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In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas
Kylie D Mason1, Cassandra J Vandenberg, Clare L Scott
1The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia.
Abstract:
Deregulated Myc expression drives many human cancers, including Burkitt's lymphoma and a highly aggressive subset of diffuse large cell lymphomas. Myc-driven tumors often display resistance to chemotherapeutics because of acquisition of mutations that impair the apoptosis pathway regulated by the Bcl-2 protein family. Given the need to identify new therapies for such lymphomas, we have evaluated the efficacy of ABT-737, a small molecule that mimics the action of the BH3-only proteins, natural antagonists of the prosurvival Bcl-2 proteins. ABT-737 selectively targets certain prosurvival proteins (Bcl-2, Bcl-x(L), and Bcl-w) but not others (Mcl-1 and A1). We treated mice transplanted with lymphomas derived either from Emu-myc transgenic mice or Emu-myc mice that also expressed an Emu-bcl-2 transgene. As a single agent, ABT-737 significantly prolonged the survival of mice transplanted with the myc/bcl-2 lymphomas but was ineffective for the myc lymphomas, probably because of the relatively higher Mcl-1 levels found in the latter. Strikingly, when combined with low-dose cyclophosphamide, ABT-737 produced sustained disease-free survival of all animals transplanted with two of three myc/bcl-2 lymphomas tested. The combination therapy was also more effective against some myc lymphomas than treatment with either agent alone. Our data suggest that antagonism of Bcl-2 with small organic compounds is an attractive approach to enhance the efficacy of conventional therapy for the treatment of Myc-driven lymphomas that over-express this prosurvival molecule.
Insights
This study shows ABT-737, a Bcl-2 inhibitor, effectively treats Myc-driven lymphomas, especially when combined with chemotherapy. This combination therapy offers a promising new approach for these aggressive cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Deregulated Myc expression is a key driver in numerous human cancers, including aggressive lymphomas.
- Myc-driven lymphomas often develop chemoresistance due to impaired apoptosis pathways involving the Bcl-2 protein family.
- Targeting prosurvival Bcl-2 proteins presents a potential therapeutic strategy for these resistant lymphomas.
Purpose of the Study:
- To evaluate the efficacy of ABT-737, a BH3-mimetic small molecule, as a potential therapy for Myc-driven lymphomas.
- To investigate the synergistic effects of combining ABT-737 with conventional chemotherapy (cyclophosphamide) in preclinical lymphoma models.
Main Methods:
- Treatment of mice bearing Myc-driven lymphomas (Emu-myc) or Myc/Bcl-2 co-expressing lymphomas with ABT-737 alone or in combination with low-dose cyclophosphamide.
- Assessment of therapeutic efficacy based on survival rates and disease-free survival.
- Analysis of Bcl-2 family protein expression (specifically Mcl-1) in relation to treatment response.
Main Results:
- ABT-737 as a single agent prolonged survival in Myc/Bcl-2 lymphomas but was ineffective in Myc lymphomas, likely due to high Mcl-1 levels.
- Combination therapy of ABT-737 and cyclophosphamide achieved sustained disease-free survival in a majority of Myc/Bcl-2 lymphoma models.
- The combination treatment demonstrated superior efficacy compared to single-agent therapy in certain Myc lymphoma models.
Conclusions:
- Antagonism of Bcl-2 proteins using small molecules like ABT-737 is a viable therapeutic strategy for Myc-driven lymphomas.
- Combining Bcl-2 inhibitors with conventional chemotherapy can enhance treatment efficacy and overcome chemoresistance in these cancers.
- This approach holds promise for developing novel therapies for Myc-driven lymphomas overexpressing Bcl-2.
