Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia

Abstract

We present an individualized systems medicine (ISM) approach to optimize cancer drug therapies one patient at a time. ISM is based on (i) molecular profi ling and ex vivo drug sensitivity and resistance testing (DSRT) of patients' cancer cells to 187 oncology drugs, (ii) clinical implementation of therapies predicted to be effective, and (iii) studying consecutive samples from the treated patients to understand the basis of resistance. Here, application of ISM to 28 samples from patients with acute myeloid leukemia (AML) uncovered fi ve major taxonomic drug-response subtypes based on DSRT profi les, some with distinct genomic features (e.g., MLL gene fusions in subgroup IV and FLT3 -ITD mutations in subgroup V). Therapy based on DSRT resulted in several clinical responses. After progression under DSRT-guided therapies, AML cells displayed signifi cant clonal evolution and novel genomic changes potentially explaining resistance, whereas ex vivo DSRT data showed resistance to the clinically applied drugs and new vulnerabilities to previously ineffective drugs. SIGNIFICANCE:Here, we demonstrate an ISM strategy to optimize safe and effective personalized cancer therapies for individual patients as well as to understand and predict disease evolution and the next line of therapy. This approach could facilitate systematic drug repositioning of approved targeted drugs as well as help to prioritize and de-risk emerging drugs for clinical testing.

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

“…However, our results, which indicate that it will be challenging to infer drug activity based solely on genomic data, are consistent with reports in adult hematologic malignancies. 16,18 As a basis for standardization, we opted for coculture on human MSCs, 27,28 which efficiently supported most of the primary ALL samples that we tested in serum-free conditions. Our assay provides better ALL cell survival and stronger correlation with in vivo drug activity in PDX models compared with monocultures (supplemental Figure 5).…”

“…The fact that we detected subsets with more proliferative activity both in vitro and in vivo, based on drug profiling, indicates that important leukemia-intrinsic features are maintained and captured under the in vitro cell culture conditions. We and others 16,18 have demonstrated the use of drug profiling for identifying phenotypes that are responsive to new therapeutic agents. We have identified recurrent ALL patients who are highly sensitive to triggering RIP1-dependent cell death with SMAC mimetics 37 or to BCL2 inhibition in BCP-ALL subsets, including TCF3-HLF ALL 35 and T-ALL subsets.…”

“…This approach will complement in vivo PDX models, which have obvious limitations in compound coverage and flexibility. 15 Drug sensitivity testing revealed individual drug response phenotypes in acute myeloid leukemia (AML) 16 and identified new strategies to bypass resistance to tyrosine kinase inhibitors (TKIs) in patients with deleterious BCR-ABL mutations. 17 Conversely, characteristic tyrosine kinase mutations could be predicted on the basis of drug activity.…”

“…18 Drug activity patterns can also identify an ALL subtype with tonic pre-BCR signaling. 19 To establish a drug profiling platform, we took advantage of PDXs from clinically relevant ALL subgroups [20][21][22][23][24] and, on the basis of previous reports, 16,18,[21][22][23]25,26 adapted a serum-free ALL coculture system on hTERT immortalized human bone marrow-derived mesenchymal stromal cells (MSCs) 27,28 to an automated microscopic image readout for drug testing. This population-based approach reveals relevant activity clusters of therapeutic agents, thus identifying actionable targets that have not yet been exploited in conventional ALL treatment.…”

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

“…Drug sensitivity and resistance testing (DSRT) was performed using an established high‐throughput platform (Pemovska et al ., 2013). Cell lines were screened with a library of 461 clinical, emerging, and experimental small‐molecule drugs at five different concentrations over a 10 000‐fold concentration range, including 69 conventional chemotherapeutics analyzed in this study.…”