scholarly journals Melanoma Brain Metastases in the Era of Target Therapies: An Overview

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1640 ◽  
Author(s):  
Paolo Becco ◽  
Susanna Gallo ◽  
Stefano Poletto ◽  
Mirko Pio Manlio Frascione ◽  
Luca Crotto ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Metastases ◽  
Target Therapy ◽  
Mapk Signaling ◽  
Janus Kinase ◽  
Clinical Activity ◽  
Tumor Resistance ◽  
Sequential Approach ◽  
Mek Inhibitors ◽  
Dismal Prognosis

Malignant melanoma is the third most common type of tumor that causes brain metastases. Patients with cerebral involvement have a dismal prognosis and their treatment is an unmet medical need. Brain involvement is a multistep process involving several signaling pathways such as Janus kinase/signal Transducer and Activator of Transcription (JAK/STAT), Phosphoinositide 3-kinase/Protein Kinase B (PI3K/AKT), Vascular Endothelial Growth Factor and Phosphatase and Tensin Homolog (PTEN). Recently therapy that targets the MAPK signaling (BRAF/MEK inhibitors) and immunotherapy (anti-CTLA4 and anti-PD1 agents) have changed the therapeutic approaches to stage IV melanoma. In contrast, there are no solid data about patients with brain metastases, who are usually excluded from clinical trials. Retrospective data showed that BRAF-inhibitors, alone or in combination with MEK-inhibitors have interesting clinical activity in this setting. Prospective data about the combinations of BRAF/MEK inhibitors have been recently published, showing an improved overall response rate. Short intracranial disease control is still a challenge. Several attempts have been made in order to improve it with combinations between local and systemic therapies. Immunotherapy approaches seem to retain promising activity in the treatment of melanoma brain metastasis as showed by the results of clinical trials investigating the combination of anti-CTL4 (Ipilimumab) and anti-PD1(Nivolumab). Studies about the combination or the sequential approach of target therapy and immunotherapy are ongoing, with immature results. Several clinical trials are ongoing trying to explore new approaches in order to overcome tumor resistance. At this moment the correct therapeutic choices for melanoma with intracranial involvement is still a challenge and new strategies are needed.

scholarly journals Immunotherapy of brain metastases: breaking a “dogma”

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Anna Maria Di Giacomo ◽  
Monica Valente ◽  
Alfonso Cerase ◽  
Maria Fortunata Lofiego ◽  
Francesca Piazzini ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Metastases ◽  
Case Series ◽  
Daily Practice ◽  
Clinical Activity ◽  
Check Point ◽  
Wide Range ◽  
Check Point Inhibitors ◽  
Clinical Responses ◽  
The Central Nervous System

Abstract Until very few years ago, the oncology community dogmatically excluded any clinical potential for immunotherapy in controlling brain metastases. Therefore, despite the significant therapeutic efficacy of monoclonal antibodies to immune check-point(s) across a wide range of tumor types, patients with brain disease were invariably excluded from clinical trials with these agents. Recent insights on the immune landscape of the central nervous system, as well as of the brain tumor microenvironment, are shedding light on the immune-biology of brain metastases. Interestingly, retrospective analyses, case series, and initial prospective clinical trials have recently investigated the role of different immune check-point inhibitors in brain metastases, reporting a significant clinical activity also in this subset of patients. These findings, and their swift translation in the daily practice, are driving fundamental changes in the clinical management of patients with brain metastases, and raise important neuroradiologic challenges. Along this line, neuro-oncology undoubtedly represents an additional area of active investigation and of growing interest to support medical oncologists in the evaluation of clinical responses of brain metastases to ICI treatment, and in the management of neurologic immune-related adverse events. Aim of this review is to summarize the most recent findings on brain metastases immunobiology, on the evolving scenario of clinical efficacy of ICI therapy in patients with brain metastases, as well as on the increasing relevance of neuroradiology in this therapeutic setting.

scholarly journals SPDR-01 Paired epithelioid glioblastoma patient-derived xenograft models to evaluate resistant mechanism for molecular target therapy

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii5-ii5
Author(s):  
Jo Sasame ◽  
Kensuke Tateishi ◽  
Naoki Ikegaya ◽  
Yohei Miyake ◽  
Taishi Nakamura ◽  
...  
Keyword(s):  
Target Therapy ◽  
Patient Characteristics ◽  
Mapk Signaling ◽  
Molecular Target ◽  
Braf V600e ◽  
Molecular Target Therapy ◽  
Mek Inhibitors ◽  
Patient Derived Xenograft ◽  
Epithelioid Glioblastoma ◽  
Pdx Models

Abstract Epithelioid glioblastoma (E-GBM) arises at younger age, commonly disseminates to cerebrospinal fluid, and results in dismal prognosis. About half of E-GBM harbors BRAF V600E mutation, thus BRAF/MEK inhibitors are expected to be specifically sensitive to E-GBM like other BRAF V600E mutant carcinomas. However, therapeutic effect is limited by the emergence of drug resistance. To overcome this issue, it is crucial to elucidate the treatment resistance mechanisms by clinically representative models. Herein, we establish 2 paired E-GBM patient-derived xenograft (PDX) models from young adult patients (YMG62 and YMG89) with BRAF V600E, TERT promoter mutations and CDKN2A homozygous deletions. The YMG62 patient received dabrafenib with trametinib, while YMG89 patient received dabrafenib monotherapy after recurrence with standard treatment. The YMG62 patient was refractory to combination therapy. The YMG89 patient was initially responded to dabrafenib, but gradually became resistant and the 2 patients died due to CNS dissemination. Paired PDX models were established from tumors prior and after molecular target therapy. All PDXs were formed as CNS dissemination model, which were recapitulated to the patient characteristics. BRAF/MEK inhibitors strongly suppressed cell viability in primary tumor (YMG89P). However, BRAF/MEK inhibitors became resistant in recurrent tumor (YMG89R). YMG62 paired PDXs were resistant to molecular target therapy. Western blotting indicated retained MAPK signaling pathway and/or increased AKT phosphorylation after BRAF/MEK inhibitors treatment in refractory and recurrent cells, which indicates crucial role of re-activation in the MAPK signaling pathway and/or PI3 kinase pathway for tumor maintenance in BRAF V600E mutant E-GBM. We have done high throughput drug screening to identify compounds to overcome resistant to molecular target therapy. Our established E-GBM paired PDX models recapitulate patient characteristics, which may uncover treatment resistant mechanism and novel therapeutic target in E-GBM.

Colorectal cancer and brain metastases: An aggressive disease with a different response to treatment

2018 ◽  
Vol 105 (5) ◽  
pp. 427-433 ◽  
Author(s):  
Georges Chahine ◽  
Tony Ibrahim ◽  
Tony Felefly ◽  
Abir El-Ahmadie ◽  
Pamela Freiha ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Brain Metastases ◽  
Median Survival ◽  
Metastatic Disease ◽  
Antiangiogenic Therapy ◽  
Response To Treatment ◽  
Aggressive Disease ◽  
Dismal Prognosis ◽  
Poor Outcomes ◽  
Different Response

Introduction: Brain metastases (BM) are rare in colorectal cancer (CRC) and are associated with a dismal prognosis. This work aims to report the rate of BM in CRC patients treated in a single institution, along with survival and prognostic factors. Methods: Medical charts for patients with histologically proven CRC were retrospectively reviewed. Results: A total of 538 patients were identified, of whom 33% developed any metastatic disease and 4.4% presented BM. Lung was the most frequently associated metastatic site (in 68% of the cases). The only factor independently associated with BM development was the presence of metastatic disease at the time of initial presentation. The median duration from initial diagnosis to BM development was 38.6 months (SD 29.1 months). Median survival after BM development was 62 days (95% confidence interval [CI] 56–68). Patients diagnosed with BM within 1 year of cancer diagnosis responded significantly better to treatment than those who acquired BM later, with a median survival after BM diagnosis of 261 days versus 61 days, respectively ( p = .002). Patients with BM who received antiangiogenic therapy had an improved median survival compared to those who did not (151 days vs 59 days, p = 0.02; hazard ratio for death 0.29 [95% CI 0.09–0.94]). Conclusion: CRC with BM is an aggressive disease resistant to standard treatment and is associated with poor outcomes. Adding antiangiogenic therapy might be of value for those patients. Patients with BM developing early in the disease course might respond better to treatment.

Clinical Activity and Safety of Cabozantinib for Brain Metastases in Patients With Renal Cell Carcinoma

JAMA Oncology ◽  
2021 ◽  
Author(s):  
Laure Hirsch ◽  
Nieves Martinez Chanza ◽  
Subrina Farah ◽  
Wanling Xie ◽  
Ronan Flippot ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Brain Metastases ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clinical Activity

scholarly journals Brain Metastases Research 1990–2010: Pattern of Citation and Systematic Review of Highly Cited Articles

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Carsten Nieder ◽  
Anca L. Grosu ◽  
Minesh P. Mehta
Keyword(s):  
Clinical Trials ◽  
Brain Metastases ◽  
Randomized Clinical Trials ◽  
Citation Rate ◽  
Prognostic Score ◽  
Median Number ◽  
Research Activity ◽  
Secondary Endpoints ◽  
Number Of Citations

Background. High and continuously increasing research activity related to different aspects of prevention, prediction, diagnosis and treatment of brain metastases has been performed between 1990 and 2010. One of the major databases contains 2695 scientific articles that were published during this time period. Different measures of impact, visibility, and quality of published research are available, each with its own pros and cons. For this overview, article citation rate was chosen.Results. Among the 10 most cited articles, 7 reported on randomized clinical trials. Nine covered surgical or radiosurgical approaches and the remaining one a widely adopted prognostic score. Overall, 30 randomized clinical trials were published between 1990 and 2010, including those with phase II design and excluding duplicate publications, for example, after longer followup or with focus on secondary endpoints. Twenty of these randomized clinical trials were published before 2008. Their median number of citations was 110, range 13–1013, compared to 5-6 citations for all types of publications. Annual citation rate appeared to gradually increase during the first 2-3 years after publication before reaching high levels.Conclusions. A large variety of preclinical and clinical topics achieved high numbers of citations. However, areas such as quality of life, side effects, and end-of-life care were underrepresented. Efforts to increase their visibility might be warranted.

scholarly journals A common goal to CARE: Cancer Advocates, Researchers, and Clinicians Explore current treatments and clinical trials for breast cancer brain metastases

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Natalie S. Joe ◽  
Christine Hodgdon ◽  
Lianne Kraemer ◽  
Kristin J. Redmond ◽  
Vered Stearns ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Brain Metastases ◽  
Detection Methods ◽  
Future Research ◽  
Breast Cancer Brain Metastasis ◽  
Patient Advocates ◽  
Breast Cancer Brain Metastases ◽  
The Brain

AbstractBreast cancer is the most commonly diagnosed cancer in women worldwide. Approximately one-tenth of all patients with advanced breast cancer develop brain metastases resulting in an overall survival rate of fewer than 2 years. The challenges lie in developing new approaches to treat, monitor, and prevent breast cancer brain metastasis (BCBM). This review will provide an overview of BCBM from the integrated perspective of clinicians, researchers, and patient advocates. We will summarize the current management of BCBM, including diagnosis, treatment, and monitoring. We will highlight ongoing translational research for BCBM, including clinical trials and improved detection methods that can become the mainstay for BCBM treatment if they demonstrate efficacy. We will discuss preclinical BCBM research that focuses on the intrinsic properties of breast cancer cells and the influence of the brain microenvironment. Finally, we will spotlight emerging studies and future research needs to improve survival outcomes and preserve the quality of life for patients with BCBM.

scholarly journals CILP Inhibits Brain Metastasis by Meditating Mast Cells via the MAPK Signaling Pathway in Breast Cancer

2021 ◽  
Author(s):  
Xiaolin Sun ◽  
Xingguo Zhou ◽  
Alei Feng ◽  
Gongwen Xu ◽  
Qiang Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mast Cells ◽  
Correlation Analysis ◽  
Brain Metastases ◽  
Signaling Pathway ◽  
Immune Cells ◽  
Cell Activity ◽  
Mapk Signaling ◽  
High Morbidity ◽  
Spearman’S Correlation

Abstract Background: Approximately 15–30% of patients with breast cancer (BRCA) eventually develop brain metastases (BMs) with high morbidity and mortality. Herein, we aimed to identify genes specific to breast cancer brain metastases (BCBM) from an immune infiltration perspective.Methods: GSE100534 and GSE125989 were obtained from the NCBI Gene Expression Omnibus (GEO), then performed normalization using Rstudio and perl 5. We constructed a Weighted Gene Co-Expression Network Analysis (WGCNA) and obtained differentially expressed genes (DEGs) in BMs sample compared with primary BRCA tissue. Then we performed GO and KEGG pathway analysis. The LinkedOmics and UALCAN analysis showed the expression of gene in BRCA. The Kaplan-Meier plotter database was used to evaluate the prognosis. The composition of significant tumor-infiltrating immune cells was assessed using the CIBERSORT algorithm. Spearman’s correlation analysis revealed the correlation between CILP gene and immune cells in TCGA cohort and Timer database. Using GSEA analysis, we conducted to identify the potential pathways in BCBM.Results: The cartilage intermediate layer protein (CILP) was a late event in BRCA (stage III to IV) with poor prognosis (P< 0.05). LinkedOmics showed that the mRNA expression of CILP was down-regulated in advanced cancer (P< 0.05). Besides, UALCAN analysis showed that CILP expression was downregulated in HER2-positive and triple-negative breast cancer which were more prone to BMs (P< 0.05). CILP was the hub gene which was significantly associated with BCBM identified by WGCNA (R2=−0.6, P=3e-06). We found that the resting infiltration of mast cells in the BCBM group was significantly lower than that in the primary BRCA group (P= 0.01). In addition, Spearman’s correlation analysis revealed that the expression of CILP positively correlated with that of mast cells (P< 0.05). Finally, the FCERI-mediated MAPK activation (NES=2.1847, P=0, FDR=0.0031), which could regulate mast cell activity, were enriched in BCBM.Conclusions: CILP can influence the progression of BRCA favored for BMs through meditating mast cells via the MAPK signaling pathway.

scholarly journals Target Therapy in Acute Myeloid Leukemia

2020 ◽  
Author(s):  
Vasko Graklanov
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Acute Leukemia ◽  
Mechanism Of Action ◽  
Myeloid Leukemia ◽  
Target Therapy ◽  
New Drugs ◽  
Cytotoxic Treatment ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is the most common form of acute leukemia in elderly patients. Over the past four decades the basic therapeutic armamentarium was the standard cytotoxic treatment. The new insights in understanding the pathogenesis of AML was the momentum that revolutionized the treatment landscape in AML. The last five years unprecedented growth has been seen in the number of target therapy drugs for the treatment of AML. These new drugs did not just have a clinical benefit as single agents but also have improved AML patient outcomes if combined with conventional cytotoxic therapy. Here, we review recent advances in target-based therapy for patients with AML focusing on their mechanism of action and the results from already published clinical trials.

scholarly journals Antiangiogenic therapies for pheochromocytoma and paraganglioma

2020 ◽  
Vol 27 (7) ◽  
pp. R239-R254 ◽  
Author(s):  
Camilo Jimenez ◽  
Sasan Fazeli ◽  
Alejandro Román-Gonzalez
Keyword(s):  
Clinical Trials ◽  
Specific Activity ◽  
Therapeutic Option ◽  
High Specific Activity ◽  
Vascular Tumors ◽  
Tumor Resistance ◽  
Skeletal Tissue ◽  
Antiangiogenic Therapies ◽  
Emergence Of Resistance ◽  
Unites States

Metastatic pheochromocytomas and paragangliomas are rare, highly vascular tumors that spread primarily to the lymph nodes, skeletal tissue, lungs, and liver. Tumor morbidity is related to their size, location, hormonal activity, vascular nature, and rate of progression. Systemic therapies for this indication are limited. Only high-specific-activity iodine-131 metaiodobenzylguanidine is approved in the Unites States for treatment of these patients, and not all patients are candidates for this radiopharmaceutical. Antiangiogenic medications are currently being evaluated in prospective clinical trials for patients with metastatic pheochromocytomas and paragangliomas, and preliminary results have been encouraging. Antiangiogenic medications frequently offer antineoplastic effects with sometimes durable responses. However, cardiovascular toxicity and the development of tumor resistance may limit their efficacy. Experience derived from clinical trials is being used to identify mechanisms to effectively improve drug toxicity and possibly prevent the emergence of resistance. Therefore, antiangiogenic medications represent a therapeutic option for patients with metastatic pheochromocytomas and paragangliomas. Furthermore, in the world of oncology, there is strong scientific interest in the development of clinical trials that combine antiangiogenic medications with other modalities such as immunotherapy, radiopharmaceuticals, and hypoxia inhibitors since these combinations may substantially enhance clinical outcomes, including survivorship. In this review, we examine the progress made to date on antiangiogenic treatments for patients with metastatic pheochromocytomas and paragangliomas.

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