Hematologic malignancies: newer strategies to counter the BCL-2 protein
- 532 Downloads
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.
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.
KeywordsBCL-2 Non-Hodgkin lymphoma DNA interference Antisense oligonucleotides Small-molecule inhibitors
This study was funded by the St. John Hospital and Medical Center Foundation and by Michigan Corporate Relations Network’s (MCRN) Small Company Innovation Program (SCIP). The authors also wish to thank Dr. Mary Walsh for assistance in editing the manuscript.
Compliance with ethical standards
Conflict of interest
The authors report no conflicts of interest in this work.
This article does not contain any studies with human participants or animals performed by any of the authors.
- Al-Katib AM, Sun Y, Goustin AS, Azmi AS, Chen B, Aboukameel A, Mohammad RM (2009). SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status. J Hematol Oncol 2(8)Google Scholar
- Davids MS, Pagel JM, Kahl BS, Wierda WG, Miller TP, Gerecitano JF, Rudersdorf NK (2013) Bcl-2 inhibitor ABT-199 (GDC-0199) monotherapy shows anti-tumor activity including complete remissions in high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Blood 122(21):872Google Scholar
- Harb W, Lakhani N, Logsdon A, Steigelman M, Smith-Green H, Gaylor S et al (2014) The BCL2 targeted deoxyribonucleic acid inhibitor (DNAi) PNT2258 is active in patients with relapsed or refractory non-Hodgkin’s lymphoma. Paper presented at the American Society of hematology annual meetingGoogle Scholar
- Large B-Cell Lymphoma. In: ClinicalTrials.gov. National Library of Medicine (US), Bethesda. 2000-(cited 2015 Dec 4). https://clinicaltrials.gov/ct2/show/study/NCT02226965. NLM Identifier:NCT02226965
- Pro B, Leber B, Smith M, Fayad L, Romaguera J, Hagemeister F, Zwiebel J (2008) Phase II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in combination with rituximab in patients with recurrent B-cell non-Hodgkin lymphoma. Br J Haematol 143(3):355–360CrossRefPubMedGoogle Scholar
- Profile AR (2002) Augmerosen, Bcl-2 antisense oligonucleotide-genta, GC 3139, GenasenseGoogle Scholar
- ProNAi Therapeutics, Inc. A Phase II study of PNT2258 in patients with relapse or refractory diffuseGoogle Scholar
- Roberts A, Gandhi L, O’Connor O, Rudin C, Khaira D, Xiong H et al (2008) Reduction in platelet counts as a mechanistic biomarker and guide for adaptive dose-escalation in phase I studies of the Bcl-2 family inhibitor ABT-263. Paper presented at the ASCO annual meeting proceedingsGoogle Scholar
- Sheikhnejad R (2009) MicroDNAs (MIDs) and transcriptional regulation. Nature Precedings http://hdl.handle.net/10101/npre.2009.3931.1
- Zhang Y, Lin Y, Min P, Zhang X, Ling X, Guo M, Yang D (2007) A novel pan inhibitor of Bcl-2 and Mcl-1 apogossypolone (ApoG2) with superior stability and improved activity against human leukemia and lymphoma cells. Cancer Res 67(9 Supplement):5182Google Scholar