Animal models of brain metastasis

Miarka, Lauritz; Valiente, Manuel

doi:10.1093/noajnl/vdab115

Cited by 16 publications

(7 citation statements)

References 94 publications

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“…Among approximately 30 HER2+ BC cell lines that have been established so far, there are only a few xenogeneic (e.g. BT474) models that can cross the blood-brain barrier (BBB) and repeatedly establish hematogenous brain metastasis (46, 47). Although BT474 and our new BCBM94 model described here can be classified as a Luminal-B HER2+ molecular subtype, their receptor profile differs substantially.…”

Section: Discussionmentioning

confidence: 99%

Overcoming brain-derived therapeutic resistance in HER2+ breast cancer brain metastasis

Ippolitov,

Lin,

Spence

et al. 2024

Preprint

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Brain metastasis of HER2+ breast cancer occurs in about 50% of all women with metastatic HER2+ breast cancer and confers poor prognosis for patients. Despite effective HER2-targeted treatments of peripheral HER2+ breast cancer with Trastuzumab +/-HER2 inhibitors, limited brain permeability renders these treatments inefficient for HER2+ breast cancer brain metastasis (BCBM). The scarcity of suitable patient-derived in-vivo models for HER2+ BCBM has compromised the study of molecular mechanisms that promote growth and therapeutic resistance in brain metastasis. We have generated and characterized new HER2+ BCBM cells (BCBM94) isolated from a patient HER2+ brain metastasis. Repeated hematogenic xenografting of BCBM94 consistently generated BCBM in mice. The clinically used receptor tyrosine kinase inhibitor (RTKi) Lapatinib blocked phosphorylation of all ErbB1-4 receptors and induced the intrinsic apoptosis pathway in BCBM94. Neuregulin-1 (NRG1), a ligand for ErbB3 and ErbB4 that is abundantly expressed in the brain, was able to rescue Lapatinib-induced apoptosis and clonogenic ability in BCBM94 and in HER2+ BT474. ErbB3 was essential to mediate the NRG1-induced survival pathway that involved PI3K-AKT signalling and the phosphorylation of BAD at serine 136 to prevent apoptosis. High throughput RTKi screening identified the brain penetrable Poziotinib as highly potent compound to reduce cell viability in HER2+ BCBM in the presence of NRG1. Successful in-vivo ablation of BCBM94- and BT474-derived HER2+ brain tumors was achieved upon two weeks of treatment with Poziotinib. MRI revealed BCBM remission upon poziotinib, but not with Lapatinib treatment. In conclusion, we have established a new patient-derived HER2+ BCBM in-vivo model and identified Poziotinib as highly efficacious RTKi with excellent brain penetrability that abrogated HER2+ BCBM brain tumors in our mouse models.

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Section: Discussionmentioning

confidence: 99%

Overcoming brain-derived therapeutic resistance in HER2+ breast cancer brain metastasis

Ippolitov,

Lin,

Spence

et al. 2024

Preprint

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“…In this view, there is a pressing need to better understand the underlying mechanisms of RN, and future strategies should focus on preventing RN development or its progression during the early stages. The design of animal models has become critical to decipher the biology of BMs seeding [ 26 ]. Specifically, animal models of brain RN following high-dose RT have been published, though the number of experimental studies in this field remains limited.…”

Section: Discussionmentioning

confidence: 99%

Presence of Activated (Phosphorylated) STAT3 in Radiation Necrosis Following Stereotactic Radiosurgery for Brain Metastases

Jablonska,

Galán,

Barranco

et al. 2023

IJMS

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Brain radiation necrosis (RN) is a subacute or late adverse event following radiotherapy, involving an exacerbated inflammatory response of the brain tissue. The risk of symptomatic RN associated with stereotactic radiosurgery (SRS) as part of the treatment of brain metastases (BMs) has been a subject of recent investigation. The activation of the signal transducer and activator of transcription 3 (STAT3) was shown in reactive astrocytes (RA) associated with BMs. Given that the pathophysiological mechanisms behind RN are not fully understood, we sought to investigate the role of STAT3 among other inflammatory markers in RN development. A mouse model of RN using clinical LINAC-based SRS was designed to induce brain necrosis with the administration of 50 Gy in a single fraction to the left hemisphere using a circular collimator of 5 mm diameter. Immunohistochemistry and multiplex staining for CD4, CD8, CD68, GFAP, and STAT3 were performed. For validation, eleven patients with BMs treated with SRS who developed symptomatic RN and required surgery were identified to perform staining for CD68, GFAP, and STAT3. In the mouse model, the RN and perinecrotic areas showed significantly higher staining for F4/80+ and GFAP+ cells, with a high infiltration of CD4 and CD8 T-lymphocytes, when compared to the non-irradiated cerebral hemisphere. A high number of GFAP+pSTAT3+ and F4/80+pSTAT3+ cells was found in the RN areas and the rest of the irradiated hemisphere. The analysis of human brain specimens showed that astrocytes and microglia were actively phosphorylating STAT3 in the areas of RN and gliosis. Phosphorylated STAT3 is highly expressed in the microglia and RA pertaining to the areas of brain RN. Targeting STAT3 via inhibition represents a promising strategy to ameliorate symptomatic RN in BM patients undergoing SRS.

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“…In vivo drug screening in these models is costly and time-consuming, dissociating from the limited survival time of the patients with BM and limiting the possibility to use these PDXs as “avatars” of cancer patients. 35 Intracranial inoculation of cancer cells induces artificial disruption of the BBB and does not recapitulate the metastatic cascade, since cancer cells do not require extravasation. Systemic inoculation of cancer cells from BM induces significant extracranial metastatic burden, which can be problematic to assess survival and to test drug efficacy in brain metastatic disease.…”

Section: Discussionmentioning

confidence: 99%

Patient-derived models of brain metastases recapitulate human disseminated disease

Faria

Cascão

Custódia

et al. 2022

Cell Reports Medicine

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Animal models of brain metastasis

Cited by 16 publications

References 94 publications

Overcoming brain-derived therapeutic resistance in HER2+ breast cancer brain metastasis

Overcoming brain-derived therapeutic resistance in HER2+ breast cancer brain metastasis

Presence of Activated (Phosphorylated) STAT3 in Radiation Necrosis Following Stereotactic Radiosurgery for Brain Metastases

Patient-derived models of brain metastases recapitulate human disseminated disease

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