Hematologic malignancies: newer strategies to counter the BCL 2 protein
IntroductionBCL 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.MethodsIn 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 conclusionDNA 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.
Journal of Cancer Research and Clinical Oncology