Challenge
Foghorn Therapeutics was evaluating FHD-286, a dual BRG1/BRM inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) as part of a multicenter Phase I study. To better understand the drug’s impact at the cellular level, the team needed high-resolution single-cell RNA sequencing (scRNA-seq) analysis of bone marrow aspirates. Given the complexity of AML biology–particularly the difficulty of accurately identifying AML blasts–this required specialized bioinformatics expertise and a partner who understood the complexities of working with patient data from clinical trials.
Action
Diamond Age partnered with Foghorn to deliver a robust, tailored bioinformatics workflow that included:
- Enhanced quality control: Rigorous filtering to remove doublets, empty droplets, and low-quality cells for cleaner, more reliable datasets.
- Accurate cell type annotation: Advanced methods, including copy number variation (CNV) analysis, to confidently identify AML blasts and immune compartments.
- Granular gene expression analysis: Tracking key marker genes and gene sets tied to AML, stemness, and differentiation to map treatment impact across cell populations.
- Integrated interpretation: Custom analysis, figures, and datasets to answer Foghorn’s specific biological questions and inform their translational and clinical strategy.
- Clinical covariate analysis: Integrating clinical data and measurements, such as dose, time points, and response into the analysis allowed the client to understand mechanisms of response.
Result
Our advanced bioinformatics capabilities and ability to utilize clinical information revealed a granular view of how FHD-286 affected different cell types within the bone marrow microenvironment. For instance, we correlated cell differentiation expression patterns in the AML blast cells to clinical response variables, which contributed to the understanding of the treatment. These critical translational insights informed the design of a combination trial now underway and supported Foghorn’s scientific leadership through co-authorship of a peer-reviewed publication: A Phase I Study of FHD-286, a Dual BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, in Patients with Advanced Myeloid Malignancies