Abstract A40: CD30: A therapeutic target of MYC-driven cancer

Abstract

The MYC oncogene induces a multitude of human malignancies and has been well characterized as a critical driver of select lymphoma subtypes. In MYC-amplified tumor progression, there is a robust dependence on MYC activity; however, strategies developed to modulate MYC function in cancer have yielded little success. Patients harboring these MYC-driven tumors would benefit from a directed therapy that circumvents explicit molecular targeting of MYC expression. Our preliminary data from an unbiased expression-profiling screen identified CD30 as a primary downstream target of the MYC oncoprotein. CD30 is a member of the tumor necrosis factor superfamily and resides on the extracellular membrane; it is highly expressed in many lymphomas while acutely restricted in normal cells. Within the last few decades, CD30 has emerged as a diagnostic marker and therapeutic target of many lymphoproliferative disorders and diseases. The biological function of CD30 is pleiotropic: CD30 stimulation is reportedly linked to cell cycle arrest, apoptosis, and proliferation through activation of the pro-survival transcription factor, NF-kB. However, the underlying mechanisms that regulate CD30 expression remain unclear. CD30-driven oncogenic pathways phenocopy those initiated by MYC, suggesting CD30's potential status as an effector of MYC-driven tumorigenic events. Here we report that CD30 is regulated at the transcriptional level by MYC. Through a genetic and biochemical approach, we define CD30 induction in a MYC-dependent manner across a variety of human cell lines of both lymphomagenic and non-lymphomagenic origin. Furthermore, in a murine lymphoma model where tumor formation is driven by a conditional allele of MYC, CD30 transcript levels are tightly correlated with MYC activity. Ultimately, CD30 induction offers a novel therapeutic avenue by which to target MYC-driven oncogenesis and has the potential to reshape detection and treatment of MYC-regulated cancer. Citation Format: Victoria Gennaro, Xiao-yong Zhang, Lauren DeSalle, Duonan Yu, Andrei Thomas-Tikhonenko, Steven McMahon. CD30: A therapeutic target of MYC-driven cancer. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A40.