The biology of brain metastases—translation to new therapies

Eichler, April F.; Chung, Euiheon; Kodack, David P.; Loeffler, Jay S.; Fukumura, Dai; Jain, Rakesh K.

doi:10.1038/nrclinonc.2011.58

Cited by 470 publications

(376 citation statements)

References 143 publications

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“…In human medicine, brain metastasis is common, especially with primary lung tumors, such as small cell carcinoma (4). These metastases occur due to the activation of WNT/TCF pathway and the dynamics of the cerebral vascularization, where the adhesion of neoplastic cells to the endothelium can occur when circulating neoplastic cells reach regions where the lumen of the capillaries is narrower and blood flow slows (4,15). Unlike the case cited above, in this case, no organ, other than the lung demonstrated metastasis.…”

Section: Discussioncontrasting

confidence: 44%

Metastatic osteosarcoma as a cause of hemorrhagic stroke in a dog

Cristo¹,

Vargas²,

Biezus³

et al. 2017

Braz. J. Vet. Pathol.

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Cristo, et al.; Metastatic osteosarcoma as a cause of hemorrhagic stroke in a dog. Braz J Vet Pathol, 2017, 10(3), 105 -110 DOI: 10.24070/bjvp.1983-0246.v10i3p105-110 AbstractThe aim of this case report is to describe an uncommon hemorrhagic cerebrovascular accident (CVA) associated with an osteosarcoma (OSA) metastasis. Cerebrovascular accident (CVA) is the acute onset of a neurological deficit from any change in blood supply resulting from a pathological process, characterizing a stroke and among all the causes, the neoplastic thrombus of osteosarcoma, specifically, is the most infrequent in clinical practice. A seven-year-old female midsize mixed-breed dog was submitted to a forelimb amputation for showing an osteoblastic OSA in proximal humerus. Three weeks later, the patient presented uninterruptible seizure and coma, resulting in death. At necropsy, it was observed a friable and reddish mass in the left frontal cortex which, microscopically was constituted by OSA metastasis in association with multiple ruptures of blood vessels and focally extensive severe bleeding, which caused a CVA. At immunohistochemistry, neoplastic cells of the humerus and the brain metastasis were positive for vimentin and osteonectin, confirming the diagnosis of osteoblastic OSA. The reports about OSA metastasis on the brain are rare in animals and humans, what could be related to the low frequency and few diagnosis ante and post-mortem. As uncommon as the description of OSA metastasis to the brain, is the CVA associated to them, demonstrating that reporting cases related to these clinical and anatomopathological lesions are important for the scientific community.

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Section: Discussioncontrasting

confidence: 44%

Metastatic osteosarcoma as a cause of hemorrhagic stroke in a dog

Cristo¹,

Vargas²,

Biezus³

et al. 2017

Braz. J. Vet. Pathol.

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“…Unfortunately, once CNS involvement is present, effective treatment options are limited and the prognosis is dismal. These issues are pressing, as the incidence of brain metastasis may be increasing due to longer patient survival owing to newer systemic therapies that control extracranial disease, along with more frequent magnetic resonance imaging surveillance 3, 5…”

Section: Introductionmentioning

confidence: 99%

Profiles of brain metastases: Prioritization of therapeutic targets

Ferguson

Zheng

Xiu

et al. 2018

Intl Journal of Cancer

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We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next‐generation sequencing with a targeted 47‐gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

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“…Furthermore, lapatinib (GlaxoSmithKline), a small-molecular-weight HER2 kinase inhibitor, thought to penetrate the blood-brain barrier better compared with trastuzumab, has shown only a modest response in patients with recurrent or progressive brain metastases (8)(9)(10). Thus, alternative strategies are desperately needed to treat patients with metastatic disease (11).…”

mentioning

confidence: 99%

Combined targeting of HER2 and VEGFR2 for effective treatment ofHER2-amplified breast cancer brain metastases

Kodack¹,

Chung

Yamashita³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Brain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Although extracranial disease is controlled with HER2 inhibitors in the majority of patients, brain metastases often develop. Because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure. We developed a mouse model of HER2-amplified breast cancer brain metastasis using an orthotopic xenograft of BT474 cells. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the breast but failed to contain tumor growth in the brain. We observed that the combination of a HER2 inhibitor with an anti-VEGF receptor-2 (VEGFR2) antibody significantly slows tumor growth in the brain, resulting in a striking survival benefit. This benefit appears largely due to an enhanced antiangiogenic effect: Combination therapy reduced both the total and functional microvascular density in the brain xenografts. In addition, the combination therapy led to a marked increase in necrosis of the brain lesions. Moreover, we observed even better antitumor activity after combining both trastuzumab and lapatinib with the anti-VEGFR2 antibody. This triple-drug combination prolonged the median overall survival fivefold compared with the control-treated group and twofold compared with either two-drug regimen. These findings support the clinical development of this three-drug regimen for the treatment of HER2-amplified breast cancer brain metastases.treatment resistance | tumor-stroma interaction | targeted therapy | tumor microenvironment | antiangiogenesis

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The biology of brain metastases—translation to new therapies

Cited by 470 publications

References 143 publications

Metastatic osteosarcoma as a cause of hemorrhagic stroke in a dog

Metastatic osteosarcoma as a cause of hemorrhagic stroke in a dog

Profiles of brain metastases: Prioritization of therapeutic targets

Combined targeting of HER2 and VEGFR2 for effective treatment ofHER2-amplified breast cancer brain metastases

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