Abstract 2772: Targeting hypoxic habitats with hypoxia pro-drug evofosfamide in preclinical models of sarcoma

Tumor habitats are phenotypically and spatially distinct intratumoral regions. Hypoxic habitats are associated with reduced accessibility of chemotherapeutics, resulting in resistance. Hypoxia targeted prodrugs (HAPs) may overcome this resistance. However, in a phase III clinical trial, the HAP evofosfamide (TH-302) did not improve survival of sarcomas when used in combination with the standard of care doxorubicin (Dox). This may have been due to a lack of patient stratification based on hypoxic status. Thus, identification of hypoxic tumor habitats (Jardim-Perassi et al. 2019) would allow for pre-therapy patient stratification, and monitoring of habitats post-therapy. Our goal was to use multiparametric (mp) MRI and co-registered histology to classify hypoxic habitats in preclinical models of sarcoma, and to use Habitat Imaging to monitor therapy response. A patient-derived xenograft (PDX) of rhabdomyosarcoma (obtained from St. Jude9s) and a syngeneic model of fibrosarcoma (RIF-1) were randomized into four groups, receiving saline (control), Dox, TH-302, or the combination (Dox + TH-302). mpMRI was acquired pre and post therapy, and parameter maps were calculated for T2, T2*, diffusion weighted imaging (DWI), and Dynamic contrast-enhanced (DCE). MRI based 3D printed tumor molds were used to guide MRI and histology co-registration. Machine learning was used to classify MRI into viable, hypoxic and non-viable tumor habitats using their co-registered histological counterparts as ground-truth. TH-302 monotherapy or the Dox + TH-302 combination reduced tumor growth and increased overall survival in the PDX model (p Citation Format: Bruna Victorasso Jardim Perassi, Wei Mu, Dominique F. Abrahams, Michal R. Tomaszewski, Jan Poleszczuk, Jack Higgins, Gary V. Martinez, Robert J. Gillies. Targeting hypoxic habitats with hypoxia pro-drug evofosfamide in preclinical models of sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2772.