Abstract
BackgroundPatients with advanced T cell lymphomas (TCLs) have limited therapeutic options and poor outcomes in part because their TCLs evade apoptosis through upregulation of anti-apoptotic Bcl-2 proteins. Subsets of TCL cell lines, patient-derived xenografts (PDXs), and primary patient samples depend on Bcl-xL for survival. However, small molecule Bcl-xL inhibitors such as ABT263 have failed during clinical development due to on-target and dose-limiting thrombocytopenia.MethodsWe have developed DT2216, a proteolysis targeting chimera (PROTAC) targeting Bcl-xL for degradation via Von Hippel-Lindau (VHL) E3 ligase, and shown that it has better anti-tumor activity but is less toxic to platelets compared to ABT263. Here, we examined the therapeutic potential of DT2216 for TCLs via testing its anti-TCL activity in vitro using MTS assay, immunoblotting, and flow cytometry and anti-TCL activity in vivo using TCL cell xenograft and PDX model in mice.ResultsThe results showed that DT2216 selectively killed various Bcl-xL-dependent TCL cells including MyLa cells in vitro. In vivo, DT2216 alone was highly effective against MyLa TCL xenografts in mice without causing significant thrombocytopenia or other toxicity. Furthermore, DT2216 combined with ABT199 (a selective Bcl-2 inhibitor) synergistically reduced disease burden and improved survival in a TCL PDX mouse model dependent on both Bcl-2 and Bcl-xL.ConclusionsThese findings support the clinical testing of DT2216 in patients with Bcl-xL-dependent TCLs, both as a single agent and in rational combinations.
Highlights
T cell lymphomas (TCLs) are a rare and heterogeneous group of lymphoid malignancies that account for approximately 10% of all non-Hodgkin lymphomas (NHLs) in high-income countries [1] and a higher fraction in lower- and middle-income countries [2]
Utilizing the BH3 profiling, a functional assay that directly interrogates the dependence on Bcl-2 anti-apoptotic proteins, we showed that most Cutaneous T cell lymphoma (CTCL) and a subset of Peripheral T cell lymphoma (PTCL), including some patientderived xenografts (PDXs) and primary patient samples, are dependent on Bcl-xL, which correlated with sensitivity to the Bcl-2/Bcl-xL inhibitor ABT263 but not the Bcl-2 inhibitor ABT199 [8]
DT2216 selectively kills Bcl-xL-dependent TCL cell lines by degrading Bcl-xL in a Von Hippel-Lindau (VHL)-dependent manner Using the BH3 profiling assay, our previous studies revealed that a fraction of human TCL cell lines are exclusively dependent on Bcl-xL for survival and are highly sensitive to Bcl-xL-specific and dual Bcl-2/BclxL inhibitors [8]
Summary
T cell lymphomas (TCLs) are a rare and heterogeneous group of lymphoid malignancies that account for approximately 10% of all non-Hodgkin lymphomas (NHLs) in high-income countries [1] and a higher fraction in lower- and middle-income countries [2]. Utilizing the BH3 profiling, a functional assay that directly interrogates the dependence on Bcl-2 anti-apoptotic proteins, we showed that most CTCLs and a subset of PTCLs, including some patientderived xenografts (PDXs) and primary patient samples, are dependent on Bcl-xL, which correlated with sensitivity to the Bcl-2/Bcl-xL inhibitor ABT263 ( known as navitoclax) but not the Bcl-2 inhibitor ABT199 ( known as venetoclax) [8]. These findings suggest that targeted inhibition of Bcl-xL could offer therapeutic benefits for some patients with TCL. Small molecule Bcl-xL inhibitors such as ABT263 have failed during clinical development due to on-target and dose-limiting thrombocytopenia
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