Venetoclax Synergizes with Radiotherapy for Treatment of B-cell Lymphomas

Abstract

Constitutive B-cell receptor signaling leads to overexpression of the anti-apoptotic BCL-2 protein and is implicated in the pathogenesis of many types of B-cell Non-Hodgkin Lymphoma (B-NHL). The BCL-2 small molecule inhibitor venetoclax shows promising clinical response rates in several lymphomas, but is not curative as monotherapy. Radiotherapy (RT) is a rational candidate for combining with BCL-2 inhibition, as DNA damage caused by RT increases the activity of pro-apoptotic BCL-2 pathway proteins, and lymphomas are exquisitely sensitive to radiation. We tested B-NHL responses to venetoclax combined with either external beam RT or radioimmunotherapy (RIT), which joins the selectivity of antibody targeting with the effectiveness of irradiation. We first tested cytotoxicity of cesium-137 irradiation plus venetoclax in 14 B-NHL cell lines representing five lymphoma sub-types. Combination treatment synergistically increased cell death in ten of 14 lines. Lack of synergy was predicted by resistance to single-agent venetoclax and high BCL-XL expression. We then assessed the efficacy of external beam RT plus venetoclax in murine xenograft models of mantle cell (MCL), germinal-center diffuse large B-cell (GCB-DLBCL), and activated B-cell (ABC-DLBCL) lymphomas. In each model, external beam RT plus venetoclax synergistically increased mouse survival time, curing up to 10%. We finally combined venetoclax treatment of MCL and ABC-DLBCL xenografts with a pretargeted RIT (PRIT) system directed against the CD20 antigen. Optimal dosing of PRIT plus venetoclax cured 100% of mice with no detectable toxicity. Venetoclax combined with RT may be a promising treatment for a wide range of lymphomas.

Development of venetoclax for therapy of lymphoid malignancies

“…81 In vitro and in vivo results also supported that radiotherapy could synergize with venetoclax for treatment of DLBCL and MCL. 82 All the above studies provide evidence for the feasibility of future combination therapy options.…”

Renewed interest for low‐dose radiation therapy in follicular lymphomas: From biology to clinical applications

“…LDRT effects described “in vivo” have been linked to enhanced “in vitro” radio sensitivity by Dubray et al In this work, the remarkable apoptosis propensity of FL cells after both radiation and other cytotoxic agents has been revealed to be secondary to the suppression of the hyper‐expressed Bcl‐2 pathway. Additional new findings were reported by O'Steen et al, showing that venetoclax, a selective inhibitor of Bcl‐2, may synergize with RT on multiple B‐cell lymphoma animal models, especially when using a radio‐immunotherapy approach targeting CD20 . Knoops et al also analyzed pre‐RT and post‐RT gene expression profiles on tissue samples of 15 FL patients .…”

MYC in Germinal Center‐derived lymphomas: Mechanisms and therapeutic opportunities

“…Like other drug combinations, the aforementioned synergy of Venetoclax with inhibitors of either the mitochondrial ribosome or PLK1 provide important proof‐of‐principle for the potential of combinatorial targeting against DHL, as well as a blueprint for following up on the plethora of MYC‐synthetic‐lethal interactions reported in the literature. Indeed, taking either Tigecycline or Volasertib as paradigms, we can surmise that other compounds showing synthetic‐lethality with MYC also have the potential to synergize with Venetoclax against DHL, and vice‐versa.…”

“…In recent years, significant progress was made toward the development of selective inhibitors of BCL2 and their potential use in cancer: one of these molecules, Venetoclax (or ABT‐199), was approved by the FDA in 2016 against chronic lymphocytic leukemia (CLL) and showed activity against other lymphomas including FL, MCL and DLBCL, albeit at lower frequencies in the latter . Venetoclax is currently a cornerstone in the development of combinatorial therapies (eg, ). Most relevant here, and as described in more detail below, two recent preclinical studies revealed that treatments that affect MYC‐expressing cells can be combined with the BCL2‐specific inhibitor Venetoclax, with major therapeutic benefits in DHL …”