(SS#I) AANS/CNS Joint Section on Tumors Neuro-oncology Trainee Award (2023 Award Winner): RAGE Inhibitor (TTP488) as an Alternative To dexamethasone For managing Cerebral Edema Following Brain Tumor Surgery
Postdoctoral Research Fellow Division of Neurosurgery, City of Hope Beckman Research Institute and Medical Center, Duarte, California, United States. Duarte, California, United States
Disclosure(s):
Mojtaba Dayyani, MD: No financial relationships to disclose
Introduction: Cerebral edema (CE) is among the major post-operative complications after neurosurgical procedures and contributes to patient morbidity. Although dexamethasone is the drug of choice to alleviate CE during the perioperative period, it has several undesirable side effects and interferes with immunotherapies in patients with malignant brain tumors. Herein, we aimed to assess the anti-inflammatory effects of TTP488 (inhibitor of receptor for advanced glycation end products) on the vasogenic edema following brain tumor resection in mice models.
Methods: Mice (C57BL/6J, n=12) harboring CT-2A glioma tumors were randomly assigned to three groups and underwent tumor resection survival surgery. TTP488 (100 μg), Dexamathasone (200 μg), and vehicle were administered perioperatively (day -4 pre-op to day 7 post-op). Cerebral edema was quantified with serial brain MRIs (7T scanner) over a 7-day period. Using manual segmentation techniques, tumor, resection cavity, ventricles, CE, and brain tissue volumes were calculated and compared among the groups. The SNAP score was used to assess post-operative neurological function. In a separate survival experiment, the effect of each drug on anti-PD-1 immunotherapy response was measured.
Results: In each group, CE peaked at 2 days and gradually diminished by day 7. On post-operative day one, mice treated with TTP488 showed markedly reduced CE compared to those treated with either dexamethasone or vehicle with mean CE volumes of 1.75±1.08%, 2.69±0.77%, and 3.87±1.07%, respectively (P=0.02, TTP488:Vehicle). Furthermore, the TTP488 group had better functional recovery scores compared to the vehicle group (P=0.04). Interestingly, unlike dexamethasone, TTP488 did not abrogate the efficacy of immunotherapy in the CT-2A glioma model.
Conclusion : To our knowledge, this is the first report that demonstrates TTP488 to be as effective as dexamethasone in alleviating CE caused by tumor resection. Furthermore, considering that TTP488 did not interfere with immunotherapy, it could be an alternative to steroids in the perioperative management of patients with brain tumors.
