Molecular programs of melanoma brain metastases (MBM)
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PROVIDER: EGAS00001005976 | EGA |
REPOSITORIES: EGA
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Project description:Melanoma brain metastases (MBM) variably respond to therapeutic interventions; thus determining patient's prognosis. However, the mechanisms that govern therapy response are poorly understood. Here, we use a multi-OMICS approach and targeted sequencing (TargetSeq) to unravel the programs that potentially control the development of progressive intracranial disease. Molecularly, the expression of E-cadherin (Ecad) or NGFR, the BRAF mutation state and level of immune cell infiltration subdivides tumors into proliferative/pigmented and invasive/stem-like/therapy-resistant irrespective of the intracranial location. The analysis of MAPK inhibitor-naive and refractory MBM reveals switching from Ecad-associated into NGFR-associated programs during progression. NGFR-associated programs control cell migration and proliferation via downstream transcription factors such as SOX4. Moreover, global methylome profiling uncovers 46 differentially methylated regions that discriminate BRAFmut and wildtype MBM. In summary, we propose that the expression of Ecad and NGFR sub- classifies MBM and suggest that the Ecad-to-NGFR phenotype switch is a rate-limiting process which potentially indicates drug-response and intracranial progression states in melanoma patients.
| S-EPMC9701224 | biostudies-literature
Project description:Relapses in the brain remain a major obstacle to cure in many patients with advanced melanoma. At present, the management of melanoma brain metastases continues to rely heavily on surgical and radiotherapeutic interventions, which have become safer and more effective with modern imaging, surgery and radiation technologies. Additionally, novel targeted and immunotherapeutic agents, shown to generate meaningful intracranial response and survival benefit in patients with melanoma brain metastases when compared with historical controls, expand systemic treatment options for this subset of patients. These systemic therapies become particularly important when intracranial disease burden precludes neuro- or radio-surgery. Considerable multidisciplinary research effort is ongoing to improve outcomes for melanoma patients with brain metastases, a key challenge in the management of advanced melanoma.
| S-EPMC6094653 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
| S-ECPF-GEOD-50496 | biostudies-other
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-05-08 | E-GEOD-50496 | biostudies-arrayexpress
Project description:Simple Summary Melanoma has the highest mortality rate of all skin cancers and its prognosis is worsened by metastasis to the brain. Before discovering new treatments for metastases, the prognosis of patients was poor. Currently, research is being conducted on new drugs using immunotherapy (immune checkpoint inhibitors: anti-PD-1, anti-CTLA-4) and targeted therapy (BRAF and MEK inhibitors) to improve the prognosis of patients. In this article, we summarize the current state of knowledge about the effects of treating brain metastases with new systemic therapies. Abstract Melanoma is a type of skin cancer in which there is a strong correlation between its occurrence and exposure to ultraviolet radiation. Although it is not the most common skin cancer, it has the highest mortality rate of all skin cancers. The prognosis of patients is significantly worsened by melanoma metastasis to the brain, which often occurs in patients with advanced disease. The formation and development of melanoma metastases to the brain involve a very complex process, and their mechanisms are not fully understood. One of the ways for metastatic melanoma cells to survive and develop cancer in the brain environment is the presence of oncogenic BRAF mutation, which occurs in up to 50% of metastatic melanoma cases. Before discovering new methods of treating metastases, the overall survival of patients with this disease was 6 months. Currently, research is being conducted on new drugs using immunotherapy (immune checkpoint inhibitors: anti-PD-1, anti-CTLA-4) and targeted therapy (BRAF and MEK inhibitors) to improve the prognosis of patients. In this article, we summarize the current state of knowledge about the results of treating brain metastases with new systemic therapies.
| S-EPMC10452790 | biostudies-literature
Project description:Brain metastases are about ten times more frequent than a brain primary tumor, being present in 20-40% of adults with systemic cancer. Together with lung cancer and breast cancer, skin cancers such as melanoma are top primary tumors which metastasizes to the brain. Advanced melanoma is well known for its propensity to metastasize to the brain, with 80% of patients presenting brain metastasis at the autopsy. However, current therapies are not very efficient and brain metastases are in most of the cases lethal. Treatment of melanoma brain metastases with surgery and/or radiation therapy results in a median overall survival of only about four months after diagnosis. New immunotherapies such as targeted or immunomodulatory drugs, many in clinical trials, have shown promise, with some immunomodulatory drugs being able to at least double the overall survival rates for patients with melanoma brain metastases. This review focuses on the recent advances and future potential of using immunotherapy, such as the newly developed immunomodulatory drugs, for melanoma brain metastases therapy. Immunomodulatory drugs bring a great promise as new tools for melanoma treatment in particular and for the treatment of other types of malignancies in general.
| S-EPMC7086063 | biostudies-literature
Project description:Opinion statementBrain metastases are a major clinical challenge occurring in up to 60% of patients suffering from metastatic melanoma. They cause significant clinical symptoms and impair the overall survival prognosis. The introduction of targeted therapies including BRAF and MEK inhibitors as well as CTLA-4 and PD-1 axis targeting immune checkpoint inhibitors have dramatically improved the treatment and prognosis of patients with extracranial metastatic melanoma. Although, similar response rates for extra- and intracranial metastases have been reported, only few data from brain metastasis specific trails are available so far. The following review will provide an overview on the currently available data on targeted therapies, remaining questions and the most important side effects in the special clinical situation of melanoma brain metastases.
| S-EPMC5378732 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2014-05-08 | GSE50496 | GEO
Project description:BackgroundHigh tumor-infiltrating lymphocytes (TILs) and hemorrhage are important prognostic factors in patients who have undergone craniotomy for melanoma brain metastases (MBM) before 2011 at the University of Pittsburgh Medical Center (UPMC). We have investigated the prognostic or predictive role of these histopathologic factors in a more contemporary craniotomy cohort from the University of North Carolina at Chapel Hill (UNC-CH). We have also sought to understand better how various immune cell subsets, angiogenic factors, and blood vessels may be associated with clinical and radiographic features in MBM.MethodsBrain tumors from the UPMC and UNC-CH patient cohorts were (re)analyzed by standard histopathology, tumor tissue imaging, and gene expression profiling. Variables were associated with overall survival (OS) and radiographic features.ResultsThe patient subgroup with high TILs in craniotomy specimens and subsequent treatment with immune checkpoint inhibitors (ICIs, n=7) trended to have longer OS compared to the subgroup with high TILs and no treatment with ICIs (n=11, p=0.059). Bleeding was significantly associated with tumor volume before craniotomy, high melanoma-specific expression of basic fibroblast growth factor (bFGF), and high density of CD31+αSMA- blood vessels. Brain tumors with high versus low peritumoral edema before craniotomy had low (17%) versus high (41%) incidence of brisk TILs. Melanoma-specific expression of the vascular endothelial growth factor (VEGF) was comparable to VEGF expression by TILs and was not associated with any particular prognostic, radiographic, or histopathologic features. A gene signature associated with gamma delta (gd) T cells was significantly higher in intracranial than same-patient extracranial metastases and primary melanoma. However, gdT cell density in MBM was not prognostic.ConclusionsICIs may provide greater clinical benefit in patients with brisk TILs in MBM. Intratumoral hemorrhage in brain metastases, a significant clinical problem, is not merely associated with tumor volume but also with underlying biology. bFGF may be an essential pathway to target. VEGF, a factor principally associated with peritumoral edema, is not only produced by melanoma cells but also by TILs. Therefore, suppressing low-grade peritumoral edema using corticosteroids may harm TIL function in 41% of cases. Ongoing clinical trials targeting VEGF in MBM may predict a lack of unfavorable impacts on TIL density and/or intratumoral hemorrhage.
| S-EPMC7860978 | biostudies-literature
Project description:BackgroundBrain metastases are a significant cause of mortality and morbidity for patients with melanoma. We hypothesize that the development of brain metastases may be explained by molecular heterogeneity between primary cutaneous melanoma (PCM) or extracranial (ECM) and brain (MBM) melanoma metastases.Materials and methodsWe compared next-generation sequencing, tumor mutational burden (TMB), and immunohistochemical staining for PD-L1 expression, among 132 MBM, 745 PCM, and 1190 ECM.ResultsThe most common genetic alterations among MBM included: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Four genes were found with higher frequency among MBM compared to PCM or ECM: BRAF (52.4% v 40.4% v 40.9%), SETD2 (11.9% v 1.9% v 3.9%), PBRM1 (7.5% v 1.6% v 2.6%), and DICER1 (4.4% v 0.6% v 0.4%). MBM showed higher TMB (p = .04) and higher PD-L1 expression (p = .002), compared to PCM. PD-L1 expression was slightly higher among MBM compared to ECM (p = .042), but there was no difference between TMB (p = .21).ConclusionsOur findings suggest a unique molecular profile for MBM, including higher rates of BRAF mutations, higher TMB and higher PD-L1 expression, and also implicate chromatin remodeling in the pathogenesis of MBM.
| S-EPMC7443369 | biostudies-literature