Umbralisib/Tgr-1202 As A Novel Dual Pi3k/Ck1 Inhibitor Has A Unique Therapeutic Role In Silencing Oncogenes In Aggressive Lymphomas

Introduction: A number of oncogenes have been shown to promote the pathogenesis and correlate with poor survival in aggressive lymphoma. For example, deregulation of C-MYC is prevalent in diffuse large B cell lymphoma (DLBCL), chromosome translocations involving C-MYC and BCL2 define “double hit lymphoma” (DHL), and chromosome translocation involving CCND1 is pathognomonic for mantle cell lymphoma (MCL). Despite impressive progress being made in the treatment of these aggressive lymphomas, the treatment options for patients with relapsed aggressive lymphoma, especially DHL, remain inadequate. Interestingly, translation of C-MYC, BCL2, CCND1, and a number of other oncogenes is highly sensitive to inhibition of the eukaryotic translation initiation factor 4F (eIF4F) (Manier et al., 2017; Wolfe et al., 2014), which is comprised of the eIF4E, eIF4A, and eIF4G subunits. However, inhibitors of eIF4F are currently not available for the clinic. eIF4F is negatively regulated by the eIF4E binding protein 1 (4E-BP1), which in the hypo-phosphorylated form sequesters eIF4E (Haghighat et al., 1995). To allow for robust initiation of translation in cancer cells 4E-BP1 is hyper-phosphorylated by upstream signals, such as mechanistic target of rapamycin (mTOR). Our recent results indicate that casein kinase 1 epsilon (CK1ε) positively regulate translation via phosphorylating4E-BP1 (Deng et al., 2016). There may be additional poorly understood signals regulating 4E-BP1. Although no CK1ε inhibitor has been developed for the clinic, we recently discovered that the PI3Kδ inhibitor umbralisib/TGR-1202 acts additionally to inhibit CK1ε. Given that TGR-1202 has demonstrated a favorable safety profile in clinical trials and is capable of targeting both PI3Kδ and CK1ε, the drug may be particularly valuable for the silencing of oncogenes in aggressive lymphoma. Our hypothesis is the following: If hyper-phosphorylation of 4E-BP1 serves as a nexus for upregulating oncogene translation, then co-targeting signals phosphorylating 4E-BP1, such as CK1ε and mTOR, may potently and synergistically silence oncogenes in aggressive lymphomas.