Improving orthotopic mouse models of patient-derived breast cancer brain metastases by a modified intracarotid injection method

Liu, Zongming; Wang, Yanzhi; Kabraji, Sheheryar; Xie, Shusen; Pan, Peichen; Liu, Zhenning; Ni, Jing; Zhao, Jean J.

doi:10.1038/s41598-018-36874-3

Cited by 22 publications

(17 citation statements)

References 25 publications

(25 reference statements)

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“…Further, the increasing availability of human brain metastasis-derived PDX and organoid preclinical models have tremendous potential to evaluate and prioritize novel therapeutic options to bring forward into the clinic. 20 Future studies should continue to incorporate and explore these questions, though our small study highlights the challenges in execution and interpretation of this work, and the prerequisite for careful and thoughtful scientific collaborations. Mass spectrometry analysis of neratinib distribution in a surgical specimen.…”

Section: Discussionmentioning

confidence: 97%

Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022

Freedman

Gelman

Agar

et al. 2020

Clinical Breast Cancer

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Background: This pilot study was performed to test our ability to administer neratinib monotherapy prior to clinically-recommended craniotomy in patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer to the central nervous system (CNS), to examine neratinib's CNS penetration at craniotomy, and to examine post-operative neratinib maintenance. Patients and Methods: Patients with HER2-positive brain metastases undergoing clinicallyindicated cranial resection of a parenchymal tumor received neratinib 240 mg orally once daily for 7-21 days pre-operatively and resumed therapy post-operatively in 28-day cycles. Exploratory evaluations of time-to-progression, survival, as well as correlative tissue, cerebrospinal fluid (CSF), and blood-based analyses examining neratinib concentrations were planned. Results: We enrolled five patients between 5/22/2013-10/18/2016. As of March 1, 2019, patients had remained on study for 1-75+ postoperative cycles. Two patients had grade 3 diarrhea. Evaluation of the CSF showed low concentrations of neratinib, nonetheless two patients remained on therapy without progression for at least 13 cycles, with one on study treatment for nearly 6 years. Neratinib distribution in surgical tissue was variable for one patient, while specimens from two others did not produce conclusive results due to limited available samples. Conclusions: Neratinib resulted in expected rates of diarrhea in this small cohort, with 2 of 5 patients on study treatment for durable periods. Although logistically challenging, we were able to test a limited number of CSF-and parenchymal-based neratinib concentrations. Our findings from resected tumor tissue in one patient revealed heterogeneity in drug distribution and tumor histopathology. ClinicalTrials.gov number: NCT01494662 MICROABSTRACT We examined neratinib administration pre-and post-operatively in 5 patients with HER2-positive brain metastases. Two patients remained on therapy for 13 cycles and nearly 6 years postoperatively. We observed low CSF drug levels and variable craniotomy specimen levels among evaluable specimens. Inclusion of novel correlative analyses will continue to be crucial in advancing our understanding of CNS drug penetration.

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Section: Discussionmentioning

confidence: 97%

Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022

Freedman

Gelman

Agar

et al. 2020

Clinical Breast Cancer

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“…Moreover, when using the standard ICA injection technique with ligation of the external carotid artery, we still observed extracranial metastasis, likely as a result of tumor cell distribution into small arterial feeder branches, such as the occipital artery (OA), pterygopalatine artery (PPA), and superior thyroid artery (STA) (fig. S3, A to C) ( 37 – 39 ). Therefore, we established a modified ICA injection technique, in which we ligated these feeder arteries, thereby greatly reducing the formation of extracranial tumors (fig.…”

Section: Resultsmentioning

confidence: 99%

Anti-EGFR VHH-armed death receptor ligand–engineered allogeneic stem cells have therapeutic efficacy in diverse brain metastatic breast cancers

et al. 2021

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Basal-like breast cancer (BLBC) shows brain metastatic (BM) capability and overexpresses EGFR and death-receptors 4/5 (DR4/5); however, the anatomical location of BM prohibits efficient drug-delivery to these targetable markers. In this study, we developed BLBC-BM mouse models featuring different patterns of BMs and explored the versatility of estem cell (SC)–mediated bi-functional EGFR and DR4/5-targeted treatment in these models. Most BLBC lines demonstrated a high sensitivity to EGFR and DR4/5 bi-targeting therapeutic protein, EVDRL [anti-EGFR VHH (EV) fused to DR ligand (DRL)]. Functional analyses using inhibitors and CRISPR-Cas9 knockouts revealed that the EV domain facilitated in augmenting DR4/5-DRL binding and enhancing DRL-induced apoptosis. EVDRL secreting stem cells alleviated tumor-burden and significantly increased survival in mouse models of residual-tumor after macrometastasis resection, perivascular niche micrometastasis, and leptomeningeal metastasis. This study reports mechanism based simultaneous targeting of EGFR and DR4/5 in BLBC and defines a new treatment paradigm for treatment of BM.

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“…Turner et al used BLI to monitor the response of two basal-like, triple-negative PDX cell lines (WHIM2 and WHIM30) to treatment (34). Liu et al described establishment of orthotopic mouse models of BCBM-PDXs and monitored their engraftment with BLI (35). To address this, we developed a novel method to label luciferase expressing PDX cells with iron-oxide particles to allow for the in vivo , longitudinal cell tracking with two imaging modalities for the first time.…”

Section: Discussionmentioning

confidence: 99%

A method for the efficient iron-labeling of patient-derived xenograft cells and cellular imaging validation

Knier

Dubois

Ronald

et al. 2021

Preprint

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There is momentum towards implementing patient-derived xenograft models (PDX) in cancer research to reflect the histopathology, tumour behavior, and metastatic properties observed in the original tumour. These models are more predictive of clinical outcomes and are superior to cell lines for preclinical drug evaluation and therapeutic strategies. To study PDX cells preclinically, we used both bioluminescence imaging (BLI) to evaluate cell viability and magnetic particle imaging (MPI), an emerging imaging technology to allow for detection and quantification of iron nanoparticles. The goal of this study was to develop the first successful iron labeling method of breast cancer cells derived from patient brain metastases and validate this method with imaging during tumour development.Luciferase expressing human breast cancer PDX cells (F2-7) were successfully labeled after incubation with micron-sized iron oxide particles (MPIO; 25 μg Fe/mL). NOD/SCID/ILIIrg-/- (n=5) mice received injections of 1×106 iron-labeled F2-7 cells into the fourth mammary fat pad (MFP). BLI was performed longitudinally to day 49 and MPI was performed up to day 28. In vivo BLI revealed that signal increased over time with tumour development. MPI revealed decreasing signal in the tumours and increasing signal in the liver region over time.Here, we demonstrate the first application of MPI to monitor the growth of a PDX MFP tumour. To accomplish this, we also demonstrate the first successful labeling of PDX cells with iron oxide particles. Imaging of PDX cells provides a powerful system to better develop personalized therapies targeting breast cancer brain metastasis.

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Improving orthotopic mouse models of patient-derived breast cancer brain metastases by a modified intracarotid injection method

Cited by 22 publications

References 25 publications

Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022

Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022

Anti-EGFR VHH-armed death receptor ligand–engineered allogeneic stem cells have therapeutic efficacy in diverse brain metastatic breast cancers

A method for the efficient iron-labeling of patient-derived xenograft cells and cellular imaging validation

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