Targeting c-Myc stability in c-Myc overexpressing large B-cell lymphoma

Project Summary
Double (DH) and triple-hit (TH) lymphomas (L) are rare high grade B-cell lymphomas with diffuse large B-cell
(DLBCL) morphology characterized by the co-occurrence of chromosomal translocations involving MYC,
BCL2, and/or BCL6. DLBCLs with dual c-Myc (>40% by immunohistochemistry, IHC) and BCL2 (>50% by IHC)
protein overexpression without translocation (double-expressor or DEL) are significantly more common than
DH/THL, accounting for 20% to 30% of DLBCL patients. Lymphoma with either DEL, DHL, or THL are here
collectively called c-Myc overexpressing LBCL and have a significantly worse prognosis compared to the c-
Myc-negative counterpart [3-year overall survival of ~30% versus 70%, respectively]. The poor clinical
outcome of this subset of lymphoma patients highlights the need for novel therapeutic strategies. Transducin
β-like protein 1 (TBL1X) was initially identified as a specific adaptor protein playing an essential role in
canonical Wnt signaling by recruiting β-catenin to the promoter region of Wnt targets such as MYC and
CCND1 to activate their transcription. Few published reports indicate that the Wnt/β-catenin signaling is
constitutively activated in DLBCL, which prompted our initial investigation in this disease. Preliminary data: Our
published work shows that, unlike normal B cells, DLBCL cells express abundant levels of TBL1. Genetic
deletion of TBL1 or pharmacologic treatment with tegavivint (Iterion), a first-in-class small molecule targeting
TBL1, induces significant DLBCL cell death in vitro and in vivo. While tegavivint was initially developed as an
inhibitor of the TBL1/β-catenin interaction, our data show that genetic deletion of TBL1 and treatment with
tegavivint reduce c-Myc protein expression in a post-transcriptional/β-catenin independent manner. We further
show that in DLBCL, TBL1 interacts with a Skp1/Cul1/F-Box (SCF) supercomplex, which controls the
proteasome-mediated degradation of critical pro-survival proteins such as c-Myc and components of mTOR
signaling such as Rheb. Collectively, these observations establish the rationale for targeting TBL1 as a novel
therapeutic strategy to promote c-Myc turnover and to disrupt the driver events coordinated by its activity in c-
Myc overexpressing LBCL. Project hypothesis: TBL1 serves as a critical modulator of c-Myc turnover and
represents a novel and attractive candidate for targeted therapy for patients with c-Myc overexpressing LBCL.
To test this hypothesis, we propose the following aims: Aim 1: Characterize the TBL1/c-Myc feedforward
circuit promoting c-Myc overexpressing LBCL cell survival. Aim 2: Initiate a Phase Ib trial with single agent
tegavivint in patients with relapsed/refractory cMyc overexpressing LBCL. Aim 3: Identify combination
strategies to maximize the therapeutic potential of tegavivint. At completion of this project, we will have a better
understanding of the TBL1-modulated mechanism through which c-Myc turnover is regulated, will have
developed a novel therapeutic strategy to treat this incurable disease, and will have begun to characterize
resistance mechanisms to tegavivint.

Grant Number: 5R01CA266682-05
NIH Institute/Center: NIH
Principal Investigator: Lapo Alinari