Predictive Biomarker Signatures For Iap Inhibitor Cudc-427

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PAThe Inhibitors of Apoptosis (IAP) are a family of functionally related proteins that serve as endogenous regulators of apoptosis. The frequent overexpression of IAP proteins allows cancer cells to evade apoptosis and develop drug resistance, making them attractive targets for cancer therapies. CUDC-427 is a potent small molecule IAP antagonist currently tested in a Phase 1 clinical trial for solid tumors and lymphomas. Although only 10% of the cancer cell lines are sensitive to single-agent CUDC-427 in vitro, significant anti-tumor activity has been observed in xenograft models. These observations highlight the importance of identifying patients with sensitive tumors to better target CUDC-427 for specific patient populations. Previously, we have reported TNF family ligand induction and decrease in XIAP levels as potential predictive biomarkers for response to CUDC-427. However, this prediction method requires the detection of biomarker levels in post-treatment samples, which may not always be feasible in clinical setting. Therefore, we sought to assess predictive genetic markers of response to CUDC-427 treatment for patient stratification.Using an in vitro cell viability assay, single-agent activity of CUDC-427 was assessed against a panel of 90 hematological and solid tumor cell lines from the Cancer Cell Line Encyclopedia (CCLE) collection. These results and genomic data available from the CCLE database including gene expression, DNA copy number and mutation status were used in the elastic net analysis to identify predictors associated with drug response. A set of gene signatures containing about 10 significant predictors identified by this approach was further validated and refined in an independent set of 61 CCLE cell lines. The clinical relevance of these gene signatures was validated by searching the cBioPortal Cancer Genomics database. The results indicate that these signatures frequently occur in several solid and hematologic cancers. To further validate this set of gene signatures, single-agent activity of CUDC-427 was evaluated in 30 patient-derived xenograft tumor models and 12 cell-line-derived xenograft models including breast and ovarian cancers as well as lymphomas. Daily treatment with CUDC-427 induced 60% or greater tumor growth inhibition in 20 of the 42 models tested, including 4 highly sensitive models that demonstrated tumor regression. Whole genome data including mutation status, DNA copy number and mRNA expression profiles of these xenograft tumors were assessed to provide independent in vivo validation and to further refine the gene signatures generated in vitro.In conclusion, a set of gene signatures identified through this work can potentially be used as biomarkers to predict in vivo activity of CUDC-427 across multiple tumor types. These results will provide a basis for the development of predictive assays to aid selection of patients whose tumors may be sensitive to CUDC-427 treatment.Citation Format: Kaiming Sun, Ze Tian, Qi Zhang, Maria Samson, Ruzanna Atoyan, Mylissa Borek, Steven Dellarocca, Brian Zifcak, Troy Patterson, Anna W. Ma, Guangxin Xu, Michael J. Wick, Richard Rickles, Jing Wang. Predictive biomarker signatures for IAP inhibitor CUDC-427. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4324. doi:10.1158/1538-7445.AM2015-4324