Abstract A258: The PARP inhibitor niraparib demonstrates synergy with chemotherapy in treatment of patient derived Ewing's sarcoma tumorGraft models.

Abstract

Ewing's sarcoma (ES) is the second most common primary tumor of bone in young adults and accounts for 40% of bone tumors in children and adolescents. With modern multimodality management, including chemotherapy, surgery, and radiotherapy, ES patients can expect a 5-year overall survival (OS) of approximately 70% for those with localized disease and 20-30% for those with metastatic disease. The oncogenic drivers behind ES, are the result of a characteristic set of EWS chromosomal translocations, most commonly the t(11;22)(q24;q12) involving the FLI1 locus. Recent studies have demonstrated that both the EWS-FLI and EWS-ERG transcription factors interact with PARP-1 and that PARP inhibitors alter transcription targets of EWS-FLI1/ERG, resulting in significantly reduced cell survival in vitro and reduced tumor growth and formation of lung metastases in animal models. Niraparib (formerly MK-4827) is a potent, orally active PARP inhibitor that is currently being evaluated in Phase III clinical trials for ovarian and BRCA related breast cancer. In an ongoing investigation of cancers with niraparib sensitivity, we investigated niraparib activity as a single agent and in combination with second line chemotherapeutic agents commonly used in Ewing's Sarcoma in patient-derived TumorGraft ES models. Champions TumorGraft models of EWS-FLI1 positive Ewing's sarcoma (CTG-0816 and CTG-0142) utilized in this study were derived directly from primary tumors of heavily pretreated ES patients. Mice bearing established subcutaneous TumorGrafts were treated with regimens of niraparib (p.o., 50-100 mg/kg/day), temozolomide (p.o., 25-50 mg/kg/day) or irinotecan (i.p., 50-100 mg/kg/week) as single agent or doublet combinations. Treatment of tumor bearing mice with single agent niraparib, temozolomide or irinotecan exhibited minimal to modest tumor growth inhibition (0-65%) across models and regimens. When niraparib was used in combination with either high dose temozolomide or irinotecan, synergistic activity was observed resulting in significant tumor regression; however toxicity was evident with pronounced weight loss and myelosuppression. By contrast, complete tumor regression with minimal evidence of toxicity was observed when full dose niraparib, given for 4 weeks, was combined with reduced doses of either chemotherapeutic; for example, niraparib administered with a reduced dose of temozolomide during week 1 and 3 or with irinotecan for three weeks. In addition to its role of inhibiting PARP mediated DNA repair, preliminary gene expression analysis of treated tumors indicates that single agent niraparib reverses components of EWS-FLI1 gene regulation. The ability to both improve tolerability while retaining efficacy when a reduced dose of chemotherapy is combined with full dose niraparib presents important translational opportunities for the clinical investigation of chemosensitization by PARP inhibitors. In conclusion, the current study utilized patient derived tumors to identify well tolerated and efficacious combinations of common second line ES therapies with niraparib. This data supports the clinical investigation of niraparib in combination with temozolomide or irinotecan in patients with Ewing's sarcoma. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A258. Citation Format: Keith M. Wilcoxen, David G. Brooks, Dhanrajan Tiruchinapalli, Nathan Anderson, Rodney Donaldson, McIver Nivens, Charlie Cook, Tin Khor, Bin Lu, Elizabeth De Oliveira, Erin Hawley, Elizabeth Bruckheimer. The PARP inhibitor niraparib demonstrates synergy with chemotherapy in treatment of patient derived Ewing's sarcoma tumorGraft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A258.

Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing’s Sarcoma

“…This is consistent with the minimal activity of single-agent PARPi in Ewing’s sarcoma xenografts, suggesting that PARPi may not trap PARP as efficiently in vivo [ 24 , 28 ]. Our results provide mechanistic insights that support on-going trials combining temozolomide with olaparib in Ewing’s sarcoma patients, a combination already validated in xenograft and orthotopic models [ 27 – 29 , 49 , 50 ]. Combination of PARPi with temozolomide would thus be predicted to enhance the level of PARP1 trapping in Ewing’s sarcoma tumors to achieve greater clinical efficacy.…”

In vivo anti-tumor activity of the PARP inhibitor niraparib in homologous recombination deficient and proficient ovarian carcinoma

“…Five mice bearing PH077 (niraparib-sensitive BRCA2 mutant tumor, Fig. 2A) were randomized at day 28 after the start of triple therapy to maintenance with niraparib 50 mg/kg/day, a dose previously shown to be efficacious [36], and four were randomized to observation. Ten additional mice from the carboplatin/paclitaxel arm entered observation.…”

Poly(ADP-ribose) polymerase inhibitors in Ewing sarcoma

“…The effect of PARPi treatment in combination with temozolomide and irinotecan in Ewing sarcoma tumour graft models has also been published for the PARPi niraparib [21 ▪▪ ] and BMN 673 [18] . The Wilcoxon group presented impressive in-vivo evidence for combining either irinotecan or temozolomide with niraparib, with complete regression of patient-derived Ewing sarcoma tumours in all tested mice using two different schedules: full-dose temozolomide (daily for 5 days) or irinotecan (once weekly) combined with niriparib (daily for 5 days), or half-dose temozolomide or irinotecan and continuous niriparib.…”