Glioblastoma Multiforme (GBM) is one of the most aggressive malignancies in humans, being highly invasive and drug-resistant, limiting the effectiveness of surgery, chemotherapy and radiotherapy. Concurrent Temozolomide (TMZ) and radiation is the standard of care for newly diagnosed GBM patients, however, patients respond poorly and prognosis remains dismal. TMZ response is limited to patients with hypermethylation of the methylguanine methyltransferase (MGMT) promoter. Despite recent advances in therapeutic strategies, treating GBM is still an unsolved clinical challenge requiring the investigation of novel approaches with better responses over approved therapies. RRx-001 is a novel ROS-mediated systemically non-toxic chemo-sensitizing epigenetic agent with vascular normalizing properties under investigation in Phase II clinical trials in brain metastases and GBM.
We assessed whether RRx-001 is an effective approach for treating GBM by testing its effects alone and in combination with TMZ both in vitro as well as in GBM mouse models. RRx-001 induced cytotoxicity in human TMZ-sensitive as well as resistant patient-derived GBM cell lines. In addition, its effect in TMZ-sensitive GBM cells was greater than the one induced by TMZ alone.
We then asked whether the in vitro effects of RRx-001 translated to therapeutic efficacy in vivo. To this end, we injected mice intracranially with a TMZ-resistant murine mesenchymal GBM cells, and treated tumor-bearing mice with RRx-001 alone and in combination with TMZ. RRx-001 treatment alone modestly prolonged survival compared to control cohorts, whereas the combination of RRx-001 and TMZ substantially prolonged survival compared to controls and either treatment alone. Moreover, histological evaluation of GBM tumors revealed that combination of RRx-001 and TMZ induced vessel hyperdilation and apoptosis compared to RRx-001 alone. Thus, in vivo RRx-001 combined to TMZ may also indirectly regulate tumor growth by modifying the tumor stroma.
These data suggest that TMZ may still affect the microenvironment in TMZ-resistant tumors and that RRx-001 enhances these effects by both directly and indirectly restricting GBM growth, making it a promising therapeutic agent alone and in combination with TMZ.
Citation Format: Veronica Steri, Bryan Oronsky, Jan Scicinski, Gabriele Bergers. RRx-001 is effective in temozolomide-sensitive and resistant GBM. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1245.