Abstract 2733: Antitumor activity of the PARP inhibitor E7449 in Ewing's sarcoma

Ewing's sarcoma affects mostly adolescents and young adults with tumors that predominate in bone, characterized by the presence of fusion proteins created by chromosomal translocations (EWS-FLI1, EWS-ERG etc.). Recent studies demonstrated an interaction between EWS fusion proteins and PARP1; increased DNA damage and elevated PARP levels upon fusion protein expression as well as sensitivity to PARP inhibition have been reported. E7449, a potent, orally available PARP inhibitor was evaluated in various xenograft models of Ewing's sarcoma as a single agent and in combination with TMZ or irinotecan, chemotherapies often used in relapsed patients. In an RD-ES (ATCC® HTB166™) Ewing's sarcoma (EWS-FLI1) s.c. xenograft model, treatment with single agent E7449 or TMZ resulted in no antitumor activity. However, when combined exquisite synergy that resulted in tumor regression and tumor-free mice was observed, even at the low E7449 combination dose of 1 mg/kg. E7449 dose responsive re-growth of tumors was observed and 8/8 mice remained tumor-free in the highest dose group (30 mg/kg) at study termination. Enhanced toxicity as measured by body weight loss was observed in combination treatment groups but mice generally recovered well. Significant antitumor activity was observed for irinotecan alone in the RD-ES model; combination with E7449 enhanced that activity. Combining TMZ and irinotecan was also efficacious in the RD-ES model. Antitumor activity was further enhanced by the addition of E7449 which also potentiated combination toxicity. Studies are ongoing to optimize dosing of E7449 and chemotherapy and to identify a treatment schedule that maximizes activity and tolerability of the various combinations. Additionally, the activity of E7449 alone and in combination was evaluated in 2 Ewing's sarcoma patient-derived xenograft (PDx) models. In one model (CTG-0143) neither TMZ nor E7449 as single agents had significant antitumor activity. However, the combination of E7449 + TMZ resulted in striking synergy and tumor regression. Although tumors were large when treatment started, significant antitumor activity was also observed with single agent irinotecan and combination treatment. The second model (CTG-0142) was sensitive to E7449 alone at high dose and to both chemotherapies (TMZ and irinotecan) as single agents. Addition of E7449 to either TMZ or irinotecan resulted in enhanced anti-tumor activity as measured by significantly delayed tumor re-growth following regress