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Published on: January 20, 2019
Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies
Luciano Nicosia1, Gary J Spencer1, Nigel Brooks2
1Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
Abstract:
CCS1477 (inobrodib) is a potent, selective EP300/CBP bromodomain inhibitor which induces cell-cycle arrest and differentiation in hematologic malignancy model systems. In myeloid leukemia cells, it promotes rapid eviction of EP300/CBP from an enhancer subset marked by strong MYB occupancy and high H3K27 acetylation, with downregulation of the subordinate oncogenic network and redistribution to sites close to differentiation genes. In myeloma cells, CCS1477 induces eviction of EP300/CBP from FGFR3, the target of the common (4; 14) translocation, with redistribution away from IRF4-occupied sites to TCF3/E2A-occupied sites. In a subset of patients with relapsed or refractory disease, CCS1477 monotherapy induces differentiation responses in AML and objective responses in heavily pre-treated multiple myeloma. In vivo preclinical combination studies reveal synergistic responses to treatment with standard-of-care agents. Thus, CCS1477 exhibits encouraging preclinical and early-phase clinical activity by disrupting recruitment of EP300/CBP to enhancer networks occupied by critical transcription factors.
Insights
Inobrodib (CCS1477), an EP300/CBP bromodomain inhibitor, effectively targets hematologic malignancies by disrupting enhancer networks. This drug shows promise in clinical trials for acute myeloid leukemia and multiple myeloma.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Hematologic malignancies like acute myeloid leukemia (AML) and multiple myeloma (MM) are driven by complex genetic alterations.
- Enhancer regions, regulated by epigenetic modifications, play a crucial role in cancer development.
- EP300 and CBP are key epigenetic regulators often implicated in cancer.
Purpose of the Study:
- To evaluate the efficacy of CCS1477 (inobrodib), a selective EP300/CBP bromodomain inhibitor.
- To investigate the mechanism of action of CCS1477 in hematologic malignancy models.
- To assess the clinical activity of CCS1477 in relapsed or refractory AML and MM.
Main Methods:
- In vitro studies using myeloid leukemia and myeloma cell lines.
- Analysis of EP300/CBP eviction from enhancer regions.
- Assessment of gene expression changes related to differentiation and oncogenesis.
- Preclinical in vivo combination studies with standard-of-care agents.
- Early-phase clinical trials in patients with relapsed/refractory AML and MM.
Main Results:
- CCS1477 induced cell-cycle arrest and differentiation in hematologic malignancy models.
- The drug promoted EP300/CBP eviction from MYB-occupied enhancers in AML cells, downregulating oncogenic networks.
- In myeloma cells, CCS1477 evicted EP300/CBP from FGFR3 and redistributed it to TCF3/E2A sites.
- Monotherapy with CCS1477 showed differentiation responses in AML and objective responses in MM patients.
- Preclinical studies demonstrated synergistic responses when CCS1477 was combined with standard therapies.
Conclusions:
- CCS1477 is a potent EP300/CBP bromodomain inhibitor with significant preclinical and early-phase clinical activity.
- The drug disrupts critical transcription factor-occupied enhancer networks, leading to anti-cancer effects.
- CCS1477 shows promise as a monotherapy and in combination regimens for treating AML and MM.
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