Molecular Profiles of Brain Metastases: A Focus on Heterogeneity

Ali, Shan; Górska, Zuzanna; Duchnowska, Renata; Jassem, Jacek

doi:10.3390/cancers13112645

Cited by 23 publications

(11 citation statements)

References 94 publications

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“…It is well known that BMs are the most common neoplastic disease affecting the CNS [ 1 , 73 ]. The peculiarity and complexity of these lesions lies in their heterogeneity, which stems not only from the nature of the primary lesion, but also from the clonal sub-population that gave rise to the metastasis [ 74 ]. On the one hand, this histological variability makes their management very complex; and on the other hand, it offers a wide range of therapeutic options, the imperative of which is to personalise treatment according to the molecular/histological profile.…”

Section: Discussionmentioning

confidence: 99%

Fluorescence and Intraoperative Ultrasound as Surgical Adjuncts for Brain Metastases Resection: What Do We Know? A Systematic Review of the Literature

Cristofori

Carone

Rocca

et al. 2023

Cancers

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(1) Background: brain metastases (BMs) are the most common neoplasm of the central nervous system; despite the high incidence of this type of tumour, to date there is no universal consensus on the most effective treatment in patients with BMs, even if surgery still plays a primary role. Despite this, the adjunct systems that help to reach the GTR, which are well structured for other tumour forms such as ultrasound and fluorescence systems, are not yet well employed and standardised in surgical practice. The aim of this review is to provide a picture of the current state-of-art of the roles of iOUS and intraoperative fluorescence to better understand their potential roles as surgical tools. (2) Methods: to reach this goal, the PubMed database was searched using the following string as the keyword: (((Brain cerebral metastasis [MeSH Major Topic])OR (brain metastasis, [MeSH Major Topic])) AND ((5-ala, [MeSH Terms]) OR (Aminolevulinicacid [All fields]) OR (fluorescein, [MeSH Terms]) OR (contrast enhanced ultrasound [MeSH Terms])OR ((intraoperative ultrasound. [MeSH Terms]))) AND (english [Filter]) AND ((english [Filter]) AND (2010:2022 [pdat])) AND (english [Filter]). (3) Results: from our research, a total of 661 articles emerged; of these, 57 were selected. 21 of these included BMs generically as a secondary class for comparisons with gliomas, without going deeply into specific details. Therefore, for our purposes, 36 articles were considered. (4) Conclusions: with regard to BMs treatment and their surgical adjuncts, there is still much to be explored. This is mainly related to the heterogeneity of patients, the primary tumour histology and the extent of systemic disease; regardless, surgery plays a paramount role in obtaining a local disease control, and more standardised surgical protocols need to be made, with the aim of optimizing the use of the available surgical adjuncts and in order to increase the rate of GTR.

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Section: Discussionmentioning

confidence: 99%

Fluorescence and Intraoperative Ultrasound as Surgical Adjuncts for Brain Metastases Resection: What Do We Know? A Systematic Review of the Literature

Cristofori

Carone

Rocca

et al. 2023

Cancers

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“…For EGFR, conflicting data exist: some studies describe 100% concordance, whereas in others, the concordance between paired primary non-small cell lung cancers (NSCLCs) and brain metastases was low. [10][11][12][13][14][15][16] A systematic review across 501 patients showed an overall EGFR receptor discordance of 10% between brain metastases and primary lung cancers, with a gain in an EGFR mutation in the brain metastases in 7% of patients. 17 Reasons for discordance could be different molecular testing techniques, as well as tumor heterogeneity that could be a result of microenvironmental differences between brain and extracranial sites, or selective pressures due to treatment between the primary tumor and brain metastasis diagnosis.…”

Section: Molecular Drivers In the Evolution Of Brain Metastases And I...mentioning

confidence: 99%

Emerging Systemic Treatment Perspectives on Brain Metastases: Moving Toward a Better Outlook for Patients

Alvarez‐Breckenridge

Remón

Piña

et al. 2022

American Society of Clinical Oncology Educational Book

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The diagnosis of brain metastases has historically been a dreaded, end-stage complication of systemic disease. Additionally, with the increasing effectiveness of systemic therapies that prolong life expectancy and improved imaging tools, the incidence of intracranial progression is becoming more common. Within this context, there has been increasing attention directed at understanding the molecular underpinnings of intracranial progression. Exploring the unique features of brain metastases compared with their extracranial counterparts to identify aberrant signaling pathways, which can be targeted pharmacologically, may help lead to new treatments for this patient population. Additionally, critical discoveries outside the sphere of the central nervous system are increasingly being applied to brain metastases with the emergence of immune checkpoint inhibition, becoming a prevalent treatment option for patients with brain metastases across multiple histologies. As novel treatment strategies are considered, they require thoughtful incorporation of agents that can cross the blood-brain barrier and can synergize with pre-existing agents through rational combinations. Lastly, as clinicians and scientists continue to understand key molecular features of these tumors, they will continue to influence the treatment algorithms that are developing for the management of these patients. Due to the complexity of treatment decisions for patients with brain metastases, an emerging tool is the utilization of multidisciplinary brain metastasis tumor boards to ensure optimal treatment decisions are made and that patients are provided access to applicable clinical trials. Looking to the future, the collective effort to understand the various tumor-intrinsic and tumor-extrinsic factors that promote central nervous system seeding and propagation will have the potential to change the clinical trajectory for these patients.

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“…Further, the unique characteristics of the brain tumor microenvironment (TME) reduce the efficacy of drugs that reach their target through the activation of reactive astrogliosis and astrocyte drug efflux pumps coopted by tumors (7)(8)(9). Additionally, brain metastases express altered molecular mutations and characteristics compared to their parent visceral tumors, creating a heterogeneous tumor landscape further hindering treatment (10,11). Cancers that are very responsive to treatment when present in circulation or visceral tissue, but become more recalcitrant to treatment when sequestered beyond the BBB include lymphoma, melanoma, and breast cancer (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases

Roemeling

Doonan

Klippel

et al. 2023

Clinical Cancer Research

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Purpose: An ongoing challenge in cancer is the management of primary and metastatic brain malignancies. This is partly due to restrictions of the blood-brain barrier (BBB) and their unique microenvironment. These challenges are most evident in cancers such as lymphoma and melanoma, which are typically responsive to treatment in systemic locations but resistant when established in the brain. We propose IRAK-4 as a potential target across these diseases and describe the activity and mechanism of oral IRAK-4 inhibitor CA-4948. Experimental Design: Human primary central nervous system lymphoma (PCNSL) and melanoma brain metastases (MBM) samples were analyzed for expression of IRAK-4 and downstream transcription pathways. We next determined the CNS applicability of CA-4948 in naïve and tumor-bearing mice using models of PCNSL and MBM. The mechanistic effect on tumors and the tumor microenvironment was then analyzed. Results: Human PCNSL and MBM have high expression of IRAK-4, IRAK-1, and NF-κB. This increase in inflammation results in reflexive inhibitory signaling. Similar profiles are observed in immunocompetent murine models. Treatment of tumor-bearing animals with CA-4948 results in the downregulation of ERK and MAPK signaling in addition to decreased NF-κB. These intracellular changes are associated with a survival advantage. Conclusions: IRAK-4 is an attractive target in PCNSL and MBM. The inhibition of IRAK-4 with CA-4948 downregulates the expression of important transcription factors involved in tumor growth and proliferation. CA-4948 is currently being investigated in clinical trials for relapsed and refractory lymphoma and warrants further translation into PCNSL and MBM.

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Molecular Profiles of Brain Metastases: A Focus on Heterogeneity

Cited by 23 publications

References 94 publications

Fluorescence and Intraoperative Ultrasound as Surgical Adjuncts for Brain Metastases Resection: What Do We Know? A Systematic Review of the Literature

Fluorescence and Intraoperative Ultrasound as Surgical Adjuncts for Brain Metastases Resection: What Do We Know? A Systematic Review of the Literature

Emerging Systemic Treatment Perspectives on Brain Metastases: Moving Toward a Better Outlook for Patients

Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases

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