Erschienen in:
04.04.2016 | Review – Clinical Oncology
Hematologic malignancies: newer strategies to counter the BCL-2 protein
verfasst von:
Abdul Shukkur Ebrahim, Hussam Sabbagh, Allison Liddane, Ali Raufi, Mustapha Kandouz, Ayad Al-Katib
Erschienen in:
Journal of Cancer Research and Clinical Oncology
|
Ausgabe 9/2016
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Abstract
Introduction
BCL-2 is the founding member of the BCL-2 family of apoptosis regulatory proteins that either induce (pro-apoptotic) or inhibit (anti-apoptotic) apoptosis. The anti-apoptotic BCL-2 is classified as an oncogene, as damage to the BCL-2 gene has been shown to cause a number of cancers, including lymphoma. Ongoing research has demonstrated that disruption of BCL-2 leads to cell death. BCL-2 is also known to be involved in the development of resistance to chemotherapeutic agents, further underscoring the importance of targeting the BCL-2 gene in cancer therapeutics. Thus, numerous approaches have been developed to block or modulate the production of BCL-2 at the RNA level using antisense oligonucleotides or at the protein level with BCL-2 inhibitors, such as the novel ABT737.
Methods
In this article, we briefly review previous strategies to target the BCL-2 gene and focus on a new approach to silence DNA, DNA interference (DNAi).
Results and conclusion
DNA interference is aimed at blocking BCL-2 gene transcription. Evaluations of this technology in preclinical and early clinical studies are very encouraging and strongly support further development of DNAi as cancer therapeutics. A pilot phase II clinical trial in patients with relapsed or refractory non-Hodgkin lymphoma, PNT2258 demonstrated clinical benefit in 11 of 13 patients with notable responses in diffuse large B cell lymphoma and follicular lymphoma. By targeting the DNA directly, the DNAi technology promises to be more effective compared with other gene-interference strategies that target the RNA or protein but leaves the dysregulated DNA functional.