Abstract B012: In vivo Mini screen to assess the Antitumor Effect of Carboxyamidotriazole orotate (CTO) and temozolomide (TMZ) in Monotherapy in Three ITCC-P4’s High-grade Glioma (HGG) Pediatric Patient
Rashida A. Karmali, Romina Walter, Johannes Gojo, Georg Kuales, Apurva Gopisetty, Jan Koster, Gilles VassalAbstract
Background:
The aim of this study was to evaluate in vivo antitumor activity of CTO, a novel, oral small molecule orotate formulation of carboxyamidotriazole (CAI). The antiproliferative and antimetastatic properties of CTO are driven by the inhibition of calcium influx through receptor-operated channels. By disrupting calcium-sensitive signaling within the VEGF and PI3K pathways, CTO suppresses FGF-2 induced tyrosine kinase activity. Pre-clinical research indicates that CTO regulates several tyrosine kinases signaling pathways influencing the tumor microenvironment. This results in the simultaneous dissociation of multiple calcium sensitive, signaling pathways critical to oncogenesis and cellular homeostasis, including the EGFR, RAS/MEK, HDAC, HSP90, WNT-β catenin, and VEGF signaling.
Methods:
Three clinically and molecularly characterized ITCC-P4’s HGG PDX models were selected based on their expression levels of BRAF, EGFR, HDAC1, HDAC2, HSP90AB1, KRAS, NRAS, PIK3CA, PTEN, TP53. In addition, the HG0067_PP01 exhibiting the BRAF mutation, HG0230_PR06 exhibiting the PIK3CA mutation and HG0356_PP01 exhibiting the BRAF mutation and HDAC2 loss. Three groups of NSG mice bearing subcutaneous tumor xenografts were treated with therapeutic regimens to compare efficacy. Mice in Group 1 served as the control and received a vehicle consisting of 40% PEG 400 in water for injection (WFI) on a schedule of five consecutive days followed by a two-day treatment hiatus. Group 2 was administered CTO orally at a dosage of 513 mg/kg once daily using the same five-day on, two-day off weekly cycle. Group 3 received TMZ via oral gavage at a dose of 17 mg/kg/day, following a cyclic dosing schedule consisting of two five-day treatment blocks (Days 1–5 and Days 15–19). Mice were monitored for effect on body weight, tumor growth inhibition and survival.
Results:
Tumor growth delay was observed for all 3 ITCC-P4’s HGG PDX models with CTO administration, while TMZ failed to elicit an inhibitory effect on tumor progression in any of the models evaluated. The minimum Treatment/Control (T/C) ratios (derived from mean relative tumor volumes) for CTO were 49.5%, 40.9%, and 31.5% across the three models. The body weight losses were increased in response to treatment with CTO in comparison to vehicle or TMZ treatment. However, the body weight losses were mostly reversed towards baseline levels by end of experiment.
Conclusion:
CTO demonstrated moderate efficacy, characterized by significant tumor growth delay across three subcutaneous HGG models. Conversely, TMZ failed to exhibit any detectable anti-tumor activity. The small sample size (n=3) represents a study limitation and studies using larger group sizes are planned before considering Phase 1 in pediatric patients with HGG.
Citation Format:
Rashida A. Karmali, Romina Walter, Johannes Gojo, Georg Kuales, Apurva Gopisetty, Jan Koster, Gilles Vassal. In vivo Mini screen to assess the Antitumor Effect of Carboxyamidotriazole orotate (CTO) and temozolomide (TMZ) in Monotherapy in Three ITCC-P4’s High-grade Glioma (HGG) Pediatric Patient Derived Xenograft (PDX) Tumor Models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Bridging Discovery and Clinical Impact in Pediatric Cancer; 2026 Sep 22-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_1):Abstract nr B012.