DT2216—a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas

Background Patients 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 dep...

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Published in:Journal of hematology and oncology Vol. 13; no. 1; pp. 95 - 13
Main Authors: He, Yonghan, Koch, Raphael, Budamagunta, Vivekananda, Zhang, Peiyi, Zhang, Xuan, Khan, Sajid, Thummuri, Dinesh, Ortiz, Yuma T., Zhang, Xin, Lv, Dongwen, Wiegand, Janet S., Li, Wen, Palmer, Adam C., Zheng, Guangrong, Weinstock, David M., Zhou, Daohong
Format: Journal Article
Language:English
Published: London BioMed Central 16.07.2020
BioMed Central Ltd
Springer Nature B.V
BMC
Subjects:
Aniline Compounds - therapeutic use
Aniline Compounds - toxicity
Animals
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Antineoplastic Agents - toxicity
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Antitumor agents
Apoptosis
Bcl-2 protein
Bcl-x protein
bcl-X Protein - antagonists & inhibitors
bcl-X Protein - metabolism
Bcl-xL
Biotechnology
Blood Platelets - drug effects
Bridged Bicyclo Compounds, Heterocyclic - therapeutic use
Cancer Research
Cell Line, Tumor
Comparative analysis
Drug Design
Drug Screening Assays, Antitumor
Drug Synergism
Female
Flow cytometry
Graft Survival
Hematology
Humans
Immunoblotting
Ligases
Liver - pathology
Lymphocytes T
Lymphoma
Lymphoma, T-Cell - drug therapy
Lymphoma, T-Cell - metabolism
Medical prognosis
Medicine
Medicine & Public Health
Mice
Mice, Inbred NOD
Mice, SCID
Neoplasia
Neoplasm Proteins - antagonists & inhibitors
Neoplasm Proteins - metabolism
Neoplasm Transplantation
Non-Hodgkin's lymphomas
Oncology
Patient-derived xenograft
Patients
Piperazines
PROTAC
Proteins
Proteolysis
Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors
Random Allocation
Spleen - pathology
Sulfonamides - therapeutic use
Sulfonamides - toxicity
T cell lymphoma
T cells
Thrombocytopenia
Toxicity
Tumors
Ubiquitin-protein ligase
Ubiquitin-Protein Ligases - chemistry
VHL
VHL protein
Vincristine
Xenograft Model Antitumor Assays
Xenografts
St Louis Missouri
United States > US
Bcl-xL
VHL
PROTAC
T cell lymphoma
Patient-derived xenograft
ISSN:1756-8722, 1756-8722
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Summary:Background Patients 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. Methods We 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. Results The 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. Conclusions These findings support the clinical testing of DT2216 in patients with Bcl-xL-dependent TCLs, both as a single agent and in rational combinations.
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ISSN:1756-8722
1756-8722
DOI:10.1186/s13045-020-00928-9