Abstract B08: Improved tumor penetration, antitumor activity, and survival of ABI-009 (nab-sirolimus) versus oral rapamycin and everolimus and investigation of mTOR pathway inhibition
Authors: Schmid Anita N. , Hou Shawn , Grigorian Berta , Desai Neil P. 
Published: December 2020

Abstract
Background: mTOR pathway is a key regulator of cell survival and proliferation and has been implicated in various indications, including oncology, hematology, and cardiovascular, metabolic, and central nervous system diseases. ABI-009, a novel mTOR inhibitor, is an intravenously (IV) administered nanoparticle form of albumin-bound sirolimus. ABI-009 is in a registrational clinical study for perivascular epithelioid cell carcinoma (PEComa), and also studied as combination or single agent in phase 1, 1/2, and 2 studies in neuroendocrine tumors, bladder cancer, glioblastoma, soft-tissue sarcomas, colorectal cancer, childhood cancers, as well as pulmonary arterial hypertension and epilepsy. ABI-009 has a distinct PK profile vs. oral mTOR inhibitors, and it is hypothesized that albumin binding to sirolimus may improve drug penetration and thus efficacy. This xenograft study was conducted to evaluate the antitumor activity, tissue penetration, and mTOR inhibition of ABI-009 vs. equal doses of oral mTOR inhibitors at clinically relevant doses.
Methods: Athymic mice were injected with UMUC3 bladder cancer cells subcutaneously into both flanks. Upon development of tumors, ABI-009, oral rapamycin and everolimus were administered at equal weekly doses of 15 mg/kg, n = 5 each group: ABI-009 IV at 7.5 mg/kg, 2x /wk; rapamycin and everolimus PO at 3 mg/kg/day, 5 days /wk; saline IV at 10 ml/kg, 3x /wk. Body weights, tumor measurements, and clinical signs were recorded 3x /wk for up to 5 wks of treatment. Tumor and blood drug concentrations were also obtained (tumor: D1 1h and 24h, D4 1h, D7; blood: D4 1h, D7). Markers for mTOR pathway activation (pS6, p4EBP1) will also be analyzed.
Results: The tumor growth inhibition (TGI) was 69.6% with ABI-009, significantly greater vs. oral rapamycin (TGI 24.3%; p &lt; 0.00001) and oral everolimus (TGI 36.2%; p = 0.0023). The median OS was also significantly longer with ABI-009 (not reached) vs. rapamycin (21 days; p &lt; 0.05) and everolimus (19 days; p &lt; 0.05). There was no statistically significant difference in body weight between the control and treatment groups. Tumor and blood drug concentrations with ABI-009 IV were significantly higher than rapamycin and everolimus at all time points tested. Tumor AUC with ABI-009 IV over 1 week were significantly higher vs. rapamycin (43 fold) and everolimus (12 fold) (p &lt; 0.0001). The higher tumor distribution with ABI-009 IV correlated with greater antitumor activity and longer animal survival. mTOR pathway inhibition in tissues is being assessed.
Conclusions: This study demonstrated significantly greater antitumor activity and prolonged survival at clinically relevant doses with ABI-009 vs. equal weekly dosing of oral mTOR inhibitors, rapamycin and everolimus. The increased efficacy of ABI-009 over the oral mTOR inhibitors may be the result of increased drug exposure and tumor penetration. The lack of significant weight loss indicated acceptable toxicity at the doses studied in each group. These findings warrant further study in the clinical setting.
Citation Format: Anita N. Schmid, Shawn Hou, Berta Grigorian, Neil P. Desai. Improved tumor penetration, antitumor activity, and survival of ABI-009 (nab-sirolimus) versus oral rapamycin and everolimus and investigation of mTOR pathway inhibition [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B08.