An Integrated Analysis of Heterogeneous Drug Responses in Acute Myeloid Leukemia That Enables the Discovery of Predictive Biomarkers

Abstract

Many promising new cancer drugs proceed through preclinical testing and early-phase trials only to fail in late-stage clinical testing. Thus, improved models that better predict survival outcomes and enable the development of biomarkers are needed to identify patients most likely to respond to and benefit from therapy. Here, we describe a comprehensive approach in which we incorporated biobanking, xenografting, and multiplexed phospho-flow (PF) cytometric profiling to study drug response and identify predictive biomarkers in acute myeloid leukemia (AML) patients. To test the efficacy of our approach, we evaluated the investigational JAK2 inhibitor fedratinib (FED) in 64 patient samples. FED robustly reduced leukemia in mouse xenograft models in 59% of cases and was also effective in limiting the protumorigenic activity of leukemia stem cells as shown by serial transplantation assays. In parallel, PF profiling identified FED-mediated reduction in phospho-STAT5 (pSTAT5) levels as a predictive biomarker of in vivo drug response with high specificity (92%) and strong positive predictive value (93%). Unexpectedly, another JAK inhibitor, ruxolitinib (RUX), was ineffective in 8 of 10 FED-responsive samples. Notably, this outcome could be predicted by the status of pSTAT5 signaling, which was unaffected by RUX treatment. Consistent with this observed discrepancy, PF analysis revealed that FED exerted its effects through multiple JAK2-independent mechanisms. Collectively, this work establishes an integrated approach for testing novel anticancer agents that captures the inherent variability of response caused by disease heterogeneity and in parallel, facilitates the identification of predictive biomarkers that can help stratify patients into appropriate clinical trials. Cancer Res; 76(5); 1214-24. Ó2016 AACR.

Relapse-Fated Latent Diagnosis Subclones in Acute B Lineage Leukemia Are Drug Tolerant and Possess Distinct Metabolic Programs

“…Improved eradication of dRIs during early treatment phases before the subclones evolve would prevent progression to more aggressive, therapy-resistant disease. Prior studies from us and others have shown that xenografting of a wide spectrum of primary patient samples provides a powerful tool to evaluate novel therapeutics and develop biomarkers (23,25,46,47). Our study suggests that extending the xenograft-based drug development paradigm by including genetic analysis to uncover subclonal responses to drug treatment will open up avenues to evaluate whether relapse-fated clones are effectively targeted.…”

Assessment of Drug Sensitivity in Hematopoietic Stem and Progenitor Cells from Acute Myelogenous Leukemia and Myelodysplastic Syndrome Ex Vivo

“…However, in the search for agents that produce durable responses, the question is not whether an agent can achieve these immediate goals, but whether it can eliminate the cells responsible for disease initiation, maintenance, and progression. Based on accumulating evidence that stem and progenitor cells play pivotal roles in various stages of MDS and AML pathogenesis [, , , , ], it has been suggested that targeting one or more of these populations will likely be necessary to eradicate these disorders [, , , , , , , ]. This realization provides the rationale for developing a method to assess the effects of therapeutic agents on MDS and AML stem and progenitor cells.…”

CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells

“…In 24 samples, CC-90009 significantly reduced CD45 + 33 + AML cells by 52-100% in injected femur (RF) and 62-99% in non-injected bones (BM), compared to vehicle-treated mice ( Figure 6D; Table 1). These samples were termed "responders" in keeping with the classification scheme we previously developed 45 . Eight "partial responders" had a less robust response to CC-90009, with 20% to 60% relative reduction.…”