Abstract A012: IDO1 PROTAC improves survival against human glioblastoma

Abstract Objective: This study was initiated to neutralize maladaptive IDO1 effects in glioblastoma (GBM). We evaluated a novel, recently patented, IDO1 protein degrader (IDO1 PROTAC) with DC50=4. 7 nM evaluated in vitro and in mouse models with human GBM. Methods: To determine the maximum tolerated dose (MTD) of IDO1 PROTAC, C57BL/6 mice received a sham intracranial injection followed by the treatment with 10-, 25-, or 50-mg/kg IDO1 PROTAC, 5 days/week × 4 weeks total, with body weight and overall survival measured longitudinally. To determine if the IDO1 PROTAC decreases IDO1 levels in vivo, and because human GBM cells do not express IDO1 in immunodeficient mice (due to the lack of human T cells), U87 was genetically engineered to express IDO1 after treatment with doxycycline (resulting in ‘U87 sgIDO1’). After intracranial injection of U87 sgIDO1 cells into NSG mice, the first dose of IDO1 PROTAC occurred at 10% of GBM-induced body weight loss, followed by a second dose 24 hr later. Tumors were resected at 4, 24, and 48 hr after the second dose and analyzed for intratumoral IDO1 protein levels and IDO1 PROTAC compound concentration in human GBM, contralateral brain without GBM, and plasma. To investigate the effect of IDO1 PROTAC on survival, doxycycline-treated mice with intracranial U87 sgIDO1 were treated twice weekly with IDO1 PROTAC and compared to vehicle control- and control PROTAC-treatment groups. To investigate the effect on mice with human immune systems, CD34+ humanized NSG mice were intracranially-engrafted with HLA allele-matched PDX GBM43 and treated twice weekly with IDO1 PROTAC or controls. Results: IDO1 PROTAC MTD is 10 mg/kg when given 5 days/week × 4 weeks with no signs of toxicity and no negative impact on survival compared to vehicle treated mice (n=4 mice/group; p0. 99). IDO1 PROTAC treatment significantly decreases intra-GBM IDO1 protein expression (n=4 mice/group; p0. 05). IDO1 PROTAC is present in the intracranial human GBM at 130 ng/g of tissue 4 hours after the last IDO1 PROTAC dose and is at a higher level compared to the plasma (n=4-5 mice/group; p0. 05). IDO1 PROTAC is not detectable in the brain without GBM at any time point. IDO1 PROTAC treatment significantly increased the survival of mice with intracranial GBM as compared to vehicle- and control PROTAC-treatment groups (n=11-14 mice/group; p0. 01). The improved survival correlated with increased body weight in IDO1 PROTAC treated- as compared to vehicle- and control PROTAC-treated humanized mice with PDX GBM43 (n=6 mice/group; p0. 05). Conclusions: IDO1 PROTAC shows promise as a new therapeutic approach that supersedes the activity of IDO1 enzyme inhibitors. IDO1 PROTAC is safe, tolerable, and potently degrades IDO1 protein inside intracranial human GBM after systemic delivery. IDO1 PROTAC treatment increases the survival of mice with intracranial human GBM PDX. Ongoing studies are investigating IDO1 PROTAC-mediated changes in human GBM-infiltrating immune cells and aim to better understand the mechanism by which IDO1 PROTAC improves GBM-related outcomes. Citation Format: Taylor Koch, Prashant V. Bommi, Sonam V. Jha, Manon Penco-Campillo, Kellen King, Kristen L. Lauing, Oluwatomilayo Odum, Lijie Zhai, William Small Jr. , Edward M. Campbell, Prabhodh S. Abbineni, Steven Kregel, Sean W. Fanning, Douglas Anderson, Anand A. Germanwala, Vikram Prabhu, Jigisha Thakkar, Gary E. Schiltz, Derek A. Wainwright. IDO1 PROTAC improves survival against human glioblastoma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (6Suppl): Abstract nr A012.