2), and loss of PTEN was correlated with earlier development of brain metastases (3), perhaps as a result of an intrinsic activation of tropism for the cerebral microenvironment. The PI3K-AKT pathway in melanoma is commonly activated via mutations in NRAS or loss of PTEN (4). Loss of PTEN not only appears to lead to higher activation of the PI3K-AKT pathway but also increases invasiveness and metastatic potential in melanoma (5). Moreover, there appears to be a strong correlation between PTEN loss and BRAF activation (4). Consistent with other reports, Niessner and colleagues (6) observed that although patients treated with vemurafenib had an extracranial response to treatment, they also showed concomitant development of brain metastases. In an analysis of matched brain and systemic metastases in 9 patie...

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“…Molecular profiling of matched CNS and extracranial metastases in smaller series of melanoma patients showed that CNS metastases distinguished themselves through specific molecular differences in the activation of the PI3K/mTOR/ Akt or HER2 or kirsten rat sarcoma (KRAS) pathway. [28][29][30][31] These studies highlight, for example, the potential of adding PI3K inhibitors or mTOR inhibitors as adjunct targeted therapy in the treatment of CNS metastases.…”

Section: Molecular Mechanisms Of Central Nervous System Metastasis Fomentioning

confidence: 99%

Interdisciplinary management of central nervous system metastasis and neoplastic meningitis: recent developments and future perspectives

Tabatabai¹,

Koch²,

Roggia³

et al. 2016

JCMT

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The incidence of metastatic disease in the central nervous system (CNS) is rising. According to current estimates, up to a third of adult cancer patients will suffer from CNS metastasis. Clinical evidence-based data from prospective randomized trials are rare, however, because CNS metastasis patients were often excluded from clinical trial participation. The management of CNS metastasis patients is therefore rather ill-defined and an interdisciplinary challenge. Recent basic and translational science data have begun contributing to a more profound understanding of the molecular mechanisms leading to invasion of tumor cells into the CNS. This report reviews advances, challenges, and perspectives in this field.

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Molecular Profiling of Patient-Matched Brain and Extracranial Melanoma Metastases Implicates the PI3K Pathway as a Therapeutic Target

Cited by 171 publications

References 42 publications

PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain MetastasesIn VitroandIn Vivo

PI3K Pathway Inhibition Achieves Potent Antitumor Activity in Melanoma Brain MetastasesIn VitroandIn Vivo

PLEKHA5: A Key to Unlock the Blood–Brain Barrier?

Interdisciplinary management of central nervous system metastasis and neoplastic meningitis: recent developments and future perspectives

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