The Combination of Venetoclax and CUDC-907 Exhibits Synergistic Activity in Venetoclax-Refractory DLBCL

CUDC-907 is a first-in-class, oral, dual inhibitor of Class I and II HDAC, as well as Class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6 and 10 and PI3K-alpha, delta and beta isoform. Preclinical studies demonstrate that CUDC-907 has potent effects on acetylated histone-regulated genes and PI3K signaling. CUDC-907 showed potent antitumor activity in multiple preclinical tumor models as well as in patients with relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL), with objective responses reported in multiple patients, including complete responses. It is currently being investigated in a Phase 2 study in patients with RR DLBCL, including those with MYC-alterations. Preclinical studies of CUDC-907 in combination with chemotherapeutic and targeted agents are in progress.

Venetoclax, a BH3 mimetic and selective BCL2 inhibitor, was recently approved for the treatment of patients with chronic lymphocytic leukemia (CLL) whose tumors had a 17p deletion. Results from a Phase 1 study of venetoclax monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma showed that patients with DLBCL exhibited short-lived responses to venetoclax. Thus, combination approaches may be required to achieve durable responses to venetoclax in DLBCL.

In our preclinical studies, we examined the combination of venetoclax and CUDC-907 in DLBCL cell lines. Interestingly, the combination exhibited the most synergy, as measured by fold-improvement over predicted additive effect, in cell lines insensitive to venetoclax. For example, OCI-Ly3 cells were insensitive to single agent venetoclax with an IC₅₀ >10uM; however, in combination with a fixed dose (12nM) of CUDC-907, venetoclax resulted in >10000-fold improvement in potency with a combination IC₅₀ of 0.001uM. Synergy was also observed in tumor growth inhibition studies in xenograft models. Western blot analysis showed that single-agent CUDC-907 simultaneously increased pro-apoptotic BIM protein and decreased anti-apoptotic BCL2 protein levels. Interestingly, the low nano-molar concentrations of CUDC-907 that were shown to regulate the BCL-2 family member proteins could also potentiate pro-apoptotic effects of venetoclax when used together in combination in WSU-DLCL2 cell line which carries MYC and BCL2 translocations. Thus, the effect of CUDC-907 on BCL2 family members appears to be the basis for the observed synergy with venetoclax, which functions to displace BIM from BCL2. These results provide a mechanistic rationale for the use of CUDC-907 in combination with venetoclax for the treatment of patients with DLBCL.