Novel drug candidates for blast phase chronic myeloid leukemia from high-throughput drug sensitivity and resistance testing

Abstract

Chronic myeloid leukemia in blast crisis (CML BC) remains a challenging disease to treat despite the introduction and advances in tyrosine kinase inhibitor (TKI) therapy. In this study we set out to identify novel candidate drugs for CML BC by using an unbiased high-throughput drug testing platform. We used three CML cell lines representing different types of CML blast phases (K562, EM-2 and MOLM-1) and primary leukemic cells from three CML BC patients. Profiling of drug responses was performed with a drug sensitivity and resistance testing platform comprising 295 anticancer agents. Overall, drug sensitivity scores and the drug response profiles of cell line and primary cell samples correlated well and were distinct from other types of leukemia samples. The cell lines were highly sensitive to TKIs and the clinically TKI-resistant patient samples were also resistant ex vivo. Comparison of cell line and patient sample data identified new candidate drugs for CML BC, such as vascular endothelial growth factor receptor and nicotinamide phosphoribosyltransferase inhibitors. Our results indicate that these drugs in particular warrant further evaluation by analyzing a larger set of primary patient samples. The results also pave way for designing rational combination therapies.

Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients

“…Treatment with a combination of TKIs and chemotherapy followed by SCT remains the backbone of treatment in these patients. New approaches to treat patients with CML‐BP that address the molecular complexity of CML‐BP are needed …”

“…New approaches to treat patients with CML-BP that address the molecular complexity of CML-BP are needed. [28][29][30] FUNDING SUPPORT Funding for this study was provided in part by The University of Texas MD Anderson Cancer Center Support Grant CA016672 (Principal Investigator: Ronald DePinho) and award P01 CA049639 (Principal Investigator: Richard Champlin) from the National Cancer Institute. None of the authors are employed by the National Institutes of Health.…”

Unsupervised discovery of dynamic cell phenotypic states from transmitted light movies

“…Growing evidence suggests leukemic stem cell (LSC) populations in AML harbor drug-tolerant sub-populations that survive drug treatment and eventually lead to relapse disease 30, 38 . To this end, a large scale screen of hundreds of drug treatment or regimen time courses can be captured via brightfield time lapse imaging 39, 40 . UPSIDE can then be employed as an unbiased method to survey and specify important morphological features associating with therapeutic response, persistence or resistance as a function of cell types, cell states and treatment.…”

Microfluidics as an Enabling Technology for Personalized Cancer Therapy

“…As done for bacterial infections for decades (where bacteria are tested against several antibiotics), taking tumor biopsies and testing the cells for their vulnerabilities against drugs would be the most direct way to determine the optimal treatment. As mentioned above, this has been successfully achieved for leukemias, but implementing such approaches for solid tumors requires several hurdles to be overcome, including the availability of typically only low cell numbers. One way to obtain enough material for ex vivo screens on biopsies from solid tumors is the isolation and expansion of tumor cells into patient‐derived cell lines .…”