P08.10 Efficacy of Temozolomide and Aldoxorubicin combination in U87-luc glioblastoma xenograft mice model

Introduction: Despite that Temozolomide (TMZ) is the standard of care recognized for its effectiveness in the treatment of glioblastoma (GBM), its prognosis remains poor. Therefore, combination chemotherapy using TMZ with other antitumor agents is now under investigation. We evaluated antitumor efficacy, tolerability and long-term response of the combination of TMZ with Aldoxorubicin (Aldoxo), a novel drug-conjugate of Doxorubicin, in a growing GBM xenograft mouse model. Materials and Methods: A human GBM cell line that expresses a luciferase reporter (U87-luc) was injected in the right lobe of the brain of Foxn1 mice. Following initial tumor growth for 7 days, mice were treated with Aldoxo (16 mg/kg, weekly intravenous administrations), TMZ (0.9 mg/kg, daily oral administrations) or their combination up to 5 weeks. Bioluminescence IVIS acquisitions have been performed at day 0, +3, +7 and then weekly until the end of experiment in order to quantify tumor growth and long-term response to therapy (until day +90). Results: In the first 28 days, all animals had developed tumors of varying size without significant difference between treated and untreated mice. At day +42, (end of treatment), there was a significant decrease in the tumors with TMZ and Aldoxo-TMZ therapy (P<0.05). At day +56, tumor volume in Aldoxo-treated mice was 4-fold smaller than in vehicle with no statistical significant difference among these groups; on the contrary, a significant tumor volume inhibition (TVI) was observed in Aldoxo-TMZ treated mice (TVI 90%, P=0,0190 vs vehicle), as well as in TMZ treated mice (TVI 92% P=0,0317 vs vehicle). Survival data showed that, although no different survival rate was in tumor-bearing mice treated with TMZ or Aldoxo-TMZ (37,5% at day +90), the combined treatment delayed the mortality compared to TMZ alone throughout the experimental period. Furthermore, by the 69-day time point all untreated mice were deceased whereas Aldoxo-treated group showed an increased survival rate at day +90 (12,5%). Conclusion: Our preliminary data demonstrated that, although the combination therapy schedule of Aldoxo and TMZ failed to significantly improve TVI in GBM xenograft mice model, it achieved a survival benefit when compared to TMZ alone, delaying mortality during the overall experimental period without adverse effects.