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Immunotherapy and targeted therapy in brain metastases: emerging options in precision medicine.

ABSTRACT: Brain metastases (BM) continue to represent an unmet clinical need in oncology. Immunotherapy and targeted therapy hold great promise in the treatment of BM. Emerging data are confirming the activity of these agents in patients with BM. Genomic studies have confirmed that clinically actionable mutations are present in BM and they can be used in clinical studies to link targeted therapies with their genetic targets. Furthermore, as molecular signatures associated with sensitivity and resistance to immunotherapies are developed, we will better be able to select BM patients who will most benefit from these therapies. Understanding the genetic and immune evolution within BM should drive the next generation of immunotherapy and target therapy, as well as increase the accuracy of the selection process for these therapies.

SUBMITTER: Lazaro T

PROVIDER: S-EPMC6020878 | biostudies-other | 2017 Apr

REPOSITORIES: biostudies-other

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Immunotherapy and targeted therapy in brain metastases: emerging options in precision medicine.

Lazaro Tyler T Brastianos Priscilla K PK

CNS oncology 20170401 2

Brain metastases (BM) continue to represent an unmet clinical need in oncology. Immunotherapy and targeted therapy hold great promise in the treatment of BM. Emerging data are confirming the activity of these agents in patients with BM. Genomic studies have confirmed that clinically actionable mutations are present in BM and they can be used in clinical studies to link targeted therapies with their genetic targets. Furthermore, as molecular signatures associated with sensitivity and resistance t ...[more]

PMID: 28425754

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Project description:ObjectiveTo broadly review the modern management of brain metastases.BackgroundBrain metastases are the commonest neurological manifestation of cancer and a major cause of morbidity in cancer patients. Brain metastases are increasing in frequency, as a result of longer life expectancy of cancer patients, more sensitive methods for brain metastasis detection and an ageing population. The proportional incidence of brain metastases according to cancer of origin, from greatest to least, is lung cancer, melanoma, renal, breast and colorectal cancers. Patients with lung cancer and melanoma are most likely to have brain metastases at diagnosis. Brain metastases cause a variety of symptoms, depending on their size and location, whether they cause mass effect and oedema, compression of the brain parenchyma, or focal neurological deficits. The major differential diagnoses of brain metastases include primary tumours and vascular/inflammatory lesions. Prognosis is dependent on the site, number and volume of lesions, the patients' performance status, age and the activity and extent of extracranial disease.MethodsEnglish literature articles in PubMed from 1950 to June 2021 were reviewed. Article bibliographies provided further references.ConclusionsTreatment of brain metastasis patients has moved from considering them as a homogenous population of patients, to individualised treatment. In those brain metastases patients of satisfactory performance status with a solitary lesion, especially one in a non-eloquent/accessible area causing significant mass effect and/or raised intracranial pressure or for whom the diagnosis is in doubt (histology needed), surgical resection is usually the treatment of choice. For multiple brain metastases, radiotherapy with or without systemic therapies are usually employed. For relatively fit patients with limited numbers of brain metastases (e.g., 4 or less), stereotactic radiosurgery is standard of care. Current clinical trials are testing the efficacy of stereotactic treatment alone for >4 brain metastases (although it is increasingly used for such patients in many centres) as well as integration of local therapies with targeted and immunological therapies in appropriately selected cases. In certain circumstances, cranial irradiation can be omitted.

Project description:The development of novel therapies for brain metastases is an unmet need. Brain metastases may have unique molecular features that could be explored as therapeutic targets. A better understanding of the drug sensitivity of live cells coupled to molecular analyses will lead to a rational prioritization of therapeutic candidates. We evaluated the molecular profiles of 12 breast cancer brain metastases (BCBM) and matched primary breast tumors to identify potential therapeutic targets. We established six novel patient-derived xenograft (PDX) from BCBM from patients undergoing clinically indicated surgical resection of BCBM and used the PDXs as a drug screening platform to interrogate potential molecular targets. Many of the alterations were conserved in brain metastases compared with the matched primary. We observed differential expressions in the immune-related and metabolism pathways. The PDXs from BCBM captured the potentially targetable molecular alterations in the source brain metastases tumor. The alterations in the PI3K pathway were the most predictive for drug efficacy in the PDXs. The PDXs were also treated with a panel of over 350 drugs and demonstrated high sensitivity to histone deacetylase and proteasome inhibitors. Our study revealed significant differences between the paired BCBM and primary breast tumors with the pathways involved in metabolisms and immune functions. While molecular targeted drug therapy based on genomic profiling of tumors is currently evaluated in clinical trials for patients with brain metastases, a functional precision medicine strategy may complement such an approach by expanding potential therapeutic options, even for BCBM without known targetable molecular alterations.SignificanceExamining genomic alterations and differentially expressed pathways in brain metastases may inform future therapeutic strategies. This study supports genomically-guided therapy for BCBM and further investigation into incorporating real-time functional evaluation will increase confidence in efficacy estimations during drug development and predictive biomarker assessment for BCBM.

Dataset Information

Immunotherapy and targeted therapy in brain metastases: emerging options in precision medicine.

Publications

Immunotherapy and targeted therapy in brain metastases: emerging options in precision medicine.

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