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Development of venetoclax for therapy of lymphoid malignancies

Huayuan Zhu1, Alexandru Almasan2

  • 1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, People's Republic of China.

Drug Design, Development and Therapy
|March 24, 2017
PubMed

Insights

Venetoclax, a BCL-2 inhibitor, shows promise in treating B-cell lymphoid malignancies like chronic lymphocytic leukemia (CLL). Understanding resistance mechanisms is key to optimizing its use in cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Dysfunction of the B-cell lymphoma-2 (BCL-2) protein family and impaired apoptosis are hallmarks of B-cell lymphoid malignancies.
  • Venetoclax is a novel, highly selective BCL-2 inhibitor designed to induce apoptosis by mimicking the BCL-2 homology 3-domain.

Purpose of the Study:

  • To review the role of the BCL-2 family in B-cell lymphoid malignancies.
  • To discuss the development and clinical outcomes of venetoclax in chronic lymphocytic leukemia (CLL) and other B-cell malignancies.
  • To explore mechanisms of venetoclax resistance and strategies to overcome them.

Main Methods:

  • Literature review of preclinical and clinical studies on venetoclax.
  • Analysis of BCL-2 family function in B-cell malignancies.
  • Examination of venetoclax resistance pathways and potential therapeutic strategies.

Main Results:

  • Venetoclax is approved for previously treated CLL patients with 17p deletion and shows efficacy against malignant cells in the bone marrow.
  • Unlike some other targeted agents, venetoclax has not shown reported relapses in some patients.
  • Preclinical studies identified potential resistance mechanisms, including MCL-1 or BCL-xL upregulation and microenvironmental signaling.

Conclusions:

  • Venetoclax represents a significant advancement in treating B-cell lymphoid malignancies, particularly CLL.
  • Understanding and addressing resistance mechanisms are crucial for maximizing venetoclax's therapeutic potential.
  • Translating mechanistic insights into clinical strategies will enhance patient outcomes.
Keywords:
BCL-2BCL-xLMCL-1chronic lymphocytic leukemiavenetoclax

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