Iap Inhibitor Cudc-427 Induces Tumor Regression Or Stasis In Preclinical Models Of B Cell Lymphoma

Evasion from apoptosis is a characteristic of human cancers. The family of Inhibitor of Apoptosis (IAP) proteins plays a pivotal role in apoptosis, proliferation, and signal transduction. Furthermore, mutations, amplifications and chromosomal translocations of IAP genes as well as aberrant expression of IAP proteins are associated with tumor progression, drug resistance and poor prognosis in various malignancies. For example, XIAP is found to be overexpressed in 55% of diffuse large B Cell Lymphomas (DLBCLs) and significantly linked to poor clinical outcome. Thus, IAP proteins have become promising targets for therapeutic intervention. CUDC-427 is a potent, oral, monovalent IAP antagonist currently in early-stage clinical testing (NCT01908413). In the present study, the anti-tumor activity of CUDC-427 was evaluated against a large panel of human cell lines of hematologic cancer origin. This screen identified DLBCL to be the most sensitive cell type. Consistent with these results, CUDC-427 activated caspase3/7 in the sensitive cell line WSU-DLCL2 but not in the resistant cell line Karpas 422. Subsequent mechanism-of-action studies demonstrated that CUDC-427 activated caspases 3, 8 and 9 by inhibiting cIAP1 and XIAP, as well as activating the non-canonical NF-ĸB pathway and inducing TNFα in WSU-DLCL2 cells. The anti-tumor effect of CUDC-427 was further confirmed in vivo using the WSU-DLCL2 xenograft model, in which daily oral administration of CUDC-427 induced 94% tumor growth inhibition in a 21-day efficacy study. TNF family ligands have been shown to act synergistically with IAP antagonists in preclinical studies. In our study, the addition of TNF family ligands significantly increased the sensitivity to single-agent CUDC-427 treatment in insensitive DLBCL cell lines. The presence of stromal cells in the culture also sensitized the insensitive Karpas 422 DLBCL cells to CUDC-427 treatment. In addition, daily treatment with CUDC-427 induced tumor regression and prolonged animal survival in the Karpas 422 xenograft model. To further elucidate the role of stromal cells and interaction between the tumor microenvironment and CUDC-427, we examined the efficacy and cytokine/chemokine profile of CUDC-427 in the A20 B cell lymphoma mouse syngeneic model. CUDC-427 treatment achieved tumor stasis in the fast growing A20 model grown in immunocompetent BALB/c mice, which may be partially due to the high levels of TRAIL in this model. In summary, CUDC-427 appears to have potent anti-tumor activity in DLBCL cell lines and in vivo models. The interaction between TNF family ligands or stromal cells with CUDC-427 in induction of tumor cell death in B cell lymphomas merits further analysis. This preclinical study supported further clinical investigation of CUDC-427 to improve patient outcomes in DLBCL. Citation Format: Ze Tian, Kaiming Sun, Troy Patterson, Ruzanna Atoyan, Mylissa Borek, Maria Samson, Brianne Hantzis, Anna W. Ma, Steven Dellarocca, Brian Zifcak, Guangxin Xu, Jing Wang. IAP inhibitor CUDC-427 induces tumor regression or stasis in preclinical models of B cell lymphoma. [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 5502. doi:10.1158/1538-7445.AM2015-5502