Dipg-46. Total Therapy for Diffuse Midline Gliomas: A Sequential, Intensive, Multi-Agent Combination Platform Is a Potent Treatment Strategy

Abstract BACKGROUND Diffuse Midline Glioma (DMG) has a dire prognosis, with a mortality rate nearing 100%. In the past, children diagnosed with Acute Lymphoblastic Leukemia (ALL) faced a similar prognosis until multi-agent chemotherapy revolutionized their survival rates. We hypothesized that implementing a comprehensive treatment strategy for DMG could yield similar efficacy. This study aimed to test the safety and efficacy of sequential, intensive, multi-agent combinations targeting epigenetic/chromatin modification (CBL0137-Panobinostat, CP), polyamine metabolism (DFMO-AMXT1501, DA), and the NF-κB pathway (ACT001) in preclinical DMG models. METHODS/RESULTS Maximum tolerated dose studies, which integrated comprehensive biochemical and hematological analyses with clinical data, tested different treatment durations and drug sequences. Tolerable doses and drug sequences were assessed in the aggressive patient-derived SU-DIPGVI orthotopic model for activity. In total six different drug combination sequences were tested for impact on survival. One particular sequence – DA/ACT001/CP – was significantly more effective compared with both vehicle and other regimens. This specific sequential regimen resulted in a 50% tumour regression rate with surviving animals maintaining tumor-free status 1 year, compared with 81-day survival in controls. This 5-agent treatment sequence (DA/ACT001/CP) was next tested in the HSJD-DIPG007 orthotopic model with a significant extension of survival (119 days) compared with single or two-agent treatments (vehicle-59 days, DA-86 days, ACT001-66 days, CP-62 days, DA/ACT001-93 days). Further enhancement of this treatment regimen through addition of radiotherapy significantly extended survival to 130 days, with one-third of the cohort showing sustained tumor regression and remaining tumor-free (by Xenogen imaging) for 220 days. CONCLUSIONS There are no effective therapies for DMG. Single and combination regimens in vivo often extend survival by days or weeks but do not generally eliminate tumors. Our “Total Therapy” strategy, inspired by successful ALL therapies, suggests that multi-agent sequential combination therapy can induce profound responses and unprecedented long-term survival in DMG animal models.