Abstract B169: A mouse avatar tumor maintenance study identified a subset of SCLC patient-derived tumor xenograft models sensitive to the PARP inhibitor niraparib
Authors: Mikule Keith , Wang Yan , Xiao Yonhong , Rocono Jill , Broudy Thomas , Wilcoxen Keith 
Published: May 2016

Introduction Small cell lung cancer (SCLC) is an aggressive form of disease that accounts for approximately 15% of all lung cancers. To date, targeted therapies have not impacted the treatment paradigm, which is dominated by platinum-based regimens. Here we evaluate the potential of niraparib, a clinical stage poly-ADP-ribose polymerase 1 inhibitor, in a cohort of 31 SCLC patient-derived xenograft (PDX) models in mice.

Methods For the initial screening study forty-two SCLC PDX models were inoculated subcutaneously into the rear flank of NOD-SCID mice. Thirty-one models were placed on study. For each model, one animal was treated with a dose of chemotherapy to mimic front line standard of care (SOC, cisplatin day 1; etoposide day 1- 3), and one animal was dosed with the same representative SOC regimen followed by a niraparib maintenance regimen (starting day 8, QDx48). Confirmatory efficacy studies were performed on six responsive models with n = 5 per group. For all efficacy studies, tumor and body weight measurements were taken three times per week. Whole exome sequencing was carried out on untreated tumor samples from six highly sensitive and four resistant models to identify biomarkers predictive of response. Sequencing was performed on DNA from fresh frozen tissue to a depth of approximately 140x mean target coverage.

Results Both the SOC, and SOC plus niraparib maintenance regimens were well-tolerated with no signs of treatment-related toxicity or significant body weight loss. Robust tumor growth inhibition (TGI) was observed in 6 of 31 (19%) models. Importantly, responses were confirmed in 6 of 6 models that were repeated with cohorts of 5 animals per treatment regimen. All tumor models that exhibited sensitivity to niraparib were considered platinum/etoposide responsive based on an anti-tumor response to the initial cisplatin/etoposide treatment. Robust TGI was observed in 6 of the 20 (30%) tumor models that exhibited sensitivity to cisplatin/etoposide treatment. Whole exome sequencing of sensitive vs. resistant tumors identified mutations in genes that may be used to further enrich for tumors that would be sensitive to maintenance niraparib treatment after first line cisplatin/etoposide treatment.

Conclusions Niraparib exhibited robust anti-cancer activity in 30% of cisplatin/etoposide sensitive SCLC PDX models challenged with a dosing regimen that mimics SOC followed by niraparib maintenance. These data provide support for the clinical development of niraparib in platinum-sensitive patients and suggest biomarkers that may be useful for additional patient enrichment strategies.

Citation Format: Keith Mikule, Yan Wang, Yonhong Xiao, Jill Rocono, Thomas Broudy, Keith Wilcoxen. A mouse avatar tumor maintenance study identified a subset of SCLC patient-derived tumor xenograft models sensitive to the PARP inhibitor niraparib. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B169.