Multimodal imaging enables early detection and characterization of changes in tumor permeability of brain metastases

Abstract

Our goal was to develop strategies to quantify the accumulation of model therapeutics in small brain metastases using multimodal imaging, in order to enhance the potential for successful treatment. Human melanoma cells were injected into the left cardiac ventricle of immunodeficient mice. Bioluminescent, MR and PET imaging were applied to evaluate the limits of detection and potential for contrast agent extravasation in small brain metastases. A pharmacokinetic model was applied to estimate vascular permeability. Bioluminescent imaging after injecting D-Luciferin (molecular weight (MW) 320D) suggested tumor cell extravasation had already occurred at week 1, which was confirmed by histology. 7T T1w MRI at week 4 was able to detect non-leaky 100 μm sized lesions and leaky tumors with diameters down to 200 μm after contrast injection at week 5. PET imaging showed that 18F-FLT (MW 244D) accumulated in the brain at week 4. Gadolinium-based MRI tracers (MW 559D and 2.066kD) extravasated after 5 weeks (tumor diameter 600 μm), and the lower MW agent cleared more rapidly from the tumor (mean apparent permeabilities 2.27×10-5 cm/s versus 1.12×10-5 cm/s). PET imaging further demonstrated tumor permeability to 64Cu-BSA (MW 65.55kD) at week 6 (tumor diameter 700 μm). In conclusion, high field T1w MRI without contrast may improve the detection limit of small brain metastases, allowing for earlier diagnosis of patients, although the smallest lesions detected with T1w MRI were permeable only to D-Luciferin and the amphipathic small molecule 18F-FLT. Different-sized MR and PET contrast agents demonstrated the gradual increase in leakiness of the blood tumor barrier during metastatic progression, which could guide clinicians in choosing tailored treatment strategies.

In Vitro Treatment of Melanoma Brain Metastasis by Simultaneously Targeting the MAPK and PI3K Signaling Pathways

“…The tumors have the highest propensity to metastasize to the brain, seen in around 50% of the melanoma patients with advanced disease [4]. Current treatment strategies of melanoma brain metastasis involve surgery, chemotherapy, radiotherapy and radiosurgery.…”

ANG1005 for breast cancer brain metastases: correlation between 18F-FLT–PET after first cycle and MRI in response assessment

“…Research is ongoing; NCT02328300 is assessing 18 F-FLT-PET and MRI for the evaluation of pseudoprogression in patients with brain metastases, and NCT01621906 is comparing MRI with 18 F-FLT-PET in patients with BCBM receiving whole-brain radiotherapy (WBRT)± the multikinase inhibitor sorafenib. The available evidence suggests that FLT-PET imaging in this setting may improve response assessment [35, 36]. Our preliminary evaluation of FLT-PET imaging for CNS disease in BCBM suggests that it is a promising tool that could serve as a complementary assessment method, supporting or clarifying MRI findings.…”

The Future of Targeted Therapies for Brain Metastases

“…The function of the blood-brain barrier was postulated to change with the size of the BM, as micrometastases might be still protected by the blood-brain barrier, while it is rather compromised in macrometastases [84]. Upon the outgrowth, BM have to induce neoangiogenesis and the neovasculature of the BM forms the blood tumor barrier, that differs from the blood-brain barrier in terms of fenestration and permeability.…”