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ASA404, a vascular disrupting agent, as an experimental treatment approach for brain tumors
Oliver Bähr1,2, Stefanie Gross1, Patrick N Harter3,2
1Dr. Senckenberg Institute of Neurooncology, Goethe-University Hospital, Frankfurt, Germany.
Abstract:
Malignant brain tumors, including gliomas, brain metastases and anaplastic meningiomas, are associated with poor prognosis, and represent an unmet medical need. ASA404 (DMXAA), a vascular disrupting agent, has demonstrated promising results in several preclinical tumor models and early phase clinical trials. However, two phase III trials in non-small cell lung cancer reported insufficient results. The aim of the present study was to determine the effects of ASA404 on brain tumors. The effects of ASA404 were evaluated in vitro and in vivo using subcutaneous, and orthotopical models for malignant glioma (U-87, LN-229, U-251, LN-308 and Tu-2449), brain metastasis (HT-29) and malignant meningioma (IOMM-Lee). The acute effects of ASA404 on tumor tissue were analyzed using conventional and immunohistochemical staining techniques [hematoxylin and eosin, MIB-1 antibody/proliferation maker protein Ki-67, cleaved caspase-8, stimulator of interferon genes (STING), ionized calcium-binding adapter molecule 1]. Furthermore, the sizes of subcutaneous tumors were measured and the symptom-free survival rates of animals with intracranial tumors receiving ASA404 treatment were analyzed. ASA404 demonstrated low toxicity in vitro, but exhibited strong effects on subcutaneous tumors 24 h following a single dose of ASA404 (25 mg/kg). ASA404 induced necrosis, hemorrhages and inhibited the proliferation, and growth of tumors in the subcutaneous glioma models. However, ASA404 failed to demonstrate comparable effects in any of the intracranial tumor models examined and did not result in a prolongation of survival. Expression of STING, the molecular target of ASA404, and infiltration of macrophages, the cells mediating ASA404 activity, did not differ between subcutaneous and intracranial tumors. In conclusion, ASA404 demonstrates clear efficacy in subcutaneous tumor models, but has no relevant activity in orthotopic brain tumor models. The expression of STING and infiltration with macrophages were not determined to be involved in the differential activity observed among tumor models. It is possible that the low penetration of ASA-404 into the brain prevents concentrations sufficient enough reaching the tumor in order to exhibit acute effects in vivo.
Insights
ASA404 (DMXAA) effectively reduced subcutaneous brain tumors by causing necrosis and inhibiting growth. However, this vascular disrupting agent showed no significant efficacy in orthotopic brain tumor models, likely due to poor brain penetration.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Malignant brain tumors like gliomas, metastases, and meningiomas have poor prognoses.
- ASA404 (DMXAA) is a vascular disrupting agent with preclinical promise but mixed clinical trial results.
- The efficacy of ASA404 in brain tumors remains to be fully elucidated.
Purpose of the Study:
- To investigate the effects of ASA404 on various malignant brain tumor models.
- To evaluate ASA404's efficacy and toxicity in vitro and in vivo.
- To explore potential mechanisms behind ASA404's activity in different tumor types.
Main Methods:
- In vitro and in vivo studies using subcutaneous and orthotopic models of glioma, brain metastasis, and meningioma.
- Analysis of tumor tissue using hematoxylin and eosin, Ki-67, cleaved caspase-8, STING, and Iba1 staining.
- Measurement of subcutaneous tumor size and symptom-free survival in animals with intracranial tumors.
Main Results:
- ASA404 showed low in vitro toxicity but significant anti-tumor effects (necrosis, hemorrhage, proliferation inhibition) in subcutaneous glioma models.
- No comparable efficacy or survival benefit was observed in any orthotopic brain tumor models.
- STING expression and macrophage infiltration did not differ between subcutaneous and intracranial tumors, suggesting they are not responsible for the differential activity.
Conclusions:
- ASA404 is effective against subcutaneous brain tumors but lacks efficacy in orthotopic brain tumor models.
- The differential activity is not explained by STING expression or macrophage infiltration.
- Poor ASA404 penetration into the brain may limit its therapeutic potential for brain tumors.
