Biology subjects

Fell, G.

Publications and source records attributed to Fell, G..

3 recordsLinked to original sources

bioRxiv2025

Dynamic BH3 profiling predicts clinical outcomes in acute myeloid leukemia

Predictive biomarkers can potentially meet the need for improved drug assignment in acute myeloid leukemia (AML). Fewer than half of AML patients have actionable mutations: consequently, targeted therapy achieves remission in only a fraction of those who have them. Dynamic BH3 Profiling (DBP), a functional assay, can measure changes in ex vivo drug-induced apoptotic priming in multiple cancers. To assess the feasibility and predictive capacity of DBP in AML, we prospectively tested DBP using a fixed-drug panel in myeloblasts from 92 patients. We generated a database combining genetic and functional annotation. Established AML clinical and genetic prognostic characteristics were associated with drug-induced apoptotic priming. We observed distinct interpatient sensitivities to single drugs or combinations with the BCL2-inhibitor venetoclax, and intrapatient apoptotic priming differences based on CD123-expression within distinct cell subpopulations. DBP further predicted the likelihood of remission to chemotherapy and targeted agents, supporting its use to identify optimal personalized therapy. Statement of significanceDynamic BH3 profiling provides patient-specific drug vulnerability data in real-time to inform prognosis and therapy selection. Key takeawaysO_LIDynamic BH3 profiling can be performed on bone marrow and leukemic blood from AML patients in 48 hours. C_LIO_LIKnown clinical prognostic factors associate with drug-induced apoptotic priming in AML. C_LIO_LIDrug-induced apoptotic priming identifies drug vulnerabilities in individual patients and predicts clinical response to chemotherapy and small molecule inhibitors. C_LI

cancer biology↗

bioRxiv2021

Cancer patient survival can be accurately parameterized, revealing time-dependent therapeutic effects and doubling the precision of small trials

Individual participant data (IPD) from completed oncology clinical trials are a valuable but rarely available source of information. A lack of minable survival distributions has made it difficult to identify factors determining the success and failure of clinical trials and improve trial design. We imputed survival IPD from [~]500 arms of phase III oncology trials (representing [~]220,000 events) and found that they are well fit by a two-parameter Weibull distribution. This makes it possible to use parametric statistics to substantially increase trial precision with small patient cohorts typical of phase I or II trials. For example, a 50-person trial parameterized using Weibull distributions is as precise as a 90-person trial evaluated using traditional statistics. Mining IPD also showed that frequent violations of the proportional hazards assumption, particularly in trials of immune checkpoint inhibitors (ICIs), arise from time-dependent therapeutic effects and hazard ratios. Thus, the duration of ICI trials has an underappreciated impact on the likelihood of their success.

cancer biology↗

bioRxiv2019

An endogenous glucocorticoid-cytokine signaling circuit promotes CD8+ T cell dysfunction in the tumor microenvironment

Identifying signals in the tumor microenvironment (TME) that promote CD8+ T cell dysfunction can inform improved therapeutic approaches for cancer. Here, we identify that Nr3c1, the gene encoding the glucocorticoid receptor (GR), is highly expressed in dysfunctional CD8+ tumor-infiltrating lymphocytes (TILs). The GR transactivates expression of multiple checkpoint receptors and loss of GR in CD8+ T cells limits dysfunctional phenotype in CD8+ TILs resulting in improved tumor growth control. We show that glucocorticoids can be produced in the TME and that they co-operate with the immunosuppressive cytokine IL-27 to promote the dysfunction gene program in CD8+ T cells. The presence of the glucocorticoid + IL27 signature in CD8+ TILs correlates with failure to respond to checkpoint blockade in melanoma patients, highlighting the relevance of this immunoregulatory glucocorticoid-cytokine circuit in tumor tissue.

immunology↗