Abstract SY38-03: Targeting post-translational activation of MYC for the treatment of cancer

Abstract

Abstract The MYC oncoprotein is considered to be one of the most important targets in cancer; however, successful targeting of MYC has not been achieved to date. MYC is a transcription factor, which binds to DNA in target genes as a heterodimer with its partner protein, MAX. While MAX is constitutively expressed, MYC protein expression is tightly regulated at multiple levels, including gene transcription, mRNA stability, protein translation, and post-translational protein stability. In cancer, MYC expression is upregulated through deregulation at many of these levels, resulting in an increase in MYC:MAX heterodimers and MYC-regulated gene expression. MYC regulated genes are involved in nearly all cellular processes, including cell intrinsic properties such as cell cycle control, cell growth and metabolism, self-renewal, migration and invasion, as well as cell extrinsic programs including angiogenesis, stromal cell expansion, and alterations in immune cell surveillance. MYC is thus a master regulator of cellular phenotype, and its deregulation contributes to tumorigenesis through many mechanisms. Importantly, elegant studies have recently demonstrated the tractability of targeting MYC for cancer therapeutics. Specifically, loss of MYC in adult tissues caused very little toxicity and metronomic expression of a MYC dominant negative protein caused no observable toxicity, but eliminated KRAS-driven pancreatic and lung tumors. Since targeting MYC directly has proven difficult, we are developing new strategies to target the post-translational activation of MYC. MYC is both stabilized and transcriptionally activated following cell stimulation via receptor tyrosine kinase signaling pathways leading to ERK mediated phosphorylation of Serine 62. We have demonstrated that Serine 62 phosphorylated MYC is upregulated in human cancer cells and that this facilitates its regulation of pro-oncogenic target genes by increasing its DNA binding activity and co-activator recruitment, as well as increasing its protein stability. We have identified Protein Phosphatase 2A (PP2A) as the enzyme responsible for dephosphorylating Serine 62. PP2A is a critical tumor suppressor that is known to inactivate multiple oncogenic signaling pathways, as well as cell cycle drivers and survival factors. Furthermore, inactivation of PP2A has been shown to be critical for the transformation of human cells, and PP2A activity is suppressed in most tested human tumors. We are utilizing a recently developed small molecule, orally available, allosteric PP2A activator drug. This drug (DTx) is in clinical development by Dual Therapeutics. We have tested this drug, as well as a peptide mimetic PP2A activator, OP449, in cell lines and in mouse models of tumorigenesis. We have observed cytotoxic activity in both breast and pancreas cancer cell lines associated with dephosphorylation of MYC at Serine 62. We have also observed reduced MYC DNA target gene binding and target gene expression with PP2A activation therapy. In order to test novel therapeutic strategies targeting MYC activity, we have developed new mouse models of Myc-driven tumorigenesis using our ROSA26-LSL-Myc mice that we generated to conditionally express transcriptionally deregulated, physiological levels of Myc in response to Cre recombinase. By crossing these mice with mice expressing other organ specific oncogenic drivers, we have developed mouse mammary tumor models representing HER2+ and Triple Negative breast cancer. We have also developed a novel mouse model of pancreatic tumorigenesis using the same strategy. All of these models appear to molecularly recapitulate the corresponding human disease, and we are using them as pre-clinical testing platforms for our PP2A activation therapy trials. So far, we have seen dramatic tumor growth inhibition and even tumor shrinkage with DTx treatment in all three of these models. This is associated with loss of Serine 62 phosphorylation in the treated tumors. Importantly, we see no signs of toxicity in vivo with this novel compound and pharmacokinetic studies look very promising for bringing this compound to the clinic. In summary, we believe that targeting pathways that post-translationally activate MYC's oncogenic potential is a promising strategy for targeting this important oncoprotein. Citation Format: Xiaoyan Wang, Amy Farrell, Mahnaz Janghorban, Brittany Allen-Petersen, Juan Liang, Tyler Risom, Michael Ohlmeyer, Goutham Narla, Rosalie C. Sears. Targeting post-translational activation of MYC for the treatment of cancer. [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 SY38-03. doi:10.1158/1538-7445.AM2015-SY38-03